MXPA04001890A

MXPA04001890A - Casein derived peptides and uses thereof in therapy.

Info

Publication number: MXPA04001890A
Application number: MXPA04001890A
Authority: MX
Inventors: Zvi Sidelman
Original assignee: Chay 13 Medical Res Group N V
Priority date: 2001-08-30
Filing date: 2002-08-29
Publication date: 2004-06-18
Also published as: PL375113A1; CA2458924A1; AU2002324323A2; CN1694719A; WO2003018606A3; NO20040880L; BR0212625A; WO2003018606A9; JP2005511499A; HUP0500995A3; ZA200401574B; WO2003018606A2; KR20040078639A; HUP0500995A2; EP1556074A2; CZ2004335A3; IL160548A0; EP1556074A4

Abstract

Biologically active peptides that are derived from or are similar to sequences identical with the N-terminus of the S1 fraction of milk casein. These peptides are capable of stimulating and enhancing immune response, protecting against viral infection, normalizing serum cholesterol levels, and stimulating hematopoiesis. The casein-derived peptides are non-toxic and can be used to treat and prevent immune pathologies, hypercholesterolemia, hematological disorders and viral-related diseases.

Description

PEPTIDES DERIVED FROM CASEIN AND ITS APPLICATIONS IN THERAPY DESCRIPTION OF THE INVENTION The present invention relates to biologically active peptides that are derived from or are similar to sequences identical to the N-terminal fraction aSl of milk casein. These peptides are able to stimulate and improve the immune response, protect against viral infection, normalize serum cholesterol levels, and stimulate hematopoiesis. The casein-derived peptides are non-toxic and can be used to treat and prevent immune pathologies, hypercholesterolemia, hematological disorders and virus-related diseases. Bioactive molecules from nutrients: In addition to the nutritional value of many foods, certain fractions and products of digestive trajectories have the ability to influence physiological processes. Some of these "extranutricionales" constituents appear in their active form in the whole nutriment, such as the immunoglobulins in the mother's milk and colostrum, phytoestrogens found in soy-based foods, polyphenolic fruit antioxidants and vitamins. Others are encoded within molecules of the nutrient, and are released in an active form during digestion or food processing, for example, antihypertensive peptides from lactoglobin [Kitts, D. (1999), Can J. Physiol. Pharmacol. 72: 4, 423-434]. Biological activity in milk proteins: Casein, the predominant milk protein, has been traditionally defined as composed of three fractions, a, ß and y, according to their electrophoretic mobility [N. J. Hipp, et al. (1952), Dairy Sci., 35: 272]. Today casein is defined according to the amino acid sequences of each of the subgroups ocSl, aS2, P and ic [W. N. Engel et al. (1984), J. Dairy Sci. 67: 1599]. In the course of digestion, the casein proteins are subjected to proteolytic cleavage by acidic proteases such as chymosin (renin), trypsin and pepsin, producing shorter peptides and causing coagulation and calcium sequestration by the resulting protein fragments. A few studies with milk compounds showed bacteriocidal activity related to casein. U.S. Patent No. 3,764,670 describes proteolytic casein extracts that possess antibiotic properties against microorganisms. The Israel Patent! No. 42863 discloses a peptide derived from casein consisting of 23 N-terminal amino acids of casein, which possess antioacterial activity. In addition, other physiologically active properties, such as similar opioid and growth factor activities have been proposed for casein or its derivatives [Kitts, D.D., (1999), ibid.]. Immune modulation activity has also been observed in casein peptides. [Coste et al. (1992), Immun. Lett. 33: 41-46)] observed improvement in rat lymphocyte proliferation after treatment with a C-terminal casein-derived peptide. However, none of these studies have determined the specific sequences in these casein peptides that confer their "extra-nutritional properties." Hematopoiesis in cancer therapy: After high-dose chemotherapy, especially after myeloablative doses of chemoradiotherapy, supported by autologous bone marrow transplantation or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT), patients are at high risk due to pancytopenia. Granulocytopenia can lead to the development of serious infectious complications, occasionally fatal from common bacteria, viruses, fungi and parasitic agents in the immediate post-transplant period. Similarly, the tramobocytopenia often results in a tendency to hemorrhage and occasionally, in platelet dependence for a long time. Whenever resistance to platelet development, episodes of bleeding can be life-threatening and hemorrhagic complications are often lethal. The risk due to granulocytopenia can be partially overcome by support measures and more effectively by the administration of. Recombinant human cytokines that can improve the reconstitution of granulocytes, particularly granulocyte colony stimulation factor (G-CSF) and factor that stimulates the granulocyte macrophage colony (GM-CSF). These agents are extremely expensive (approximately $ 200-400 / day / patient) and occasionally cause side effects due to hypersensitivity reactions, fever, bone pain and occasionally vascular filtration syndromes, including pericarditis and pleuritis. Some of the side effects may be due to other cytokines that can be intrinsically released by these hematopoietic growth factors. In addition, the use of these hematopoietic growth factors may be prohibitive in patients with tumor cells that support G-CSF or GM-CSF receptors, such as in acute and chronic myeloid leukemias and in myelodysplastic syndromes. While greater progress has been made in treating patients at risk for pancytopenia from the use of hematopoietic cytokines, no progress has been made in the treatment of thrombocytopenia. After the high dose of chemotherapy, and especially after ASCT, patients are at risk of thrombocytopenia which can take many months even up to 3 years and some thrombocytopenic patients can never recover. Many patients previously treated with multiple blood products become resistant to platelets and therefore thrombocytopenia may be impossible to overcome, even temporarily, despite intensive platelet transfusions and frequencies from a single donor. Platelet resistance and prolonged thrombocytopenia represent a common cause of death in ASCT centers around the world. Currently, several new recombinant cytokines such as recombinant human interleukin-3 (rhIL3) and recombinant human interleukin-6 (rhIL6) are being investigated as potential agents for improving megakaryocytopoiesis and platelet reconstitution. Unfortunately, pre-elimination clinical trials showed that although rhIL3 and rhILÉ can improve platelet reconstitution, such effects are not by surprising means and can take considerable time. Clearly, prolonged thrombocytopenia represents a major problem in clinical Bone Marrow Transplant centers today, so no satisfactory solution has yet been found. There is thus a widely recognized need for, and it would be highly advantageous to have a well defined, safe, inexpensive and rapidly effective hematopoiesis stimulator, and specifically megakaryocytopoiesis, lacking the above limitations. Thrombotopyetine (TPO) in regulation of hematopoiesis and platelet function: TPO seems to be the major regulator of platelet production in vivo, although the increase in the growth factor derived from kidney and liver in platelet deficiencies is not caused by the adaptation of TPO biosynthesis in these organs. Rather, a "feed-back loop" seems to exist where the number of circulating platelets determines how much of the circulating TPO is available to the bone marrow for platelet production. In addition, it has been shown that TPO is a cytokine that acts early with important multilination effects: TPO alone, or in combination with other cytokines that act early, can (i) promote viability and suppress apoptosis in progenitor cells; (ii) regulate the production and function of hematopoietic pluripotent cells; (iii) drive the cell division of inactive multipotent cells; (iv) induce multilineage differentiation and (v) improve the formation of multiline colony cining granulocytes, erythrocytes, macrophages and megakaryocytes (MK, CFU-GEMM). In addition, TPO stimulates the production of more limited progenitors for granulocyte / monocyte, megakaryocyte and erythroid colonies, and stimulates the adhesion of primitive human bone marrow and megakaryocytic cells to fibronectin and fibrinogen. Thus, TPO is an important cytokine for hematologists / clinical transplants: for the mobilization, amplification and ex vivo expansion of pluripotent cells and committed precursor cells for autologous and allogeneic transplantation [von dem Borne, A. E. g. Kr. , et al., (1998) Thrombopoiet i n: it's role in platelet disorders and as a new drug in clinical medicine. In Bailliers Clin. Hematol. June: 11 (2), 427-45]. In addition to the effects of TPO on hematopoiesis, this potent growth factor primes platelets for several agonists and modulates platelet extracellular matrix interactions. Although it does not itself cause platelet aggregation, TPO deregulates aggregation induced by aDP, especially in the second wave of aggregation, deregulates release and granule production (ADP, ATP, serotonin, etc.) of thromboxane B2, increases platelet binding to collagen and potentiates platelet aggregation induced by shear stress. TPO also stimulates the activity of P N, inducing the release of IL-8 and priming the production of oxygen metabolite, improving proBALBemente antimicrobial defense. Clinical studies suggest that the value of TPO to understand and treat a variety of hematological conditions. In patients with idiopathic aplastic anemia (AA), high levels of TOP still persist in remission after immunosuppressive therapy, indicating a hematopoietic defect. TPO is elevated in other forms of aplastic thrombocytopenia as well, but not in conditions of increased platelet destruction. Apparently, the reactive increase in TPO production is insufficient in cases of destructive thrombocytopenia. In this way, TPO is not only a therapeutic option for aplastic, but also for destructive thrombocytopenia. Thrombopoietic agents are of greater clinical interest, for the prevention and / or treatment of pathological or treatment-induced thrombocytopenia, and a substitute for platelet transfusions. Of the cytokines evaluated, all but marginally potent IL-11s have been estimated unacceptable for clinical use. TPO is widely believed to convert the cytokine of choice for treatment of trobocytopenia. Human recombinant TPO (Genentech) has recently become available, allowing for acute pharmacokinetic determinations and clinical tests. Thus, the potential applications of TPO encompass the areas of supportive care (post chemo / radio-therapy, bone marrow transplantation and pluripotent cell), hematological disease (AA, myeloid splasia, congenital and acquired thrombocytopenia), liver diseases, transfusion (expansion, harvest, mobilization and storage of platelets) and surgery (including liver transplantation). Of particular interest is the potential use of TPO / EPO / G-CSF cocktail for myelodysplasia, combination of G-CSF and TPO for peripheral pluripotent cell mobilization and TPO to harvest CD34 + cells and ex vivo expansion of megakaryocytes for platelet reconstitution higher. However, similar to other hematopoietic agents under consideration for clinical application, TPO is expensive and potentially antigenic at therapeutically effective levels. Thus, it would be advantageous to have a safe, inexpensive and readily available thrombopoiesis stimulator capable of increasing TPO activity. Fraction aSl of casein. : The aSl fraction of casein can be obtained from milk proteins by several methods [D. G. Schmidith and T. A. J. Paynes (1963), Biochim. , Biophys. Minutes 78: 492; m. P. Thompson and C.A. Kiddy (1964), J. Dairy Sci. , 47: 626; J. C. Mercier, et al. (1968), Bull. Soc. Chim. Biol. 50: 521], and the complete amino acid sequence of the aSl fraction of casein was determined by J. C. Mercier et al. (1981) (Eur. J. Biochem. 23:41). The genomic and coding sequences of the casein bovine aSl fraction have also been cloned and sequenced using recombinant DNA techniques [D. Koczan, et al. (1991), Nucí. Acids Res. 19 (20): 5591; mc night, R.A., et al. (1989), J. Dairy Sci. 72: 2464-73]. The proteolytic unfolding and identification of N-terminal fragments from the aSl fraction of casein has been documented [J. C. Mercier, et al. (1970), Eur. J. Biochem. 16: 439; P.L. H. McSweeney et al. (1993), J. Dairy Res., 60: 401], as having intestinal absorption and appearance of this fragment in mammalian plasma after ingestion of whole milk proteins [Fiat, A.M., et al. (1998) Biochimie, 80 (2): 2155-65]. Meisel, H. and Biockelmann, W. [(1999), Antonie Van Leeuwenhoek, 76: 207-15] detected amino acid sequences of immunopéptidos, casoquininas and casomorfinas in peptides liberated by bacteria of lactic acid digested of fractions of casein a and ß. Of particular interest is the anti-aggregant and thrombolytic activity demonstrated by the C-terminal portions of the α and α-casein fractions [Chabance, B. et al (1997), Biochem. Mol. Biol. Int. 42 (1) 77-84; Fiat AM. et al. (1993), J. Dairy Sci. 76 (1): 301-310]. Previous studies documented bioactive peptides encoded in the N-terminal amino acid sequence aSl, but no mention was made of using these protein fragments, specific sequences or synthetic peptides defined to improve hematopoiesis, prevent viral infection or modulate the development of diseases autoimmune According to the present invention, there is provided a method for preventing or treating an autoimmune disease, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. Further in accordance with the present invention there is provided a method for preventing or treating a viral disease, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Furthermore, according to the present invention there is provided a method for preventing viral infection, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. In addition, according to the present invention, a method for inducing hematopoiesis is provided, the method is accomplished by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. In addition, according to the present invention there is provided a method for inducing proliferation of hematopoietic stem cells, the method is carried out by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl.

In addition, according to the present invention there is provided a method for inducing proliferation and differentiation of hematopoietic stem cells, the method is effected by administering to a subject therewith a therapeutically effective amount of a peptide derived from an N-terminal portion of casein. ocSl. In addition, according to the present invention, a method for inducing megakaryocytopoiesis is provided, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein SE. Furthermore, according to the present invention there is provided a method for inducing erythropoiesis, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of aIS casein. In addition, according to the present invention there is provided a method for inducing leukocytopoiesis, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of aIS casein. In addition, according to the present invention there is provided a method for inducing thrombocytopoiesis, the method is effected by administering to a subject therewith a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. In addition, according to the present invention there is provided a method for inducing plasma cell proliferation, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Further, according to the present invention there is provided a method for inducing dendritic cell proliferation, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Further, according to the present invention there is provided a method for inducing macrophage proliferation, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. In addition, according to the present invention there is provided a method for preventing or treating thrombocytopenia, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. In addition, according to the present invention there is provided a method for preventing or treating panci openia, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Furthermore, according to the present invention, there is provided a method for preventing or treating granulocytopenia, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsI casein. In addition, according to the present invention, there is provided a method for preventing or treating hyperopic erythema, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. . In addition, according to the present invention, there is provided a method for preventing or treating cholesteremia, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. In addition, according to the present invention, there is provided a method for preventing or treating glycosuria, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. further, according to the present invention, there is provided a method for preventing or treating diabetes, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. In addition, according to the present invention, there is provided a method for preventing or treating AIDS, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. In addition, according to the present invention, a method for preventing or treating HIV infection is provided, the mécodo is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. . In addition, according to the present invention, a method is provided for avoiding or treating conditions associated with myeloablative doses of chemoradiotherapy supported by autologous bone marrow transplantation or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT), the The method is accomplished by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsI casein. In addition, according to the present invention, there is provided a method for treating a treatable condition of erythropoietin, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein Sl . In addition, according to the present invention, there is provided a method for increasing the effect of erythropoietin, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Further, according to the present invention, there is provided a method for treating a treatable condition of thrombopoietin, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. . In addition, according to the present invention, there is provided a method for increasing the effect of thrombopoietin, the method is carried out by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. In addition, according to the present invention, a method for improving peripheral pluripotent cell mobilization is provided, the method is accomplished by administering to a subject in need thereof an amount of a pharmaceutical composition comprising effective amounts of thrombopoietin and a derivatized peptide. of an N-terminal portion of casein aSl. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating an autoimmune disease, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating a viral disease, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, a pharmaceutical composition for preventing viral infection is provided, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, a pharmaceutical composition for inducing hematopoiesis is provided, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. further, according to the present invention, there is provided a pharmaceutical composition for inducing haematopoietic pluripotent cell proliferation, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-thermal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing hematopoietic pluripotent cell proliferation and differentiation, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically carrier acceptable In addition, according to the present invention, a pharmaceutical composition for inducing megakaryocytopoiesis is provided, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, a pharmaceutical composition for inducing erythropoiesis is provided, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing leukocytopoiesis, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing thrombocytopoiesis, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing cell proliferation in plasma, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of rxSl casein and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing dendritic cell proliferation, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention, there is provided a pharmaceutical composition for inducing macrophage proliferation, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a macromically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating thrombocytopenia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein otS1 and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating panciropenia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating granulocytopenia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier.

In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating hyperlipidemia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of caserne aSl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating cholesteremia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating glycosuria, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating diabetes, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating AIDS, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating HIV infection, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating conditions associated with myeloablative doses of chemoradiotherapy supported by autologous bone marrow transplantation or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT), The pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for treating a treatable condition of thrombopoietin, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, a pharmaceutical composition for increasing the effect of thrombopoietin is provided, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of ccSl casein and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for improving peripheral pluripotent cell mobilization, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically carrier acceptable In addition, according to the present invention, there is provided a pharmaceutical composition for inducing hematopoiesis, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing hematopoietic pluripotent cell proliferation, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. . In addition, according to the present invention, a pharmaceutical composition is provided for inducing proliferation and differentiation of hematopoietic stem cells, the pharmaceutical composition comprises, as active ingredients, t ombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, a pharmaceutical composition for inducing megakaryocytopoiesis is provided, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl and a carrier farrr.acéu: only acceptable . In addition, according to the present invention, there is provided a pharmaceutical composition for inducing erythropoiesis, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing leukocytopoiesis, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing thrombocytopoiesis, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating thrombocytopenia, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention, there is provided a pharmaceutical composition for preventing or treating pancytopenia, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating granulocytopenia, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for treating or preventing an indication selected from the group consisting of autoimmune disease or condition, viral disease, viral infection, hematological disease, haematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, hyperlipidemia, hypercholesterolemia, qlucosuria, hyperglycemia, diabetes, AIDS, HIV-1, T helper cell disorders, dendritic cell deficiencies, macrophage deficiencies, pluripotency cell disorders to hematopoietic including platelet disorders, lymphocyte, plasma cell and neutrophil, pre-leukemic conditions, leukemic conditions, disorders of the immune system resulting from chemotherapy or radiation therapy, disorders of the human immune system resulting from treatment of diseases of immune deficiency and bacterial infections, the pharmaceutical composition comprises, as an ingredient Active a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for treating or preventing an indication selected from the group consisting of hematological disease, haematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, dendritic cell deficiencies, macrophage deficiencies, disorders of the hematopoietic pluripotent cell including platelet, lymphocyte, plasma cell and neutrophil disorders, pre-leukemic conditions, leukemic conditions, myelodysplastic syndrome, aplastic anemia and bone marrow insufficiency, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a method for improving the colonization of donated blood pluripotent cells in a myeloablative receptor, the method is carried out by treating a donor of the blood pluripotent cells donated with a peptide derived from an N-terminal portion. of casein aSl before the donation and implantation of blood pluripotent cells donated in the recipient. In addition, according to the present invention, a method is provided for improving the colonization of donated blood pluripotent cells in a myeloablative receptor, the method is performed by treating the blood pluripotent cells donated with a peptide derived from an N-terminal portion of casein ocSl. before implanting donated blood pluripotent cells into the recipient. In addition, according to the present invention, a method is provided for improving the colonization of blood pluripotent cells in a myeloablative receptor, the method is performed by treating the blood pluripotent cells donated with a peptide derived from an N-terminal portion of casein to S1 before of implanting the donated blood pluripotent cells in the recipient. In addition, according to the present invention, a method is provided to improve the colonization of blood pluripotent cells donated in a myeloablative receptor, the method is carried out by treating a donor of the blood pluripotent cells donated with a peptide derived from a N-portion. terminal casein aSl and thrombopoietin before donation and implant in the recipient blood donated pluripotent cells. In addition, according to the present invention, a method is provided for improving the colonization of donated blood pluripotent cells in a myeloablative receptor, the method is performed by treating the blood pluripotent cells donated with a peptide derived from an N-terminal portion of casein aSl. and thrombopoietin before implanting donated blood pluripotent cells into the recipient. In addition, according to the present invention, there is provided a method for improving the colonization of donated blood pluripotent cells in a myeloablative receptor, the method is performed by treating the blood pluripotent cells with a peptide derived from an N-terminal portion of casein Sl and thrombopoietin before implanting donated blood pluripotent cells into the recipient. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for preventing or treating an autoimmune disease. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for preventing or treating a viral disease. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for preventing viral infection is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for inducing hematopoiesis is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of ccSl casein for the preparation of a medicament for inducing proliferation of hematopoietic stem cells is described. In addition, in accordance with the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for inducing the proliferation and differentiation of hematopoietic pluripotent cells. further, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for inducing megakaryocytopoiesis. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for inducing erythropoiesis is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for inducing leukocytopoiesis is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a drug for inducing thrombocytopoiesis. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of ocsl casein to induce cell proliferation in plasma is described. Furthermore, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for inducing dendritic cell proliferation is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for inducing macrophage proliferation. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of ocsl casein for the preparation of a medicament for preventing or trng thrombocytopenia is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for preventing or trng pancytopenia. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of ocsl casein for the preparation of a medicament for preventing or trng granulocytopenia is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for preventing or trng hyperlipidemia. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for preventing or trng cholesteremia. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for preventing or trng glycosuria. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for preventing or trng diabetes. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for preventing or trng AIDS is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for preventing or trng HIV infection is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for preventing or trng conditions associated with myeloablative doses of chemoradiotherapy supported by bone marrow transplantation is described. autologous or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT). In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl for the preparation of a medicament for trng trble condition is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for increasing the effect of thrombopoietin. further, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described for the preparation of a medicament for improving peripheral pluripotent cell mobilization. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein a Sl for the preparation of a medicament for improving the colonization of blood pluripotent cells donated in a myeloablative receptor is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein a Sl for the preparation of a medicament for improving the colonization of blood pluripotent cells donated in a myeloablative receptor is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of ocsl casein for the preparation of a medicament for improving the colonization of blood pluripotent cells in a myeloablative receptor is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for preventing or treating an autoimmune disease is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier for preventing or treating a viral disease is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for preventing or treating a viral infection is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for inducing hematopoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for inducing proliferation of hematopoietic pluripotent cell is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to induce proliferation and differentiation of stem cells is described. hematopoietic In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for inducing megakaryocytopoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of otSl casein and a pharmaceutically acceptable carrier for inducing erythropoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocsl and a casein is described. pharmaceutically acceptable carrier to induce leukocytopoiesis. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to induce thrombocytopoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to induce cell proliferation in plasma. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to induce dendritic cell proliferation is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from a -terminal portion of ocsl casein and a pharmaceutically acceptable carrier for inducing macrophage proliferation is disclosed. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier for preventing or treating thrombocytopenia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier for preventing or treating pancytopenia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to prevent or treat gonorrhea and topenia is described. .

In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ".SI casein and a pharmaceutically acceptable carrier to prevent or treat hyperlipidemia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for preventing or treating cholesteremia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for preventing or treating glucosurxa is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for preventing or treating diabetes is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for preventing or treating AIDS is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to prevent or treat an HIV infection is described. . In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to prevent or treat conditions associated with doses is described. myeloablative chemoradiotherapy supported by transplantation of autologous bone marrow or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT). Further, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for treating a treatable condition of thrombopoietin is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to increase the effect of the t-rhombbopoyet is described. ina. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier, peptide derived from a N-portion is described. terminal casein aSl to improve the colonization of blood pluripotent cells donated in a myeloablati o receptor. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to improve the colonization of blood stem cells is described. in a myeloablative receptor. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, tromoopoietin and a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to improve cell mobilization is described. peripheral pluripotential. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein Sl and a pharmaceutically acceptable carrier for inducing hematopoiesis is described. further, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for inducing proliferation of hematopoietic stem cells is described. In addition, according to the present invention, there is described the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of cxSl casein and a pharmaceutically acceptable carrier to induce cell proliferation and differentiation. hematopoietic pluripotent. Furthermore, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for inducing megacariotopoiesis is described. Further, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier for inducing leukocytopoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier to induce thrombocytopoiesis is described. Furthermore, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier for preventing or treating thrombocytopenia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier for preventing or treating pancytopenia is described.

In addition, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein Sl and a pharmaceutically acceptable carrier for preventing or treating granulocytopenia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier for preventing or treating a selected indication of the group consisting of autoimmune disease or condition, viral disease, viral infection, hematological disease, hematological deficiencies, rhombocytopenia, pancytopenia, granulocytopenia, hyperlipidemia, hypercholesterolemia, giucosuria, hyperglycemia, diabetes, AIDS, HIV-1, cell disorders T helper, dendritic cell deficiencies, macrophage deficiencies, hematopoietic pluripotential cell disorders, including platelet disorders, lymphocyte, plasma and neutrophil cell, pre-leukemia conditions, leukemia conditions, immune system disorders resulting from chemotherapy or therapy by radiation, system disorders human immune that results from the treatment of diseases of immune deficiency and bacterial infections.

In addition, according to the present invention, there is described the use of a pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier to prevent or treat a selected indication of the group consisting of haematological disease, nema to 1 logic deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, dendritic cell deficiencies, macrophage deficiencies, hematopoietic pluripotent cell disorders including platelet disorders, lymphocyte, plasma and neutrophil cell, preconditions leukemic, leukemic conditions, myelodysplastic syndrome, aplastic anemia and bone marrow failure. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to enhance the colonization of depleted blood stem cells is described. in a myeloablative receptor. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as active ingredients, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier to improve the colonization of blood pluripotent cells in a receiver my eloablati o. According to additional features in the preferred embodiments of the invention described below, the peptide is a fragment derived by fragmentation of rxSl casein. According to yet other features in the described preferred embodiments the peptide is a synthetic peptide. According to yet still other features in the preferred embodiments described, the peptide has a sequence as set forth in one of SEQ. FROM IDENT. NOs: 1-25. In addition, according to the present invention there is provided a purified peptide having an amino acid sequence selected from the group consisting of SEQ. OF TDENT. NOs: 1-25. Further in accordance with the present invention there is provided a pharmaceutical composition comprising a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25 and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition comprising trcmbopoietin and a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25 and a pharmaceutically acceptable carrier. The present invention successfully addresses the deficiencies of currently known configurations by providing peptides for the treatment of human disease, whose peptides are derived from the N-terminal portion of casein aSl and possesses no detectable toxicity and high therapeutic efficacy. BRIEF DESCRIPTION OF THE DRAWINGS The invention is described herein, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is emphasized that the details shown are by way of example and for illustrative discussion purposes of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and easily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings which makes apparent to those skilled in the art as the various forms of the invention can be included in the practice. In the drawings: FIGURE 1 describes the stimulation of the activity of the Natural Killer Cell (NK) in murine bone marrow cells cultured by peptides derived from natural casein. Lysis of 35S-labeled YAC target cells by cultured murine bone marrow cells incubated in the presence or absence of 100ug per ml of natural casein-derived peptides is expressed as the fraction of total radioactivity released from YAC cells in the supernatant of culture (% of Release 5S). Figure 1 depicts NK activity in an effector / target cell ratio of 25: 1 to 50:] .. Figures 2a and 2b describe the stimulation of Natural Killer (NK) cell activity in Peripheral Blood Pluripotent Cells. (PBSC) human cultured by peptides derived from natural casein. Lysis of K562 target cells labeled 3jS by human PBSC cultured from Granulocyte Colony Stimulation Factor (G-CSF) treated donors incubated without (0 pg) or with increased concentrations (5-500 pg per ml) of peptides Natural casein derivatives are expressed as the fraction of total radioactivity released from KS562 cells in the culture supernatant (% Release 3BS). Figure 2a depicts NK activity of two blood samples from the same patient, incubated at different effector cell ratios: target (1:25 and 1:50). Figure 2b represents the NK activity of blood samples from normal and affected donors incubated in the same effector cell: ob ective relationship. The tables represent an effector cell: ob ective ratio of 100: 1, diamonds represent an effector cell: ob ective ratio of 50: 1. FIGURES 3a-3c describe the stimulation of proliferation of Natural Killer (NK) and T cell (T) cells from Human Peripheral Pluripotent Cells (PBSC) cultured by peptides derived from natural casein. The proliferation of NK and T cells in PBSC cultured from the Granulocyte Colony Stimulation Factor treated donors incubated with or without peptides derived from natural casein are expressed as the percentage (%) of cells that bind the anti-cell UCHTi antibody -T fluorescent anti-CD3 / FITC, or anti-NK cell antibody 1M0C-1 fluorescent RPE / anti CD56 (DAKO A / S Denmark). The controls are anti-mouse IgG antibody, conjugated with FITC and RPE. Figure 3a represents the percentage of CD56 fluorescent antibody binding of cultured human PBSC (5 independent samples) after 10 days of incubation with (peptides) or without (control) 100 pg per ml of peptides derived from natural casein. Figure 3b represents the percentage of cultured human PBSC cells that bind the fluorescent anti-CD3 (T cell) antibody, after 14 days of incubation with (peptides) or without (control) 100 pg per ml of peptides derived from natural casein. Figure 3c represents the percentage of cultured human PBSC cells that bind the anti-CÜ3 antibody (fluorescent T cell) and the cells that bind both CD and CD5G antibodies (cells such as T and NK) after 28 days of incubation with (peptides) or without (control) 100 pg per ml of peptides derived from natural casein. FIGURE 4 describes the stimulation of Natural Killer (NK) cell activity in human Peripheral Blood Puripotent Cells (PBSC) cultured by synthetic peptides derived from casein. Lysis of K562 target cells labeled 35S by cultured human PBSC (from a breast cancer patient) incubated without (0 pg) or with increased concentrations (10-500 pg per ml) of synthetic peptides derived from casein is expressed as the fraction of the total radioactivity released from the K562 cells in the culture supernatant ("Release." The peptides represent N-terminal sequences of 1-10 (the, diamonds), 1-11 (2a, frames) , and 1-12 (3rd, triangles) first amino acids of the N-terminal portion of casein aSl (see Table 3 below for synthetic peptide sequences). FIGURES 5a-5c describe the stimulation of proliferation of cultured human cells of different origin by peptides derived from natural casein. The proliferation of cultured human cells after 14-21 days of incubation with increased concentrations of the peptides derived from natural casein is expressed as the amount of [3 H] -thymidine incorporated in each sample. Figure 5a represents the incorporation of a tag in two samples (PBSC 1, frames, 15 days of incubation, and PBSC 2, diamonds, 20 days of incubation) of human peripheral blood Pluripotent Cells incubated with or without (ctrl) 50-600 μg by me of peptides derived from natural casein. Figure 5b depicts the incorporation of f ¾H] -thymidine in cultured human bone marrow cells after 21 days of incubation with or without (ctrl) 50-600 μg per ml of peptides derived from natural casein. Bone marrow was donated by patients with cancer in remission (Auto BM, closed boxes, BM 1, triangles, and BM 2, open boxes), or healthy volunteers (normal BM, diamonds). Figure 5c depicts the incorporation of [3 H] -thymidine in cultured human cord blood cells after 14 days of incubation with or without (ctrl) 50-1000 μg per ml of peptides derived from natural casein. The cord blood cells were donated by two separate donors (C.B. 1, triangles, C.B.2, squares). Figure 6 shows a Table describing the proliferation of blood cell progenitors from human bone marrow and cord blood in response to incubation with peptides derived from natural casein. The relative cell number x 104 per ml, which reflects the proliferation of cultured cells, was determined by counting cells as described in the Examples, section that follows. The bone marrow of healthy volunteers (Bone Marrow) and Cord Blood from normal births (Cord Blood) was incubated for 13 (Cord Blood) or 14 (Bone Marrow) days in the presence of growth factors and AB serum , with or without increasing the concentrations of peptides derived from natural casein (25-500 pg / ml). FIGURE 7 shows a table describing the effect of in vitro incubation with synthetic peptides derived from casein in the relative distribution of megakaryocyte, erythroid, plasma and dendritic cells (differential count) in CFU-GE M colonies from progenitor cells of Murine bone marrow The cells were classified into macroscopic colonies harvested from murine bone marrow cells prepared similarly to the previously described CFU-GEMM colonies. Cells were incubated with hematopoietic factors, and 25 pg or more of synthetic peptides derived from casein, for 14 days. The differential count is expressed as the total percentage of total cells represented by individual cell types. FIGURE 8 describes the stimulation of reconstitution of the peripheral white blood cell in mice transplanted with bone marrow, orally speaking in response to treatment with peptides derived from natural casein. The cell counts represent the number of white blood cells (x 104 per ml, as counted in a hemocytometer). Mice (n = 6 per group) received sub-lethal irradiation and syngeneic bone marrow transplantation (106 cells per mouse) on the next day, and intravenous administration of 1 mg by receptor peptides derived from natural casein (peptides: tables) or 1 me per recipient serum albumin (CONTROL: diamonds) one day later. FIGURE 9 describes the stimulation of platelet reconstitution in mice transplanted with myeloablative bone marrow in response to treatment with peptides derived from natural casein. Platelet counts (PLT) represent the number of thrombocytes (x 106 per ml, as counted in a hemocytometer). Mice (n = 60 per group) received lethal irradiation and syngeneic bone marrow transplantation (106 cells per mouse) on day 1, and intravenous administration of 1 mg per receptor peptides derived from natural casein (Peptides, diamonds) or 1 mg for human serum albumin receptor (control, squares). FIGURES 10a-10f describe the penetration and nuclear uptake of FITC-conjugated peptides, natural casein derivatives into cultured human T lymphocyte cells, as recorded by fluorescent microscopy. Fl and F2 are identical fractions of the FITC-conjugated peptides derived from natural casein. The Sup-cells were incubated. with 100 pg per ml of FITC-conjugated peptides derived from natural casein as described in the Examples, section that follows. At the indicated times, the cells were washed from the free label, fixed in formalin and prepared to be viewed and recorded by Confocal Laser Scanning Microscopy. Figures 10a to lOf are selected images of cells from consecutive incubation times, demonstrating that FITC-conjugated peptides derived from natural casein penetrating the cell membrane Sup- ?? (Figures 10a, 10b), and that are concentrated in the core (Figures 10c-10f). FIGURE 11 shows a Table describing the stimulation of cell proliferation of the Sup-Ti lymphocyte in response to incubation with peptides derived from natural casein. The Sup-Ti cells (5000 per well) were incubated with increased concentrations (50-1000 pg per ml) of peptides derived from natural casein, counted in their wells at the indicated post-culture times and pulsed with [3H] -thymidine for 18 days. hours. The proliferation index is the ratio of the average of the incorporation of [3H] -thymidine in cultured cells with peptides derived from natural casein (triplicate samples) divided by the incorporation into cultured cells without peptides derived from natural casein (control). FIGURE 12 shows a Table demonstrating the inhibition of HIV-1 infection of CEM lymphocytes by peptides derived from natural casein. The cells were either in contact with the HIV-1 virus pre-incubated 3 hours with natural casein-derived peptides (3 hours), or pre-incubated on their own with increased concentrations (50-1000 μl per ml) of Natural casein-derived peptides for the indicated number of hours (24 and 48 hours) before contact with HIV-1 virus, as described in the Examples, section that follows. On day 15 post-infection, the cells were counted for cell numbers and evaluated for HIV-1 infection severity by the P'4 antigen assay, as described in the Examples, section below. The control cultures were IF: CEM cells contacted with HIV-1 virus without pre-treatment with peptides derived from natural casein, and UIFrCEM cells grown under identical conditions without peptides derived from natural casein and without contact with the HIV-1 virus. FIGURE 13 shows a Table describing inhibition of HIV-1 infection of CEM lymphocytes by synthetic peptides derived from casein. The CEM cells were contacted with HIV-1 virus which had been pre-incubated with various concentrations (10-500 g per ml) of synthetic peptides derived from natural casein (IP, 3P and P) for 3 hours ( in the presence of the peptides), as described in the Examples, section that follows. On day 7, post infection, the cells were counted for cell numbers and evaluated for the severity of HIV-1 infection by the P 4 antigen assay, as described in the Examples, section below. IF) were CEM cells contacted with the HIV-1 virus without pre-treatment with peptides derived from natural casein FIGURE 14 describes the prevention by peptides derived from natural casein Type 1 Diabetes (IDDM) in mice Diabetic No Obese (NOD) females Glucosuria was verified at intervals for 365 days post-treatment in female NOD mice receiving once (triangles and squares) or twice weekly injection of 100 pg of peptides derived from natural casein for 5 weeks (5 or 10 total injections) and untreated controls All controls developed glycosuria and subsequently died FIGURE 15 describes the reduction of synthetic peptides derived from hypercolic casein sterol / diet-induced hyperlipidemia in C57 Bl / 6 female mice. Total cholesterol (TC), High Density Lipoproteins (HDL) and Low Density (LDL), were evaluated in pooled blood of two (2) mice per sample of hypercholesteroid / hyperlipidemic mice receiving casein-derived B peptides (IP), C, 2a or 3P, or without treatment (control). The "normal" samples represent the control mice without feeding the atherogenic diet. FIGURE 16 shows a Table describing the stimulation of hematopoiesis in cancer patients in response to injections of peptides derived from natural casein. Peripheral blood from five female cancer patients either receiving or having received chemotherapy, as described above, was counted for total 31-cell globules (BC, x 103), platelets (PLT, x 103), erythrocytes (RBC). , x 103 >; and Hemoblogma (gm by al) before (n) and then n + ...) intramuscular injections with peptides derived from natural casein, as described above. Patient 1 releases G.T .; Patient 2 releases E.C .; Patient 3 releases E. S.; Patient 4 releases J.R. and patient 5 releases D.M. FIGURE 17 describes stimulation by peptides derived from natural casein of thrombocytopoiesis in a patient resistant to platelet with Acute Myeloid Leukemia (M-l). The thrombocyte reconstitution was expressed as the change in peripheral blood platelet content (PLT, x 106 per ml), counted as described above at the indicated intervals after intramuscular injection (as described in the Examples, section below). follows) of 100 pg of peptides derived from natural casein. FIGURE 18 describes stimulation by peptides derived from natural casein of thrombocytopoiesis in a patient resistant to platelet with Acute Myeloid Leukemia (-2). The thrombocyte reconstitution was expressed as the change in peripheral blood platelet content (PLT, x 106 per ml), counted as described above at the indicated intervals after the intramuscular injection (as described in the Examples section). below) of 100 mg of peptides derived from natural casein. The present invention is of biologically active peptides that are derived from, or are similar to, sequences identical to the N-terminal of the Sl fraction of milk casein, compositions containing it and methods for using the same in, for example, stimulating and improving the immune response, protect against viral infection, normalize serum cholesterol levels, and stimulate hematopoiesis. The casein-derived peptides are non-toxic and can be used to treat and prevent, for example, immune pathologies, hyperclesterolemia, hematological disorders and virus-related diseases. The principles and operation of the present invention can be better understood with reference to the accompanying drawings and descriptions.

Before explaining at least one embodiment of the invention in detail, it will be understood that the invention is not limited in this application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other modalities or of being practiced or carried out in various ways. Also, it will be understood that the phraseology and terminology used herein is for the purpose of the description and should not be considered imitative. As used herein, the term "treatment" includes substantially inhibiting, reducing or reversing the progression of a disease, substantially improving clinical symptoms of a disease. As used herein, the term "prevent" includes substantially preventing the appearance of clinical symptoms of a disease. As used herein, the term "peptide" includes native peptides (either degradation products, synthetically synthesized peptides or recombinant peptides) and mimetic peptides (typically synthetically synthesized peptides), limes such as peptoids and semi-peptides that are peptide analogs, which may have, for example, modifications that supply the most stable peptides while in a body. Such modifications include, but are not limited to, cyclization, N-terminal modification, C-terminal modification, peptide-binding modification, including but not limited to, CH 2 -NH, CH 2 -S, CH 2 -S = 0, 0 = C-NH, CH2-0, CH2-CH2, S = C-NH, CH = CH or CF = CH, modification of the main structure and modification of the residue. Methods for preparing peptide mimetic compounds are well known in the art and are specified, for example in Quantitative Drug Design, C.A. Ramsden Gd. , Chapter 17.2. F. Choplin Pergamon Press (192), which is incorporated for reference as if it were completely established in the present. Additional details are provided in this respect hereinafter. Thus, a peptide according to the present invention can be a cyclic peptide. The targeting can be obtained for example, through amide bond formation, for example, by incorporating Glu, Asp, Lys, Orn, di-amino butyric acid (Dab), di-aminopropionic acid (Dap) at various positions in the chain (bonds -CO-NH or -NH-CO). The cyclization from the main structure to the main structure can also be obtained through the incorporation of modified amino acids of the formulas HN ((CH2) n ~ C00H) -C (R) H-C00H or HN ((CH2) n-COOH) - C (R) -H-NH 2, where n = 1-4, and furthermore where R is any natural or non-natural side chain of an amino acid. Cyclization through the formation of S-S junctions through the incorporation of two Cys residues is also possible. The side chain additional to the side chain cyclization can be obtained through the formation of an interaction bond of the formula - (-CH? -) uS-CH2-C-, where n = 1 or 2, which is possible , for example through the incorporation of Cys or homoCys and reaction of its free SH group with, for example, Lys, Orn, Dab or bromoacetylated Dap. The peptide linkages (-CO-NH-) within the peptide can be substituted, for example, by N-methylated linkages (-N (CH 3) -CO-), ester linkages (-C (R) HCOOC (R) - N), ketomethylene linkages (-CO-CH2-), a-aza linkages (-NH-N (R) -CO-), wherein R is any alkyl, eg, methyl, carba linkages (-CH2-) NH-), hydroxyethylene (-CH (OH) -CH2-) bonds, thioamide (-CS-NH-) bonds, olefinic double bonds (-CH = CH-), retroamide bonds (-NH-CO-), derivatives of peptide (- (R) -CH2-CO-), wherein R is the "normal" side chain, naturally presented at the carbon atom. These modifications can occur in any of the junctions next to the peptide chain and even several times (2-3) at the same time. The natural aromatic amino acids, Trp, Tyr and Phe, can be replaced by synthetic non-natural acid such as TIC, naphilelanine (nol), Phe methylated ring derivatives, halogenated derivatives of Phe or o-methyl-Tyr. The following Tables 1-2 list all the amino acids of natural origin (Table 1) and non-conventional or modified amino acids (Table 2). Table 1 Amino Acid Abbreviation of Three Symbol of a letter letter Alanine Wing Arginine Arg R Asparagine Asn N Aspartic Acid Asp D Cyss Cyster C Glutamine Gln Q Glutamic Acid Glu E Glycine Gly G Histidine His H Isoleucine lie I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Triptofan Trp W Tyrosine Tyr I Valine Val V Any amino acid as in Xaa X as above Table 2 Amino Acid Code Aminoacetic Code Unconventional Unconventional A-aminobutyric acid Abu L-N-methylalanine Nmala a-amino-a-methylbutorate Mgabu L-N-methylarginine Nmarg aminocidopropane-Cpro L-N-methylasparagine Nmasn Acid Carboxylate L-K-methylaspartic Nmasp Aminoisobutyric acid Aib L-N-methylcysteine Nmcis aminonorbomil- Norb L-N-methylglutamine Nmgin carboxylate L-K-methylglutamic acid Nmglu cyclohexylalanine Chexa L-N-methylhistidine Nmhis cyclopentylalanine Cpen L-N-methylxsoleucma Nmile D-alanine Dal L-N-me ileucine Nmleu D-Arginine Darg L-N-Methylilisine Nmlis D-aspartic acid Dasp L-N-methylmethionine Nmme D-ci steina DCys L-N -methylnorleucine Nmnle D-glutamine Dgln L-N-methylnorvaline Nmnva D-glutamic acid Dglu L-N-methylornithine Nmorn D-histidine Dhis L-N-methylphenylalanine Nmphe D-Isoleucine Dile L-N-methylproline Nmpro D-Leucine Dleu L-N-Methylserine Nmser D-lysine Dlys L-N-Methyltreonine Nmthr D-methionine Dmet L-N-methyltriptofan Nmtrp D-ornithine Dorn L-N-methyltyrosine Nmtyr D-Phenylalanine DP and L-N-methylvaline Nmval D-proline Dpro L-N-methylethylglycine Nmetg D-serine Dser L-N-methyl-t-butylglycine Nmtbug D-threonine Dthr L-norleucine Nle D-triptofan Dtrp L-norvaline Nva D-tyrosine Dtyr a-methyl-aminoi sobutyrate Maib D-valine Dval ct-methyl-y-aminobutyrate Mgabu D-c-metilalanina Dmala a-metilciciohexilalanina Mchexa D-a-methylarginine Dmarg a-methylciclopentilalanina Mcpen D-a-methylaparagine Dmasn a-methyl-a-naptilalanina Manap D-a-methylaspartate Dmasp a-methylpenici lamina Mpen D-a-methylcysteine Dmcys N- (-aminobutyl) glycine glu D-a-methylglu amine Dmgln N- (2-aminoethyl) glycine Naeg D-oc-methylhistidine Dmhis N- (3-aminopropyl) glycine Norn D-ot-methylisoleucine Dmile N-amino-a-methylbutyrate Nmaabu D-a-metilleucine Dmleu -naf ilalanine Anap D- -metillisina Dmlys N-bencilglicina Nphe D-a-Methylmethionine Dmmet N- (2-carbamylethyl) glycine Mgln D-a-methylorni tina Dmorn N- (carbamylmethyl) glycine Nasn D-a-methyl phenylalanine Dmphe N- (2-carboxyethyl) glycine Nglu D-ot-methylproline Dmpro N- (carboxymethyl) glycine Nasp D- -methyl serine Dmser N-cyclobutylglycine Ncbut D-a-metiltreonina Dmthr N-cicloheptilglicina Nchep D-a-me iltriptofan Dmtrp N-cyclohexylglycine Nchex D-a-methyltyrosine Dmty N-cyclodecylglycine Ncdec D-a-methyl aline Dmval N-cyclododeclglicine Ncdod D-a-methylalin Dnmala N-cyclooctylglycine Ncoct D-a-methylarqinine Dnmarg N-cyclopropylglycine Ncpro D-oc-metilasparagine Dnmasn N-cycloundecylglycine Ncund D-a-methylasparatate Dnmasp N- (2, 2-diphenylethyl) gly Nbhm D-a-methylcysteine Dnmcys N- (3, 3-diphenylpropyl) gl Nbhe D-N-methyleucine Dnmleu N- (3-indolylilethyl) glycine Nhtrp D-N-methyllisine Dnmlys N-me tyl-y-aminobutyrate Nmgabu N-methylcyclohexylalanine Nmchexa D-N-methylmethionine Dnmmet D-N-meti 1orn11 ina Dnmorn N-methylcyclopentilalanine Nmcpen N-methylglycine Nala D-N-methylphenylalanine Dnmphe N-methylaminoisobutyrate Nraaib D-N-methyl lproline Dnmpro N- (1-methylpropyl) glycine Nile D-N-methylserine Dnmser N- (2-methylpropyl) glycine Nile D-N-methylserine Dnmser N- (2-methylpropyl) glycine Nleu D-N-methytrethine Dnmthr D-N-methyltriptofan Dnmtrp N- (1-methylethyl) glycine Nva D-N-meti Iti rosina Dnmtyr N-metila-na tilalaniña Nmanap D-N-methyl alina Dnmval N-methylpenicillami to Nmpen Y-aminobutyl acid Gabu N- (p-hydroxyphenyl) glycine Nhtyr L-t-butylglycine Tbug N- (thiomethyl) glycine NCys L-ethylglycine Etg Penicillamine Pen L-homophenylalanine Hphe L-a-methylalanine Mala L-methylarginine Marg L-ct-metilasparagine Masn L-a-metilaspartato Masp L-a-methyl-t-but i1glicina Mtbug L-a-metilcisteina Cys L-metiletilgliciria Metg L-a-methylglutamine Mgln L-a-methylglutamate Mglu L- -methylhistidine his L-a-methylhomophenylalanin hphe L-a-methylisoleucine Mile N- (2-methylthioethyl) glycine Nmet D-N-methylglutamine Dnmgln N- (3- uanidinopropi 1) glycine Narg D-N-methylglutamate Dnmglu N- (1-hydroxyethyl) glycine Nthr D-N-methylhistidine Dnmhis N- (hydroxyethyl) glycine Nser D-N-Methyl Isoleucine Dnmile N- (imidazolylethyl) glycine Nhis D-N-methyleucine Dnmleu N- (3-indolyl-ethyl) glycine Nhtrp D-N-methyllisine Dmnlys N-me Lil-and-aminobutyrate Nmgabu N-methylcyclohexylalanine Nmchexa D-N-methylmethionine Dnmmet D-N-Methylornithine Dnmon N-methylcyclopentilalanin Nmcpen N-methylglycine Nala D-N-methylphenylalanine Dnmphe N-methylaminoisobu- rate Nmaib D-N-methyl rolin Dnmpro - (1-net llpropyl) glycine Nile D-N-methylserine Dnmser N-! 2-methylpropyl) glycine Nleu D-N-methyltreonine Dnmthr D-N-methyltriptofan Dnmtrp N- (1-methylethyl) glycine Nval D-N-Methylsyrosine Dnmtyr N-Methylaptilalanine Nmanap D-N-methylvaline Dnmval N-methylpenicillamine Nmpen Acid? -aminobutyric Gabu N- (p-hydroxyphenyl) glycine Nntyr L-x-butylglycine Tbug N- (iorr.ethyl) glycine Ncys L-Ethylglycine Etg Penicillamine Pen L-homophenylalanine Hphe L-a-methylalanine Mala L-methylarginine Marg L-a-metilasparagine Masn L-a-methylaspartate Masp L-a-methyl-t-buty1glycine Mtbug L-a-methylcystin Mcys L-me lethlyglycine Metg L-oc-methylglutamine Mgln L-a-methylglutamate Mglu L-a-methylhistidine Mhis L-a-methyl omofenilalanin Mhphe L-a-methylisoleucine Mile N- (2-methylthioethyl) glycine Nmet L-cc-methyleucine Mleu L-a-netillisin Mlys L-a-Methylmethionine Mmet L-a-Methylnorleucine Mnle L-a-methylnorvaline Mnva L-a-methylornithine Morn L-a-methylphenylalanine Mphe L-a-netilproline Mpro L-a-metilserina Mser L-a-metiltreonina Mthr L-a-methylvaline Mtrp L-a-methyltyrosine Mtyr L-a-Methylilleucine Mval N L-N-methylhomophenylalanin. NmhFe N- (N- (2, 2-diphenylethyl) Nnbhm N- (N (3, 3-diphenylpropyl) Nnbhe carbamylmethylglycine carbamylmethyl (1) glycine 1-carboxy-l- (2,2-diphenyl-N-dimethylamino) cyclopropane A peptide according to the present invention may be used in a manner in the place or be a part of portions such as proteins and display portions such as bacteria and display phages. The peptides of the invention can also be chemically modified to give active dimers or multimers, in a polypeptide chain or covalently crosslinked chains. Additionally, a peptide according to the present invention includes at least two, optionally at least three, optionally at least four, optionally at least five, optionally at least six, optionally at least seven, optionally at least eight, optionally at least nine, optionally at least ten, optionally at least eleven, optionally at least twelve, optionally at least thirteen, optionally at least fourteen, optionally at least quinte, optionally at least sixteen, optionally at least seventeen, optionally at least eighteen, optionally at least nineteen, optionally at least twenty, optionally at least twenty-one, optionally at least twenty-two, optionally at least twenty-three, optionally at least twenty-four, optionally, at least twenty-five, optionally at least twenty-six, optionally at least twenty-seven and sixty, or more amino acid residues (also referred to in the present interchangeably as amin oacids). Accordingly, as used herein, the term "amino acid" or "amino acids" is understood to include all 20 naturally occurring amino acids, those amino acids often post-translationally modified in vivo, including, for example, hydroxyproline, phosphoserine and phosphothreon .to; and other unusual amino acids, including but not limited to 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine and ornithine. In addition, the term "amino acid" includes both amino acids D and L. As used herein, the phrase "derived from an N-terminal portion of casein aSl" refers to peptides as this term is defined herein, for example, casein cleavage products aSl (referred to herein as peptides derived from natural casein), synthetic peptides chemically synthesized to correspond to the amino acid sequence of an N-terminal portion of casein ccSl (referred to herein as synthetic peptides derived from casein ), similar peptides (homologs) to an N-terminal portion of casein Sl, for example, peptides characterized by one or more amino acid substitutions, such as, but not limited to, permissible substitutions, with the proviso that at least 70%, preferably at least 80%, more preferably at least 90% similarity is maintained, and their functional counterparts. The terms "homologs" and "functional homologs" as used herein means peptides with any insertions, deletions and substitutions that do not affect the biological activity of the peptide. As used herein, the term "casein aSl" refers to casein to S1 of a mammal, including, but not limited to, farm mammals (e.g., cows, sheep, goats, mares, camels, deer and buffaloes) human beings and marine mammals. The following provides a list of caseins aSl having a known amino acid sequence, identified by their GenBank Accession Nos. (NCBI) and source: CAA26982 (Ovis arles (sheep)), CAA51022 [Capra hircus (goat)), CAA42516 ( Bos taurus (bovine)), CAA55185 (Homo sapiens), CAA38718 (Sus scrofa (pig)), P09115 (rabbit) and 097943 (Camelus dromedurius (camel)).

As used herein, the term "N-terminal portion" refers to casein M amino acids raSl derived from the first 60 amino acids of casein aSl, where M is any of the integers between 2 and 60 (including the numbers integers 2 and 60). Preferably, the term refers to the first M-amino acids of casein aSl. The peptides of the invention can be obtained by extraction from milk as previously described, or by synthesis of the solid phase peptide. The purification of the peptides of the invention was carried out by standard techniques known to the person skilled in the art. The purification of the peptides of the invention is carried out by standard techniques, known to the person skilled in the art, such as high performance liquid chromatography (HPLC). Fragmentation of milk casein to obtain the peptides of the invention can be effected using various enzymatic and / or chemical means. As further detailed herein below and exemplified in the Examples of the section that follows, the peptides of the present invention have a variety of therapeutic effects. In the Examples, numerous analyzes are provided in this section with which one of ordinary skill in the art can test a specific peptide designed in accordance with the teachings of the present invention for a specific therapeutic effect. Any of the peptides described herein may be administered per se or formulated into a pharmaceutical composition that can be used to treat or prevent a disease. Such a composition includes as an active ingredient any of the peptides described herein and a pharmaceutically acceptable carrier. As used herein, a "pharmaceutical composition" refers to a preparation of one or more of the peptides described herein, with other chemical components as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. Further, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not invalidate the biological activity and properties of the compound administered. Examples, without limitations, of carriers are: propylene glycol, saline, emulsions and mixtures of organic solvents with water. Herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Techniques for drug formulation and administration can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition. Suitable routes of administration may, for example, include oral, rectal, transmucosal, transdermal, intestinal or parenteral delivery, including intramuscular, sucuutive and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or infraocular injections. The pharmaceutical compositions of the present invention can be manufactured by processes well known in the art, for example by means of conventional mixing, solvent, granulation, tablet making, spraying processes, emulsification, encapsulation, entrapment or lyophilization. Pharmaceutical compositions for use in accordance with the present invention can thus be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active peptides into preparations which can be used pharmaceutically. The appropriate formulation is dependent on the chosen route of administration.

For injection, the peptides of the invention can be formulated in aqueous solutions, preferably in physiologically compatible regulators such as Hank's solution, Ringer's solution, or physiological saline regulator with or without organic solvents such as propylene glycol, polyethylene glycol. For transmucosal administration, penetrating substances are used in the formulation. Such penetrants are generally known in the art. For oral administration, the peptides can be easily formulated by combining the active peptides with pharmaceutically acceptable carriers well known in the art. Such carriers allow the peptides of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, then adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl cellulose, sodium carbomethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, the disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salt such as sodium alginate. Dragee centers are provided with suitable coatings. Concentrated sugar solutions which may optionally contain arabic gem, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, varnish solutions, and suitable organic solvents or solvent mixtures may be used for this purpose. The coloring matter or pigments can be added to the coatings of tablets or dragees for identification or to characterize different combinations of active ingredient doses. The pharmaceutical compositions, which may be used orally, include soft-fit gelatin capsules as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The soft-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active peptides can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffins, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration. For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration by inhalation, the peptides according to the present invention are conveniently supplied in the form of an aerosol spray pressure of a pressurized pack or a nebulizer with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dose unit can be determined by providing a valve to supply a measured quantity. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound and a suitable powder such as lactose or starch. The peptides described herein may be formulated for parenteral administration, eg, bolus injection or continuous infusion. The formulations for injection can be presented as a unit dose, for example, in ampules or in multi-dose receptors with optionally an added preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active peptides can be prepared as appropriate oil injection suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the peptides to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in the form of powder for constitution with a suitable vehicle, for example, sterile, aqueous, pyrogen-free, before use. The peptides of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, using for example, conventional suppository bases such as cocoa butter or other glycerides. The pharmaceutical compositions described herein may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. Those of ordinary skill in the art can easily determine the optimal dosage and dosing methodology for any of the peptides of the invention. For any peptide used in accordance with the teachings of the present invention, a therapeutically effective amount is also referred to as a therapeutically effective dose, which can be estimated initially from cell culture assays or in animal tests in vivo. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes IC50 or IC100 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Initial doses can also be estimated from in vivo data. By using these initial guidelines someone who has common experience in the art could determine an effective dose in humans. In addition, the toxicity and therapeutic efficacy of the peptides described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining LD5o and ED50. The dose ratio between the toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD50 and ED50. Preferred are peptides that exhibit high therapeutic indices. The data obtained from these cell culture assays and animal studies can be used to formulate a dose range that is not toxic for use in humans. The dose of such peptides preferably falls within a range of circulating concentrations that include the EDM with little or no toxicity. The dose may vary within this range depending on the dosage form used and the route of administration used. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see for example, Fingí et al., 1975, In: The Pharmacological Basis of Therapeutics, chapter 1, page 1). The amount and range of dosage can be adjusted individually to provide plasma levels of the active ingredient that are sufficient to maintain the therapeutic effect. The usual doses of the patient for the oral administration range of 1-1000 mg / kg / administration, commonly of about 10-500 mg / kg / administration, preferably of about 20-300 mg / kg / administration and of higher Preference of approximately 50-200 mg / kg / administration. In some cases, therapeutically effective serum levels will be achieved by administering multiple doses each day. In cases of local administration or selective consumption, the effective local concentration of the drug can not be released at the plasma concentration. One skilled in the art will be able to optimize therapeutically effective local doses without undue experimentation. Depending on the severity and sensitivity of the condition to be treated, the dose may also be a single administration of a slow release composition, with the course of treatment lasting from several days to several weeks or until the cure is effected or achieved. the decrease of the disease state. The amount of a composition to be administered will of course depend on the subject to be treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.The compositions of the present invention may, if desired, be presented in a packaging or Qistribution device, such as an FDA approved kit, which may contain one or more dosage unit forms containing the active ingredient. The package may, for example, comprise sheet metal or plastic, such as a transparent plastic package. The package or distributor device can also be accompanied with instructions for administration. The package or distributor may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency that regulates the manufacture, use or sale of pharmacists, whose notice is reflective of approval by the agency in the form of compositions or administration human or veterinary Such notice, for example, may be a mark approved by the United States Food and Drug Administration for prescription drugs or an insertion of the approved product. Compositions comprising a peptide of the invention formulated in a pharmaceutically acceptable carrier can also be prepared, placed in an appropriate container, and labeled for the treatment or prevention of an indicated condition or induction of a desired event. The appropriate indication in the brand can include treatment and / or prevention of a disease or condition autoinnune, viral disease, viral infection, bacterial infection, hematological disease, hematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, hyperlipidemia, hypercholesterolemia, glucosuria, hyperglycemia, diabetes , AIDS, HIV-1 infection, T helper cell disorders, dendritic cell deficiencies, macrophage deficiencies, hematopoietic pluripotential cell disorders including platelet disorders, lymphocyte, plasma and neutrophil cell, proliferation of hematopoietic pluripotent cell , proliferation and differentiation of hematopoietic pluripotent cell, pre-leukemia conditions, leukemia conditions, immune system disorders resulting from chemotherapy or radiation therapy, and human immune system disorders resulting from the treatment or diseases of Immune fiction. The pharmaceutical compositions according to the invention can be useful in maintaining and / or restoring the constituents of the blood system, in balancing blood cell counts, in balancing levels of metabolites in the blood, including sugar, cholesterol, calcium, uric acid, urea and enzymes such as alkaline phosphatase. In addition, the pharmaceutical compositions of the invention may be useful for inducing blood cell proliferation, modulating the white and / or red blood cell counts, particularly increasing white and / or red blood cell counts, raising the blood level of hemoglobin and modulating platelet counts. . The term "balance" as used herein, in relation to the levels of certain physiological parameters, means changing the levels of referred parameters and presenting them closer to normal values. The term "normal values" as used herein in relation to physiological parameters, means values that are in the range of values of human beings or healthy animals. In the specifically preferred embodiments, the peptides of the invention balance counts of red blood cells, white blood cells, platelet level and hemoglobin. The pharmaceutical compositions of the invention can be used to activate the proliferation of blood cells. In addition, the pharmaceutical compositions can be used for the treatment and / or prevention of hemopoietic stem cell disorders, including platelet, lymphocyte, plasma cell and neutrophil disorders, as well as deficiency and malfunction under conditions of pre-leukemia and leukemia and thrombocytopenia. In addition, the pharmaceutical compositions can be used for the treatment and / or prevention of cell proliferative diseases. In this connectionIt is important to note that the pharmaceutical compositions of the invention are advantageous in stimulating the immune response during chemotherapy or radiation treatments, alleviating the negative effects, reducing vomiting induced by chemotherapy and irradiation and promoting a faster recovery. Still still, the pharmaceutical compositions of the invention can be used for the stimulation of the human immune response during the treatment of diseases associated with immune deficiency, for example HIV and autoimmune diseases. The compositions of the invention can also be intended for veterinary use. The pharmaceutical compositions of the invention can be used in the treatment and / or prevention of, for example, disorders involving abnormal levels of blood cells, disorders involving the production and differentiation of hemopoietic stem cells, platelet treatment, lymphocyte disorders and / or neutrophil, for the treatment of pre-leukemic and leukemic conditions and for the treatment of thrombocytopenia. The pharmaceutical compositions of the invention can also be used in the treatment of cell proliferative diseases and diseases involving human deficiency, such as HIV, and of autoimmune diseases. In addition, the pharmaceutical compositions of the invention can be used to modulate the immune response during chemotherapy or radiation treatments, for example, by reducing vomiting associated with chemotherapy. While the present invention is reduced for practice, it was surprisingly observed that the peptides of the invention exert a synergistic effect of proliferation and human hematopoietic germ cell differentiation with the addition of other hematopoietic growth factors. Of noteworthy significance was the potentiation of erythropoietin-mediated stimulation of erythroid colony formation and the dose-dependent enhancement of thrombopoietin induction (TPO) of megakaryocyte proliferation by peptides of the present invention. Human recombinant EPO (rh) is currently an approved therapy for indications such as renal anemia, premature anemia, cancer and anemia associated with AIDS, and for pre-elective surgical treatment (Sowade, B et al Int J Mol Med 1998; 1: 305). Thus, according to the present invention, there is provided a method for treating a condition treatable with erythropoietin, the method effected for administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein Sl. Further in accordance with the present invention there is provided a method for increasing the effect of erythropoietin, the method effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein Sl. Thrombopoietin is a cirocin that acts in advance with important multilineage effects: TPO alone, or in combination with other cytokines that act in time, can (i) promote viability and suppress apoptosis in progenitor cells; (ii) regulate the production and function of hematopoietic pluripotent cells; (iii) drive the cell division of inactive multipotent cells; (iv) induce multilineage differentiation and (v) improve the formation of multilineage colonies containing granulocytes, erythrocytes, macrophages and megakaryocytes (MK, CFU-GEMM). In addition, TPO stimulates the production of more limited progenitors for granulocyte / monocyte, megakaryocyte and erythroid colonies, stimulates the adhesion of primitive human bone marrow and megakaryocytic cells to fibronectin and fibrinogen. In this way, TPO is an important cytokine for hematologists / clinical transplants: for mobilization, amplification and ex vivo expansion of pluripotent cells and precursor cells compromised by autologous and allogeneic transplantation. In addition, the administration of TPO to healthy platelet donors has been used to improve pheresis yields. However, the clinical application of TPO therapy is complicated by, among other considerations, relatively high costs of the recombinant human rhTPO cytokine and the potential antigenicity of TPO with repeated administration. The combined treatment with TPO and the peptide of the present invention, either together in a pharmaceutical composition comprising both, or separately, can cause a proven, non-toxic, inexpensive increase of TPO effects in the proliferation and function of the cell. . In such combination, the peptide of the present invention can be applied to the treatment of, in addition to the aforementioned conditions, disorders such as myelodysplastic syndrome (MDS), aplastic anemia and complications of hepatic failure. The pre-treatment of platelet donors with the peptide of the present invention, alone or in combination with TPO, can still further improve the efficiency of pheresis performances. Thus, in accordance with the present invention, there is provided a method for treating a treatable condition of thrombopoietin, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from the N-terminal portion of a casein aSl. In addition, according to the present invention, there is provided a method for increasing the effect of thrombopoietin, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocs 1 casein. Furthermore, according to the present invention, a method for improving peripheral pluripotent cell mobilization is provided, the method is carried out by administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising effective amounts of thrombopoietin and a peptide derived from an N-terminal portion of casein ocSl. In addition, according to the present invention, there is provided a pharmaceutical composition for treating a treatable condition of thrombopoietin, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein otS1 and a pharmaceutically acceptable carrier. further, according to the present invention, there is provided a pharmaceutical composition for increasing the effect of thrombopoietin, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for improving peripheral pluripotent cell mobilization, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein Sl and a pharmaceutically acceptable carrier. . In addition, according to the present invention, there is provided a pharmaceutical composition for inducing hematopoiesis, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing proliferation of hematopoietic stem cells, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing proliferation and differentiation of hematopoietic stem cells, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically carrier acceptable.

In addition, according to the present invention, a pharmaceutical composition for inducing megakaryocytopoiesis is provided, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention, there is provided a pharmaceutical composition for inducing erythropoiesis, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl and an acceptable pharmaceutical carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing leukocytopoiesis, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for inducing thrombocytopoiesis, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating thrombocytopenia, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating pancytopenia, the pharmaceutical composition comprises, as active ingredients ombopoietin and a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for preventing or treating granulocytopenia, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition for treating or preventing an indication selected from the group consisting of hematological disease, haematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, dendritic cell deficiencies, macrophage deficiencies, cell disorders. hematopoietic pluripotential including platelet, lymphocyte, plasma and neutrophil cell disorders, pre-leukemic conditions, leukemic conditions, myelodysplastic syndrome, aplastic anemia and bone marrow failure, the pharmaceutical composition comprises, as active ingredients, thrombopoietin and a peptide derived from a portion N-terminal casein aSl and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a pharmaceutical composition comprising thrombopoietin and a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25 and a pharmaceutically acceptable carrier. In addition, according to the present invention, there is provided a method for improving the colonization of donated blood pluripotent cells in a myeloablati receptor or, the method is performed by treating a donor of blood pluripotent cells donated with a peptide derived from an N-terminal portion. of casein aSl and thrombopoietin before the donation and implantation of blood pluripotent cells donated in the recipient. In addition, according to the present invention, a method is provided for improving the colonization of donated blood pluripotent cells in a myeloablative receptor, the method is performed by treating the blood pluripotent cells donated with a peptide derived from an N-terminal portion of casein aSl. and thrombopoietin before implanting the blood pluripotent cells donated in the recipient. further, according to the present invention, there is provided a method for improving the colonization of blood pluripotent cells in a myeloablative receptor, the method comprising treating the blood pluripotent cells with a peptide derived from an N-terminal portion of casein aSl and thrombopoietin before implant the blood pluripotent cells donated in the recipient. Further in accordance with the present invention, there is described the use of a pharmaceutically acceptable composition, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for treating a treatable condition of thrombopoietin. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, such as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier to increase the effect of thrombopoietin is disclosed. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable peptide derived from an N-terminal portion of casein is described. aSl to improve the colonization of pluripotent cells from donated blood in a myeloablative receptor. Further in accordance with the present invention, there is described the use of a pharmaceutically acceptable composition, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier to improve the colonization of blood pluripotent cells in a myeloablative receptor Further in accordance with the present invention, there is described the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier to improve peripheral pluripotent cell mobilization . Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for inducing hematopoiesis is described. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of ocsl casein, and a pharmaceutically acceptable carrier for inducing proliferation of hematopoietic stem cells is described. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of ocsl casein, and a pharmaceutically acceptable carrier to induce proliferation and differentiation of stem cells is described. hematopoietic Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for inducing megakaryocytopoiesis is described. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for inducing erythropoiesis is described. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of cxSl casein, and a pharmaceutically acceptable carrier for inducing leukocytopoiesis is described. In addition according to the present invention, the use of a pharmaceutically acceptable composition is described, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier to induce thrombocytopoiesis. Further in accordance with the present invention, there is described the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating thrombocytopenia. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating pancytopenia is described. Further in accordance with the present invention, there is described the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating granulocytopenia. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating a selected indication of the group that consists of autoimmune disease or condition, viral disease, viral infection, haematological disease, hematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, hyperlipidemia, hypercholesterolemia, glycosuria, hyperglycemia, diabetes, AIDS, HIV-1, helper T cell disorders, deficiencies of dendritic cells, macrophage deficiencies, hematopoietic pluripotential cell disorders including plagueta, lymphocyte, plasma and neutrophil cell disorders, pre-leukemic conditions, leukemic conditions, immune system disorders, resulting from chemotherapy or radiation therapy, of the human immune system resulting from the treatment of diseases of bacterial and immunodeficient infections. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of ocsl casein, and a pharmaceutically acceptable carrier for preventing or treating a selected indication of the group consisting of hematologic disease, hematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, dendritic cell deficiencies, macrophage deficiencies, hematopoietic pluripotential cell disorders, including platelet disorders, lymphocyte, plasma and neutrophil cell, pre-leukemic conditions, conditions leukemia, myelodysplastic syndrome, aplastic anemia and bone marrow failure. Further in accordance with the present invention, the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of ocsl casein, and a pharmaceutically acceptable carrier to improve the colonization of blood pluripotent cells is described. donated in a myeloablative receptor. Further in accordance with the present invention, there is described the use of a pharmaceutically acceptable composition, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier to improve colonization of blood pluripotent cells. in a myeloablative receptor. The invention further relates to an anti-bacterial pharmaceutical composition comprising as an active ingredient at least one peptide of the invention and to the use of the peptides of the invention as anti-bacterial agents. As detailed in the Examples of the following section, the peptides of the invention and pharmaceutical compositions comprising as an active ingredient a peptide of the invention, they can be used in the treatment and prevention of cellular blood disorders, cell proliferative diseases, diseases that involve immune deficiency and autoimmune diseases. Thus, according to the present invention, there is provided a method for preventing or treating an autoimmune disease, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Furthermore, according to the present invention there is provided a method for preventing or treating a viral disease, the method is effected by administering to a subject in need of the same a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. In addition, according to the present invention there is provided a method for preventing a viral infection, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Furthermore, according to the present invention there is provided a method for inducing hematopoiesis, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-ierminal portion of casein aSl. In addition, according to the present invention there is provided a method for inducing proliferation of hematopoietic stem cells, the method is carried out by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. In addition, according to the present invention there is provided a method for inducing proliferation and differentiation of hematopoietic stem cells, the method is carried out by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein. aSl. In addition, according to the present invention there is provided a method for inducing megakaryocytopoiesis, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. Furthermore, according to the present invention there is provided a method for inducing erythropoiesis, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. In addition, according to the present invention there is provided a method for inducing leukocytopoiesis, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Furthermore, according to the present invention there is provided a method for inducing zrombocytopoiesis, the method is carried out by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Further, according to the present invention there is provided a method for inducing cell proliferation in plasma, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Further, according to the present invention there is provided a method for inducing dendritic cell proliferation, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. In addition, according to the present invention there is provided a method for inducing macrophage cell proliferation, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. further, according to the present invention there is provided a method for preventing or treating thrombocytopenia, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. In addition, according to the present invention there is provided a method for preventing or treating pancytopenia, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. Further, according to the present invention a method for preventing or treating granulocytopenia is provided, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ccSl casein. Furthermore, according to the present invention there is provided a method for preventing or treating hyperlipidemia, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. Furthermore, according to the present invention there is provided a method for preventing or treating hypercholesterolemia, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aS 1. In addition , according to the present invention there is provided a method for preventing or treating glycosuria, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein "SI. In addition, according to the present invention there is provided a method for preventing or treating diabetes, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. In addition, according to the present invention there is provided a method for preventing or treating AIDS, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. In addition, according to the present invention a method for preventing or treating HIV infection is provided, the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsI casein. In addition, according to the present invention there is provided a method for preventing or treating conditions associated with myeloablative doses of chemotherapy supported by autologous bone marrow transplantation or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BT), the The method is accomplished by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsI casein. In addition, according to the present invention there is provided a pharmaceutical composition for preventing or treating an autoimmune disease, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier. In addition, according to the present invention there is provided a pharmaceutical composition for preventing or treating a viral disease, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier.

In addition, according to the present invention there is provided a pharmaceutical composition for preventing viral infection, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for inducing hematopoiesis, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for inducing proliferation of hematopoietic stem cells, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for inducing proliferation and differentiation of hematopoietic stem cells, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically carrier. acceptable Further, according to the present invention there is provided a pharmaceutical composition for inducing megakaryocytopoiesis, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention there is provided a pharmaceutical composition for inducing erythropoiesis, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for inducing leukocytocytosis, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for inducing thrombocytopoiesis, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for inducing cell proliferation in plasma, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for inducing dendritic cell proliferation, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for inducing macrophage proliferation, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention there is provided a pharmaceutical composition for preventing or treating thrombocytopenia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention there is provided a pharmaceutical composition for preventing or treating pancytopenia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention, a pharmaceutical composition is provided for the prevention or treatment of graminocytopenia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for preventing or treating hyperlipidemia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for preventing or treating hypercholesterolemia, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for preventing or treating glycosuria, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. Further, according to the present invention there is provided a pharmaceutical composition for preventing or treating diabetes, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention there is provided a pharmaceutical composition for preventing or treating AIDS, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention there is provided a pharmaceutical composition for preventing or treating HIV infection, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. In addition, according to the present invention there is provided a pharmaceutical composition for preventing or treating conditions associated with myeloablative doses of chemoradiotherapy supported by autologous bone marrow transplantation or peripheral blood pluripotency cell (ASCT) or allogeneic bone marrow transplantation (BMT), The pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat an autoimmune disease is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat a viral disease is described. Furthermore, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to prevent viral infection is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to induce hematopoiesis is described. Furthermore, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to induce the proliferation of hematopoietic stem cells is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to induce proliferation and differentiation of hematopoietic stem cells is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to induce megakaryocytopoiesis is described. In addition, according to the present invention the use of a peptide derived from an N-terminal portion of casein aSl to induce erythropoiesis is described. Furthermore, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to induce leukocytopoiesis is described. further, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to induce thrombocytopoiesis is described. In addition, according to the present invention the use of a peptide derived from an N-terminal portion of casein aSl to induce cell proliferation in plasma is described. Furthermore, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to induce dendritic cell proliferation is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to induce macrophage proliferation is described. In addition, according to the present invention the use of a peptide derived from an N-terminal portion of ocsl casein to prevent or treat thrombocytopenia is described. In addition, according to the present invention the use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat pancytopenia is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of ocSl casein to prevent or treat granulocytopenia is described. In addition, according to the present invention the use of a peptide derived from an N-terminal portion of ocsl casein to prevent or treat hyperlipidemia is described. Furthermore, according to the present invention the use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat cholesteremia is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat glycosuria is described. In addition, according to the present invention the use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat diabetes is described.

In addition, according to the present invention the use of a peptide derived from an N-terminal portion of otSl casein to prevent or treat AIDS is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of otSl casein to prevent or treat HTV infection is described. Furthermore, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat conditions associated with myeloablative doses of chemoradiotherapy supported by autologous bone marrow transplantation or peripheral blood germ cell ( ASCT) or allogeneic bone marrow transplantation (BMT). In addition, according to the present invention the use of a peptide derived from an N-terminal portion of casein aSl to treat a treatable condition of thrombopoietin is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to increase the effect of thrombopoieme is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl to improve peripheral pluripotential cell mobilization is described. In addition, according to the present invention, the use of a peptide derived from an N-terminal portion of casein aSl is described to improve the colonization of pluripotent cells from donated blood in a myeloablate receptor. Furthermore, according to the present invention, the use of a peptide derived from an N-terminal portion of ctSl casein to improve the colonization of blood pluripotent cells in a myeloablative receptor is described. Furthermore, according to the present invention the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating an autoimmune disease is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating a viral disease is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ccSl casein, and a pharmaceutically acceptable carrier for preventing or treating a viral infection is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for inducing hematopoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocsl casein, and a pharmaceutically acceptable carrier to induce hematopoietic pluripotent cell proliferation is disclosed. . In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier to induce proliferation and differentiation of stem cells is described. hematopoietic In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ccSl casein, and a pharmaceutically acceptable carrier for inducing megakaryocytopoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein, and a pharmaceutically acceptable carrier for inducing erythropoiesis is described. further, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein, and a pharmaceutically acceptable carrier for inducing leukocytopoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein Sl, and a pharmaceutically acceptable carrier for inducing thrombocytopoiesis is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for inducing cell proliferation in plasma is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for inducing dendritic cell proliferation is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein, and a pharmaceutically acceptable carrier for inducing macrophage proliferation is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating thrombocytopenia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating pancytopenia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of otSl casein, and a pharmaceutically acceptable carrier for preventing or treating granulocytopenia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein Sl, and a pharmaceutically acceptable carrier for preventing or treating biperlipidemia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ccSl casein, and a pharmaceutically acceptable carrier for preventing or treating cholesteremia is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating glycosuria is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier for preventing or treating diabetes is described. Further, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein otS1, and a pharmaceutically acceptable carrier for preventing or treating AIDS is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ccSl casein, and a pharmaceutically acceptable carrier for preventing or treating HIV infection is described. In addition, according to the present invention, the use of a pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein Sl, and a pharmaceutically acceptable carrier for preventing or treating conditions associated with myeloablative doses of chemoradiotherapy supported by bone marrow transplantation is described. autologous bone or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT). In addition, according to the present invention there is provided a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25.In addition, according to the present invention there is provided a pharmaceutical composition comprising a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25 and a pharmaceutically acceptable carrier. The present invention successfully addresses the deficiencies of currently known configurations by providing peptides for the treatment of human disease, whose peptides are derived from the N-terminal portion of ccSl casein and have no detectable toxicity and high therapeutic efficacy. Additional objects, advantages and novel features of the present invention will become apparent to one of ordinary skill in the art upon examination of the following examples, which are not intended to be limited. Additionally, each of the various embodiments and aspects of the present invention as outlined above and as claimed in the claims, of the following section finds experimental support in the following examples. EXAMPLES Reference is now made to the following examples, which together with the foregoing descriptions, illustrate the invention in a non-limiting manner. MATERIALS AND EXPERIMENTAL METHODS Preparation of peptides derived from natural casein: The casein fraction of cow's milk was isolated as described by Hipp et al. (1952), ibid, and subjected to exhaustive proteolytic digestion with chymosin (also known as reniña) (20 ng per ml) at 30 ° C. At the end of the reaction, the solution was heated to inactivate the enzyme, and the digestion was precipitated as paracaseinate by acidification with an organic acid, acetic acid or trichloroacetic acid. The paracaseinate was removed by centrifugation, and the supernatant fraction, which contains the fragments of the peptide of interest, is re precipitated as caseicidin by higher acid concentrations. The resulting caseicidin was lyophilized after resuspension, dialysis and neutralization. The resulting powder preparation was evaluated for biological activity as described below, and separated by HPLC by peptide analysis. HPLC analysis of peptides derived from natural casein: Peptides derived from natural casein were analyzed by two-step HPLC as described above. Initially, freeze-dried casein digestions were separated using a reverse phase of C18 with a gradient of 0.1% (w / w) aqueous trifluoroacetic acid-acetonitrile. Detection was in accordance with UV absorption at 214 nm. After this, the samples were analyzed by HPLC (MS) loop spectroscopy equipped with an electrospray source. The mass calculations represent the mass of the ionized peptide samples, which is derived from the retention times. After separation, the amino acid composition of the peptides was determined with a gas phase microsequencer (Applied Biosystems 470A). The following data are representative: Eight peptide peaks were normally observed of which 3 were higher peaks that have Rt values of 17.79, 19.7, 23.02 and 5 were minor peaks that have Rt values of 12.58, 14.96, 16.50, 21.9 and 25.1, whose Rt values represent the molecular mass of 2764, 1697, 1880, 2616, 3217, 2333, 1677 and 1669 Da, respectively. In Rt of 17.70 (corresponding to 2,764 Da) a major peak of a peptide of 23 amino acids representing 1-23 amino acids of casein "SI having the sequence RPKHPIKHQGLPQEVLNENLLRF (SEQ ID NO: 22, see McS eeny et al. ., 1993, ibid for the complete casein sequence ccSl). Other peptides were at positions 208-224 of casein β, positions 16-37 of casein aSl and positions 197-222 of aSl as a precursor of casein. Other peptides were also presented. Synthetic peptides derived from casein: Peptides of increased lengths corresponding to the 2-26 N-terminal amino acids of casein aSl, were synthesized by NoVetide Ltd., Haifa, Israel, with purity of > 95 (HPLC).

Quality Control includes: HPLC, Mass Spectroscopy (El), amino acid analysis and Peptide Content. Table 3 below provides the sequence of these peptides: Table 3 Identification (Sequence Term-N Term-C) No of amino acids SEC DE 74 RP 2 1 IP RPK 3 2 2P HPKH 4 3 P RP HP 5 4 < 1P RPKHP1 6 5 5P Rl 'HPIK 7 6 and RPKHPIKH 8 7 X RPKHPI HQ 9 8 the RPKHP1 HQG 10 9 2a RPKHP1KHQGL 11 10 3a RPKHPIKHQGLP 12 11? RPKHPIKHQGLPQ 13 12 B RPKHPIKHQGLPQE 14 13 C RPKHP1KHQGLPQEV 15 14 1) RPKHP1 HQGLPQEVI. 16 15 1; RPKHPI HQGL.PQEVLN 17 16 18 17 G 1- RPKHP1KHQGLPQEVLNE RPKHP1KHQGLPQEVLNEN 19 Nov. 18 RPKHP1 I IQGLPQEVL.NENL 20 RPKHP1KHQGLPQEVLNENLL January 19 21 20 22 21 J lU'KHPIKHQGLPQEVLNENLLR RPKHPI IIQGLPQEVLNENLLRF 23 22 24 23 1. RPKHPI HQGLPQEVLNENLLRFF RPKHPIKHOGI.PQEVLNENLLRFFV 25 24 N RPKHPIKHQGLPQEVLNENLLRFFVA 26 25 Juvenile Diabetes (Type I, IDDM) in Non-Obese Diabetes (NOD) mice: Peptides derived from natural casein: NOD mice are a model commonly used for the investigation of autoimmune disease and human juvenile diabetes. NOD female mice of six weeks received either one or two injections per week of 100 pg of peptides derived from natural casein, for a total of 5 or 10 treatments. The control mice did not receive treatment. The severity of the disease was determined according to glycosuria, which was measured using Combi test accessions [Gross, D.J. et al. (1994), Diabetology, 37: 1195]. The results were expressed as the percent of glucosuria-free mice in each sample over a period of 365 days. Synthetic peptides derived from casein: In another experiment, female NOD mice, 6 weeks of age received one injection per week of 100 pg of synthetic peptides derived from casein for a total of 5 treatments. The control mice did not receive treatment. The results were expressed as the number of healthy mice in the various treated groups. Intraperitoneal Glucose Tolerance Test (1PGTT): The glucose tolerance test is the definitive method to investigate glucose metabolism and diabetic tendencies in mammals. Twenty-five (25) weeks after receiving synthetic peptides derived from casein, the response to a glucose load was evaluated with an intraperitoneal glucose tolerance test. The glucose injection consisted of lg / kg of body weight. Glycemic values were determined from blood extraction before the test (0 minutes) and 60 minutes after loading. Plasma glucose levels were determined with a Glucose Analyzer 2 (Beckman Instruments, Fullerton, CA) and expressed as mmoles / L. Normal values do not exceed 14Q mmoles / L. Stimulation of proliferation of Natural Killer (NK) cells: From Blood Pluripotential Cells Human Periphery (PBSC): PBSC were separated from G-CSF-treated subjects on a FICOLL gradient, washed twice with RPM1-1640 medium and plated in 1.5 ml wells with or without peptides derived from natural casein or derived synthetic peptides of casein, as indicated, (0-500 μg per ml). After two days of incubation the cells were evaluated for Natural Killer activity by measuring the radioactivity released from 35S-labeled target cells K562 (EG-709A, 185.00 MBq, 2.00 mCi EASYTAGth Methionine, L- [35S] 43.48 TBq per mmol, 1175.0 Ci per mmol, 0.488 mi, Boston USA). Two concentrations of effector cells (2.5 x 105 and 5 x 10 5 cells per well) were incubated with 5 x 10 3 target cells per well (effector cell ratios: ob ective 50: 1 and 100: 1, respectively) in culture dishes. of tissue from 96 U-shaped bottom wells. The cells were incubated for 5 hours at 37 ° C in 5% CO 2, 95% air and precipitated for 5 minutes by centrifugation at 1000 rpm. The release of 35S was measured in 50μ samples? of the supernatant liquid. From Bone Marrow (BM) cells: Bone marrow was harvested from 4 untreated BALB / c and C57B1 / 6 mice. The bone marrow was harvested from long bones of the front and back legs of the mice by injection of the medium using a 25 gauge needle. Extracted cells were washed with RPMI 1640, were counted in a hemocytometer and stained vital (20 μ? of cells in 380 μ? acetic acid / triptan blue), then planted in culture bottles at 2-5 x 10 ° cells per ml in RPMI-1650 containing 10% Fetal Calf Serum, antibiotics and glutamine with or without 100 μg per ml of peptides derived from natural casein. Cell cultures were incubated in 5% CO2, 95% air for 12-15 days at 37 ° C, harvested for 10 minutes at 1500 rpm, counted and plated in 51Cr U-shaped bottom wells (Cromium -51, 740 MBq, activity 2.00 mCi) or 35S (NEG-70A, 185.00 MBq, 2.00 mCi EASYTAGth Methionine L- [35S] 43.48 TBq per mmole, 1175.0 Ci per mmole, 0.488 mi, Boston USA) murine lymphoma cells marked (YAC) in any cellular effector relation: obj etivo of 25: 1 or 50: 1. The NK activity is expressed as the radioactivity in percent in cell-free supernatants. Proliferation of human cells in culture: Peripheral blood (PB) was collected from healthy or affected patients. Affected patients received no treatment other than G-CSF supplementation before plasmapheresis. Bone marrow (BM) cells were collected from the consent of healthy patients or patients affected in remission after chemotherapy by aspiration. Blood was collected from the umbilical cord during normal births. Human cells from the various origins were separated on a F1COLL gradient, washed twice with RP I-1640 medium, and plated in 0.2 ml in wells of flat bottom tissue culture at the indicated concentrations with or without peptides derived from natural casein or with or without synthetic peptides derived from casein, as indicated. All treatments, including controls, were repeated in triplicate. Cell proliferation was measured by 3 H incorporation: radioactive thymidine was added Specific activity of [thymidine (methyl- [3 H]) 5 Ci per my 37 MBq per ml, ICN Corp.] after incubation for the indicated number of days . The cells were then incubated 16-20 hours with the tag, harvested and washed with a medium. The radioactivity incorporated in a scintillation counter β was measured. Proliferation of K562 leukemia and colon cancer cell lines: Colon and K562 are established lines of cancer cells grown in culture. Both cell lines were cultured in culture bottles of 5% C02, 95% air at 37 ° C, harvested and washed with a medium before being planted in tissue culture wells at x 105 cells (K562) or 3 x 103 cells (Colon) per well. Peptides derived from natural casein were added to the wells, at the indicated concentrations and after 9 (K562) or 3 days (Colon) incubation, labeled thymidine was added as described above. The harvest and measurement of the radioactive incorporation was as described above. Detection of NK and T Cell proliferation fluorescent antibody in Human Peripheral Blood Pluripotent Cells (PBSC): Peripheral blood pluripotential cells (PBSC) were collected by plasmapheresis from human subjects who received G-CSF treatment, separated into a FICOLL gradient, were washed twice with RPMI-1640 medium containing 10% Fetal Calf Serum and incubated in culture bottles at 3 ° C in 5% CO2, 95% air with or without peptides derived from natural casein in the concentrations indicated. After 10, 14 or 28 days of incubation with natural casein-derived peptides, the presence of T cells (CD3 surface antigen) and NK cells (CD56 surface antigen) was detected by direct immunofluorescence using fluorescent anti-CD3 antibody (clone) CD3 / FITC UHCTj), anti-CD56 fluorescent antibody (clone CD56 / RPE MOC-lj (DAKO A / S, Denmark) and antibodies of IgGl / RPE and mouse IgGl / FITC as a control.The detection of fluorescently labeled cells was performed using fluorescence activated cell sorting (FACS) .Bio Marrow Cell (BM) hematopoiesis stimulation in culture: Megakaryocyte proliferation in multipotential colonies (CFU-GEMM) from murine bone marrow cells: Bone marrow cells Main (1 x 105 per ml) of C3H / HeJ mice of 8-12 weeks were cultured in serum free methylcellulose-I DM medium for 8-9 days at 5% C02, 95% air at 37 ° C. The medium, suitable for the growth of multipotential colonies (CFU-GEMM), contained 1% BSA (Sigma), 104 M thioglycerol (Sigma), 2.8 x 10 ~ 4 M human transferrin (F, Biological industries, Israel), 10% of WEH1-CM as a source of IL-3 and 2 units per ml of erythropoietin (rhEPO, R & amp;; D Systems, Minneapolis). Colonies were classified after 8.9 days using an Olympus dark field microscope. These were classified with a micropipette, cytocentrifuged and stained with May-Grunwald-Giemsa for differential counts. At least 700 cells were counted per preparation. Proliferation of Dendritic cells in CFU-GEMM: Multipotent colonies (CFU-GEMM) cultured from major bone marrow cells as described by the above megakaryocyte proliferation assay were harvested, stained and counted for dendritic cells. At least 700 cells were counted per preparation. Proliferation of Plasma Cells in CFU-GEMM: The ultipotent colonies (CFU-GEMM) grown from major bone marrow cells as described by the previous megakaryocyte proliferation assay were harvested, stained and counted for cells in plasma. At least 700 cells were counted per preparation. Proliferation of Macrophore cells in CFU-GEMM: Multipotent colonies (CFU-GEMM) cultured from primary bone marrow cells as described by the previous megakaryocyte proliferation assay were harvested, stained and counted for macrophage cells. At least 700 cells were counted per poop preparation. Red Blood Cell Proliferation in CFU-GEMM: Multipotent colonies (CFU-GEMM) cultured from primary bone marrow cells as harvested from the previous megakaryocyte proliferation assay were collected, stained and counted for red blood cells. At least 700 cells were counted per preparation.

Proliferation of Polymorphonuclear Cells (PMN = in CFV-GEMM: Multipotent colonies (CFU-GEMM) were harvested from major bone marrow cells as described by the proliferation analysis of r.egacariocyte above, stained and counted for cells Polymorphonuclear cells - At least 700 cells were counted for each preparation Proliferation of megakaryocyte and erythroid cells from human bone marrow and cord blood cells A bone marrow sample was processed from an apparently healthy human by separation density gradient using Histopaque-107 (Sigma Diagnostics) to obtain a purified population of mononuclear cells (MNC) Colony analysis was performed in a plating medium containing final concentrations of 0.92% methylcellulose (4000 centripase powder, Sigma Diagnostic ), rehydrated in Dulbecco's medium modified Iscoves containing 36 mM bicarb sodium onate (Gibco), 30% fetal bovine serum (FBS) (Hyclone), 0.292 mg / ml glutamine, 100 units per ml penicillin and 0.01 mg per ml streptomycin (Biological Industries, Beit Haemek). Cord blood from normal births was collected and prepared as mentioned above. The colony assay medium containing 10 ° MNC per ml was plated in wells in triplicate in a 24-well tissue culture plate (Greiner), 0.33 ml per well. Cultures were incubated at 37 ° C in 5% CO ?, 95% air and 55% relative humidity with or without peptides derived from natural casein or synthetic peptides derived from casein, at the indicated concentrations. The plates were classified after 14 days for colonies containing more than 50 cells. Megakaryocytes were identified by indirect immunofluorescence using a highly specific rabbit antibody that recognizes human platelet glycoproteins, and a goat anti-rabbit IgG conjugated to FITC. Aggregate growth factors included 15 ng per ml of leuomax (GM-CSF) (Sandoz Pharma) and 5 vol.% By volume of conditioned medium (CM) induced by human phyto-hemagglutinin-m (Difco Lab) to induce development of granulocyte-monocyte colonies (CFU-G). Erythropoietin (EPO) 2 units / ml was used to induce the formation of erythroid colonies (erythroid-BFU-E unit that forms rash). Alternatively, human bone marrow cells from the consent of voluntary donors or patients undergoing autologous bone marrow transplantation were pre-cultured in a medium containing 10-1000 pg per ml of natural casein-derived peptides, grown on semi-agar -solid, and classified for hematopoietic granulocyte-macrophage colonies (GM-CFU) in 7 or 14 days post-treatment. Megacar iocitopoiesis was measured in normal bone marrow cells from the consent of healthy human donors either by classifying the number of megakaryocytes in liquid culture samples (RPMI-1640 plus 10% of human AB serum, glutamine and antibiotics) with or without 100 pg per ml of peptides derived from natural casein, or in a methyl cellulose analysis to evaluate colony formation. 2 x 103 bone marrow cells were seeded in the presence of a standard growth factor in combination with or without peptides derived from natural casein. Megakaryocytes were counted in the methylcellulose assay with an inverted microscope on days 12-14 after sowing. Clinical tests using peptides derived from natural casein: In a series of tests, a single dose containing 50 mg of natural casein-derived peptides was administered intramuscularly to human subjects in 3 tanks, for a period of 2 hours. Clinical parameters were verified at the indicated intervals. In other tests, patients in various stages of treatment for and / or remission of cancer and metastatic disease received peptides derived from natural casein one c twice, and were checked for changes in peripheral blood cell count. Inhibition of HIV infection in vitro from human llnfocyte cells: Peptides: Peptides (either peptides derived from natural casein or synthetic peptides derived from casein (2-26 amino acids in length, see Table 3) supplied as lyophilized powder were resuspended in a complete medium RMPI and were added to cell cultures at final concentrations of 50 to 100 pg per ml.Cells: Several types of freshly isolated human cells (primary cells) and cell lines are known to be susceptible in HIV-1 infection n Vitrus, although essentially any cell still displays low surface levels of the CD4 molecule that can be considered a potential target for HIV-1 infection.Two commonly used human cell lines that are highly sensitive for HIV-1 infection were chosen, CEM and Sup-Tl. CEM is a human T4-lymphoblastoid cell line derived by GE Foley et al. [(1965), Cá cancer 18: 522] from the peripheral blood leukocyte layer of a 4-year-old Caucasian woman with acute lymphoblastic leukemia. These cells were continuously kept in suspension in medium, and have been widely used for infectivity, antiviral agents and neutralizing antibodies analysis. Sup-Tl is a human T-lymphoblastoid cell line isolated from pleural effusion of an 8-year-old man with Sin Hodgkin T cell lymphoma [Smith, S. D. et al. [(1984) Cancer Research 44: 5657]. This cell expresses high levels of surface CD4 and is useful in studies of cell fusion, cytopathic effect and HIV-1 infectivity. The Sup-Tl cells were cultured in suspension in an enriched medium. Medium: 3e cultured cells in an RPMI-1640 complete medium enriched with 10% fetal bovine serum, 2 mM glutamine and 2 mM penicillin-streptomycin (GIBCO). Virus: The strain of HIV virus used was HIV-1IIIB, originally designated HTLV-IIIB. Concentrated peripheral blood culture fluids from several patients with AIDS or related diseases were used to establish a permanent productive infection in H-9 cells. This virus of subtype B has a high capacity to replicate in human T-cell lines. The amount of viral substance was 5.38 ng per ml in stock solution. Peptides labeled with FITC: FITC F-1300 was used (fluorescein isothiocyanate, isomer 1, Sigma (F25o-2) St. Louis, MI, USA) having maximum excitation / emission of approximately 494/520 nm, respectively. The reactive fluorescein amine derivative is proBALBe the most common fluorescent derivatization reagent for covalently labeled proteins. The FITC-conjugated peptides derived from natural casein were prepared by covalently binding FITC to the amine groups of lysine. Evaluation of capture of HIV-1 antigen P24: An HIV-1 P24 antigen capture analysis kit was designed to add the HIV-1 P core antigen, which is proportionally related to the degree of viral production in cells. This kit was purchased from the AIDS Vaccine program of SAIC-NCI-Frederick Cancer Research Institute, P.O. Box B. Frederick, M.D. 21702, USA and included 96-well plates with monoclonal antibody to HIV-1 P24, anti-HIV serum P24 primary rabbit-antibody, antibody conjugated with anti-rabbit IgG peroxidase antibody-secondary goat (H + L), the TMB peroxidase substrate and standard HIV-1 P24 lysate. The P24 HIV-1 antigen capture analysis was analyzed by Organon-Technica ELISA reader at 450 nm with reference to 650 nm. HIV-1 antigen capture P24 ELISA: HIV infection was measured with an indirect enzyme immunoassay that detects P24 HIV-1 core antigens in tissue culture media. The tissue culture supernatant was reacted with anti-HIV-1 P24 from primary rabbit and visualized by goat anti-rabbit IgG conjugated with peroxidase. The reaction was terminated by adding 4N H? S04, wherein the color intensity developed was given to the amount of the HIV-1 antigen present in the tissue culture supernatant. Level of Biological Hazard 3 (BL-3) laboratory: All virus production, isolation and infection, tissue culture of HIV-1 infected cells, P24 antigen containing supernatant to harvest antigen P24 ELISA capture, was performed at the Hebrew University BL-3 facility, Hadassah Medical School and They agreed with the bio security practices established by N1H and CDC (USA). Flow cytometry: A FACSort cell sorter (Becton &Dickinson, San Jose, CA, USA) was used to (i) determine the percentage of CD4 positive CEM and batches of sup-Tl cells before infection with HIV-1 to ensure the same degree of infection in each experiment; and (ii) detect T cells harboring FITC-conjugated peptides derived from natural casein in their cytoplasm and nucleus. C02 incubator: For HIV-1 viral culture production cells, cells and viruses pre-treated with peptides derived from natural casein and cells that were further incubated with HIV-1, were all kept in the humidified CO 2 incubator during the duration of the experiment. HIV infection of human cultured COA cells: For longer incubations, cells were preincubated (CEM, Sup-Tl) with several increased concentrations of peptides derived from natural casein (50-1000 pg per ml) or casein-derived peptides (10- 500 pg per mi) for 24 (for synthetic and natural peptides) and 48 (only for natural peptides) hours and HIV-1IIIB (45 pg per ml final concentration) was added to each well after this. For the shorter incubations (3 hours), HIV-1IIIB was pre-incubated with the peptides for 3 hours and then added to the cells (5000 cells / well) in tissue culture plates. The cultures were IF (Infected, cells cultured with HIV-1 and without peptides), FIU (Uninfected, cells grown without HIV-1 and without peptides) and FIU + Ch (Not infected + peptides derived from natural casein, cells cultured in the presence of peptides derived from natural casein {.50-1000 pg per ml}.) to test the effect of the peptides derived from natural casein and synthetic peptides derived from casein in viability and cell growth. The cells were counted for viability and proliferation rate on day 7, 10 and 14 after infection (the day of harvest of the culture supernatant of the P24 antigen). Supernatants of cell and tissue culture (media) were harvested and used immediately in 1/10 volume of 10% Triton X-100. These samples were further incubated at 37 ° C for 1 hour and maintained at -80 ° C until tested for the P2 antigen.

Confocal microscope. A Zeiss LSM 410 confocal laser scanning system coupled to the inverted TW Zeiss Axiovert 135M microscope, which uses the confocal laser scanning microscope technique, was used to detect the penetration of FITC-conjugated peptides into cells. T cells were incubated with FITC-conjugated peptides derived from natural casein in 5% C02, 95% air, incubator at 37 ° C, after which the cells were washed 3 times with phosphate buffered saline (PBS) ) to remove unbound FITC peptides. The cells were fixed with 3.8% formalin for 10 minutes, washed twice with PBS and resuspended in 50-100 μ? of PBS before seeing the cells under the microscope. The selected images of cells from different time points of incubation (15 minutes, 30 minutes, 1 hour, 1.5 hours and 3 hours) displaying several amounts of FITC peptides derived from natural casein in their cytoplasm and nucleus were stored in a unit. 3.5"Zip (230 MB) and processed for photographs using Photoshop software. [3H] -thymidine incorporation test To test the effect of natural casein-derived peptides on T cell proliferation, various concentrations of derived peptides of natural casein (10 mg / ml of existence in RPMI) were added to the Sup-Tl cell cultures in 96-well flat-bottom microwell plate (5000 cells / well) as described by HIV-1 infection in Sup-Tl cells The cells were counted and their viability was determined by exclusion of triptan blue dye. [3-H] -thymidine at each time point (3, 7, 10 and 14 days) for 18 hours (overnight) and harvested on glass fiber filters for radioactivity reading (Incorporation of [3-H] -thymidine in cellular DNA is proportional to the degree of cell proliferation). Toxicity of peptides derived from natural casein in normal transplanted and normal myeloablative mice and guinea pigs: Intramuscular or intravenous injections of up to 5,000 mg of peptides derived from natural casein per kg of animal were administered in a single dose, or in three doses normal animals. A variety of strains were used, including BALB / c, C3H / HeJ and non-obese Diabetic (NO) mice. The mice were either monitored for 10 months before sacrificing them and post-mortem examination (toxicity test) or observed for 200 days (survival classification). The guinea pigs received a single intramuscular injection of 20 mg of peptides derived from natural casein per animal. Fifteen days later they were sacrificed and examined by pathology. Leukocyte and platelet reconstitution in bone marrow transplant recipient mice: BALB / c mice were lethally sub-irradiated in a 70 cm skin source at a dose of 50 cGy per minute for a total of 600 cGy. The irradiated mice were reconstituted with syngeneic bone marrow as described above and injected intravenously 24 hours later with 1 mg per animal of peptides derived from natural casein, synthetic peptides derived from casein (13-26 amino acids, see Table 3 above), or albumin of human serum (controls), following a double-blind protocol. The leukocyte reconstitution was determined according to the cellular cut in peripheral blood collected at indicated intervals of 6 to 12 days post-treatment. Platelet reconstitution was determined by cell count in blood collected from the retro orbital plexus, in flasks containing EDTA, at intervals indicated from day 6 to day 15 after treatment. In a further series of experiments, the CBA mice were lethally irradiated (900 cGy), reconstituted with BM cells and treated with peptides derived from natural casein or human serum albumin as described above. Platelet reconstitution was evaluated as mentioned above. In a third series of experiments, mice were irradiated (800 cGy), reconstituted and injected intraperitoneally with 100 g of synthetic peptides derived from casein (peptides 3a and 4P, representing the first 6 and 12 amino acids of N-terminal casein aSl, respectively - see Table 3 above ) daily, on days 4, 5, 6 and 7 after the transplant. The platelet reconstitution was evaluated 10 and 12 days after the transplant. Reconstitution of recipient mice in bone marrow transplantation: C57B1 / 6 mice were lethally irradiated in a remote 70 cm skin source, dose of 50 cGy per minute, for a total of 900 cGy. Irradiated mice were reconstituted with syngeneic bone marrow cells from mice that were either treated one day prior to bone marrow harvest with 1 mg per animal of natural casein or saline-derived peptides (controls), following a double glare protocol. In one experiment, the survival of mice was verified for 18 days. In another experiment the mice were sacrificed after 8 days and colonization of the spleen was verified. Synthetic peptides derived from casein that significantly reduces cholesterol levels: The ability of casein-derived peptides to reduce cholesterol levels in 7-week-old female C57Bl / 6j mice was evaluated after ingesting an atherogenic diet. The mice were divided into groups of 8. A control group was fed a normal diet. A second control group was fed the modified diet of Thomas Hartroft containing cholate (#TD 88051: Teklad, Madison, WI) [Gerber, D.W. et al., Journal of Lipid Research, 42, 2001]. The remaining experimental groups were all fed the modified diet of Thomas Hartroft. After one week of diet, the serum cholesterol values increased significantly and the synthetic peptides derived from casein were injected intraperitoneally, 1 mg per mouse, followed by a second injection of 0.1 mg one week later. Blood cholesterol levels were determined according to the Roche Cholesterol Test based on Roeschlou & amp;; Allin (Roche, Inc., Germany). EXPERIMENTAL RESULTS Peptides derived natural casein: Originated the observation of curdled milk occasionally failed to support bacterial growth, a fragment of casein possessing bacteriocidal properties was isolated milk proteins (US Patent No. 3,764,670 to Katzirkatchalsky, et al. al.). Crude peptides derived natural casein proteolysis were prepared by acidic precipitation of the soluble fraction of casein proteolytic extract, dialysis and lyophilization. When tested for biological activity after extended storage, it was observed that this crude preparation, when lyophilized and stored at 4 ° C, remains active. { in vitro and in vivo) for at least 24 months. To identify the peptides contained in the natural caserne-derived peptides, the lyophilized crude preparation was fractionated using high performance liquid chromatography (HPLC), as described above. All lyophilized samples analyzed showed similar retention time profiles, with contents as described above. Thus, a major component of the crude peptides derived the natural casein preparation is the N-terminal fragment of casein ocSl. Peptides derived natural casein are non-toxic in rodents and humans: Extensive investigation of the short- and long-term effects of high doses of peptides derived natural casein in mice, rats, guinea pigs and human volunteers confirmed the absence of toxicity, teratogenicity or adverse side effects of the preparation. In a series of tests, single doses representing 7,000 times the estimated effective dose of natural casein-derived peptides were administered intramuscularly to mice. The examination of post-mortem pathology of the mice in 14 days post-treatment did not reveal toxic effects in internal organs or other abnormalities. Similar toxicity tests in guinea pigs revealed no abnormalities two weeks after 'single intramuscular doses of 20 mg of peptides derived natural casein. In another series of experiments, high doses of peptides derived natural casein administered to healthy mice had no effect on several hematological parameters measured two weeks later, including white blood cells (WBC), red blood cells (RBC), hemoglobin (HGB), electrolytes, glucose and others. A third series of experiments tested repeated high doses of 100 mg per kg of body weight in mice and rats for two weeks, without revealing allergic responses, cutaneous or anaphylactic delay and without pathological effects until post-mortem examination. When the natural casein-derived peptides were tested for their effect on the long-term survival of irradiated BALB / c and C3H / HeJ mice reconstituted with bone marrow, the survival of the treated mice (18 of 27 BALB / c and C3H / HeJ; 66%) clearly exceeded the survival rates of the controls treated with albumin (4 of 26 BALB / c and C3H / HeJ, 15%). Standard teratogeneicity tests [for details see, for example, Drug Safety in Pregnancy, Folb and Dakes, p. 336, Elsevier; Amsterdam, New York, Oxford (1990)] in mice treated with peptides derived natural casein revealed no effect of the peptides on any developed parameters. Similar to this lack of toxicity or side effects when tested in rodents, peptides derived natural casein were safe when administered to humans as well. The comparison of blood and urine samples seven healthy human volunteers before, during and 7 days after the intramuscular injection of peptides derived natural casein revealed no changes in any of the clinical parameters. No other negative effects were observed. In this way, the treatment of high and extended doses of rodents with peptides derived natural casein did not reveal apparent toxic effects., pathological, hypersensitivity, teratogenic, serological or any other negative effect. In addition, peptides derived from the administration of natural casein to irradiate mice, at risk of short and long-term complications, conferred a significant survival advantage over 200-300 days. These and the absence of any undesirable effects in healthy human volunteers receiving peptides derived from natural casein through injections clearly demonstrate the safety of the peptide in parenteral administration. Bone marrow reconstitution in transplanted recipient mice: When C57B1 / 6 mice were lethally irradiated and reconstituted with syngeneic bone marrow from mice that were either treated one day before bone marrow collection with 1 mg per animal peptides Natural or untreated casein derivatives, the survival of irradiated mice that received bone marrow from treated mice exceeded that of irradiated mice that received bone marrow from untreated mice (survival of irradiated mice that received bone marrow from treated mice was 15 between 18, 10 days after irradiation; while the survival of the irradiated mice that received bone marrow cells from control mice treated with saline was 4 out of 17, 10 days after irradiation). Spleens derived from irradiated mice that received bone marrow from treated mice included approximately two to three times as many colonies per spleen, when compared to spleens from irradiated mice that received bone marrow cells from control mice treated with saline (1 -5 colonies when compared to 0-3 colonies). Peptides derived from natural casein that stimulates lymphocyte proliferation: Natural killer (NK) and cytotoxic T cells are crucial in the ability of the immune system to protect against invasion by infectious pathogens and cancer cells, either by active cytoxicity and the secretion of immunoregulatory lymphokines. Immune compromise, such as in AIDS or following chemotherapy, results in weakened, abnormal cellular NK or T activity. When normal murine bone marrow cells from BALB / c and C57B1 / 6 mice were cultured in the presence of 100 pg per ml of natural casein-derived peptides, a clear increase in NK activity was observed in both effector cell ratio groups: objective . In addition, the comparison between the two groups revealed a clear dose response relationship. In the effector / target cell ratio 1:25 the NK activity average rose from 13.93% to 30.77% and in the effector / target cell ratio 1:50 the NK activity average rose from 13.68% to 44.05% (Figure 1). Similar experiments using pluripotent Human Peripheral Blood Cells from donors treated with the Granulocyte Colony Stimulating Factor demonstrated an even more significant concentration-dependent stimulation of target cell lysis by peptides derived from natural casein. In the first set of experiments (Figure 2a), NK activity was measured in blood samples taken from a patient and incubated at two effector cell: obj etivo ratios with increased peptides derived from natural casein concentration. Only 4% release of 35S was measured in the control untreated PBSC culture. Almost the same percentage of radioactivity (4%) was found in the lowest peptide concentration (5) ig per ml). However, at the highest peptide concentrations, in the range of 10 pg per ml of up to 100 pg per ml, a release of 10.8-14.9% was measured by 35 S effector cell: ob ective 100: 1 ratios. 8.3-14.5% of 35S for cell and fector ratios: 50: 1 objective (Figure 2a). When PBS cells from normal (patient 1) and affected human donors (patients 2-6) were incubated with increased concentrations of natural casein-derived peptides, a significant improvement in NK cell activity of affected patients could be measured. Thus, while peptides derived from natural casein had a minimal effect of NK activity from normal patients (increased from 13-15% 35S release, patient 1), PBS cells from breast cancer and patients with Lymphoma Non -Hodgkins (patients 3 and 4, for example) exhibited dramatic dose-dependent increases in NK activity (3.5 to 10.8% of 35S, 12.2 to 19.1% of 3jS, respectively) (Figure 2b) Peptides derived from natural casein that stimulates prolif ration of CD56 surface antigen positive (NK) cells: In other series of Peripheral Blood Pluripotential Cell (PBSC) experiments of 5 human donors receiving GCSF treatment were incubated with peptides derived from natural casein for 10, 14 or 28 days, then they were evaluated for the presence of the antigen CD 56. A dramatic increase was observed sometimes in the detection of antigen CD 56 in the cells treated with peptide of all donors except one (patient 1). A representative response is described in Figure 3a: After 10 days of incubation with or without peptides derived from natural casein, the presence of positive (NK) cells with CD56 surface antigen was detected by direct immunofluorescent staining. Overall, incubation with peptides derived from natural casein increased the average percentage of cells stained positively for CD56 from 0.64% in the control group to 2.0% after treatment (Figure 3a). Peptides derived from natural casein that stimulates the proliferation of CD3 surface antigen (T) positive cells: The effect of natural casein-derived peptides on the proliferation of CD3 surface antigen (T) positive cells in PBS cells of 5 subjects was evaluated by direct immunofluorescence. In all, except one patient (patient 4), 14 days of incubation with peptides derived from natural casein the proliferation of T cell significantly increased, up to more than 5 times in some. Taken together, the average percentage of cells stained positively for CD3 increased from 19.45% in the control group to 35.54% in the treated group (Figure 3b).

Peptides derived from natural casein that stimulates the proliferation of positive cells (NK / T cells) CD56 and CD3: In a further experiment the PBSC of 7 patients were incubated with peptides derived from natural casein for 28 days, and the effect on the proliferation of NK / T cells (positive surface antigen CD56 and CD3) was detected by immunofluorescence. Incubation with peptides derived from natural casein stimulated T cell proliferation greater than 5 times in some cases (patient 6), while the average percentage of CD3 (T) positive cells increased from 2.08% in the control group to 6.49. % in the treated group. The number of CD56 and CD3 surface antigen positive (NK / T) cells increased from 1.1¾ in the control to 4.3% in the treated group (Figure 3c). Thus, peptides derived from natural casein stimulated the proliferation of both T lymphocytes and natural killer cells of normal murine and human blood cell progenitors. Significantly, the greatest immune stimulating effect of the natural casein-derived peptides was observed in human donors having initially low T cell and NK lev(Figures 3a-c). Synthetic peptides derived from casein that stimulates human lymphocyte proliferation in vitro: When synthetic peptides derived from casein representing the first 3 to 26 casein residues aSl were incubated with human PBSC cells from healthy patients and with cancer (see below), a significant increase in NK cell activity was observed. The target cell lysis was higher (3 to more than 5 times that of the controls) in PBSC cultures of patients with Non-Hodgkin's Lymphoma and Breast Cancer after two days of incubation with as little as 10 g per ml of peptides containing the first 9 or more casein residues aSl (Figure 4). Under identical conditions, none of the peptides tested had a significant effect on NK activity in PBSC cultures of healthy human donors. Thus, even low concentrations of peptides containing the first 10 residues of the N-terminal sequence of casein aSl are capable of selectively stimulating lymphocyte proliferation in vitro in cells of cancer patients. Similar stimulation of NK cell activity was observed when PBS cells from human donors with hematopoietic disease were incubated with synthetic peptides derived from casein representing the first 3 amino acid residues of casein aSl. Incubation of the PBS cells with the peptides increased the objective cell lysis from 2 to more than 8 times that of the treated controls. Of the 5 patients tested, three (3) responded to 25 ug / ml of peptide concentration, one (1) responded to 100 g / ml peptide concentration and one (1) to 250 μ9 / p? 1. Three out of five (5) patients responded to 25 yg / ml. No significant effect on NK activity in PBSC cultures of healthy human donors treated with the synthetic peptide representing the first 3 amino acids of casein Sl was observed, confirming the selective nature of the human lymphocyte-stimulating properties of casein-derived peptides. Stimulation of hematopoiesis in human blood cell progenitors: Differentiated blood cell progenitors in a variety of blood cells: macrophages, monocytes, granulocytes, lymphocytes, erythrocytes and megakaryocytes. Progenitor cells are abundant in the bone marrow, but are also found in peripheral blood after the treatment of Granulocyte Colony Stimulating Factor (PBSC cells) and recent Cord Blood. When increased concentrations (50-600 μg per ml) of peptides derived from natural casein were added to cultures of human bone marrow, PBSC and cord blood, an increase in cell proliferation was observed, as measured by the incorporation of [3H] ] -thymidine (Figures 5a-5c). The proliferation of human PBSC was most effected by 300 pg per ml (Figure 5a) after 15 days in the culture. An even greater effect was observed for cord blood cells in culture (3 to 4 times increased in the incorporation of [3 H-thymidine] after 14 days of incubation (but not after 7 days) with peptides - casein derivatives natural (600 μg per ml, Figure 5c). Human bone marrow cells cultured from three of four oonators also reacted strongly (3 to 5 times increased at incorporation) to peptides derived from natural casein (300. Ig per ml) after 21 days of incubation (Figure 5b) ). Thus, peptides derived from natural casein that stimulate the proliferation of human blood cell progenitors from bone marrow as well as other sources. Interestingly, the incubation of cultured human K562 cell lines (Chronic Myeloid Leukemia) and Colon (colon cancer) with high concentrations (up to 500 μg per ml) of peptides derived from natural casein under similar conditions had no effect on the incorporation of [JH] -thymidine. Thus, peptides derived from natural casein that stimulate the proliferation of human blood cell progenitors but not cancer cell growth in vitro. Stimulation of megakaryocytopoiesis by casein-derived peptides: Peptides derived from natural casein that stimulates megakaryocyte progenitor proliferation in cultured murine bone marrow cells: The development of multinucleated megakaryocytes in the bone marrow of primitive pluripotent cells, mature to giant cells and leads to hundreds of thrombocytes per megakaryocyte. Thrombocytes are crucial for clot formation and thrombocytopenia is a major concern in myeloablative conditions (after chemotherapy or radiotherapy). Primary bone marrow cell cultures can be induced to form CFU-GM (Granulocyte and. Monocyte) colonies and CFU-GEMM colonies (Granulocyte, Erythroid, Macrophage and megakaryocyte), which contain additional blood cell types. Colony counts reflect expansion of specific progenitors, cell numbers reflect proportions of proliferation and reflected differential cell counts, whose specific cell lineages have developed [Patenkin, D. et al. (1990), Mol. Cel. Biol. 10, 6046-50]. In the cultured murine bone marrow cells incubated with erythropoietin and IL-3, the addition of 25 μg per ml of natural casein-derived peptides for 8 days increased the number of two CFU-GEMMs and half over the controls, stimulating a three-fold increase in relative cell numbers per colony in CFU-GEMM. In a similar series of experiments, the addition of peptides derived from natural casein to bone marrow cells incubated with erythropoietin and conditioned medium (see Materials and Experimental Methods) stimulated a concentration-dependent increase in the percentage of early and late megakaryocytes (15% of megakaryocytes without peptides, at 50% with 500 pg per ml of peptides derived from natural casein). Thus, 8 days of treatment with peptides derived from natural casein stimulated a significant increase in the formation and development of megakaryocyte in primary bone marrow cultures. Synthetic peptides derived from casein that stimulates megakaryocyte progenitor proliferation in cultured marine bone marrow cells: Similar to the above and under similar experimental conditions, synthetic peptides derived from casein representing the first 5 to 24 amino acids of casein «SI increase the percentage of early and late megakaryocytes of 15% without the synthetic peptide to more than 40% with 25 μg per ml of synthetic peptides (Figure 7). Thus, 8 days of treatment with peptides derived from synthetic casein representing the first 5, 6, 11, 12, 17, 18, 19, 20, 21 and 24 amino acids stimulate a significant increase in megacariocir formation and development. in primary murine bone marrow culture. The still appreciable stimulation was observed, even softer with the other synthetic peptides derived from casein. Peptides derived from natural casein that stimulates megakaryocytosis in cultured human bone marrow cells: When 100 pg per ml of natural casein-derived peptides were added under conditions similar to human bone marrow cell cultures from healthy donors, CFU-GM colony formation was increased with or without additional stimulation factors (GM-CSF, CM). Peptides derived from natural casein also stimulate colonies that form erythroid cells in the presence of erit ropoyet ina. F, 1 treatment of human bone marrow cells with thrombopoietin (TPO) stimulates the formation of megakaryocyte colony (MK). In addition to 300 pg per ml of natural casein-derived peptides to cells treated with TPO stimulates more than a two-fold increase (16 colonies per 2 x 10 5 cells without peptides, 35 colonies per 2 x 10 5 with peptides derived from natural casein) in proliferation of MK colony. In the presence of additional nematodetic factors, such as serum hSCF and human AB-3 IL, from erythropoietin, 14 days of incubation with peptides derived from natural casein stimulated an almost three-fold increase in CFU-GEMM colonies of bone marrow cells human (158 colonies with 500 pg per ml of peptides derived from natural casein, 68 colonies with the factors alone), but had a smaller effect (one and a half times) in the formation of CFU-GEMM of the cultured blood cord. The relative cell number of counts in the human bone marrow and the blood cord colonies reflect megakaryocyte cell proliferation in response to the addition of 25 ug per ml of natural casein-derived peptides (see Table shown in Figure 6). Thus, incubation of cultured primary human bone marrow and cord blood cells with peptides derived from natural casein stimulates the development and proliferation of committed megakaryocyte and erythroid cell colonies. Significantly, the synergy observed between TPO and peptides derived from natural casein to stimulate megakaryocytopoiesis indicates a likely role for this potent hematopoietic growth factor in the mechanism of peptides derived from stimulating properties of casein, and also suggests the likelihood of similar increase in a weight range of effects mediated by TPO by peptides derived from natural casein. Peptides derived from natural casein and synthetic peptides derived from natural casein that potentiates the effect of Erythropoietin (EPO) on cultured human bone marrow cells: The effect of synthetic peptides and natural casein derivatives on erythroid cell proliferation on bone marrow cells Human cultivation was evaluated under the same conditions indicated above for megakaryocytopoiesis. When added in the presence of EPO, 50-300 pg / ml of peptides derived from natural casein, or 100 μ? / P ?? of Synthetic peptides derived from casein (F, Table 3, SEQ ID NO: 18) stimulated at one and a half (synthetic peptide) to four times the proliferation of erythroid cell precursors (appearance of BFU-E colonies) compared to bone marrow cells treated with EPO alone. Thus, peptides derived from natural casein and their synthetic derivatives act to potentiate the erythropoietic stimulation effects of EPO, and as such can be used to augment a wide range of clinically important EPO-mediated effects. synthetic peptides derived from casein eessttiimmuullaa ooff tthhee pprroolliiffeerraacciióónn ccéélluullaass DDeennddrrííttiiccaass iinn CCFFUU - GGEEMMMM ooff tthhee mmuurriinnoo :: ssee eevvaalluuaarroonn eeffeeccttooss ooff tthhee ppééppttiiddooss SSiinnttééttiiccooss ddeerriivvaaddooss iinn tthhee ccaasseeíínnaa pprroolliiffeerraacciióónn ooff tthhee ccéélluullaa ddeennddrrííttiiccaa iinn ccéélluullaass mméédduullaa óósseeaa pprriimmaarriiaa ooff tthhee mmuurriinnoo bbaajoo mmiissmmaass ccoonnddiicciioonneess ddeelliinneeaaddaass ppoorr llaa eessttiimmuullaacciiónn ddee The synthetic peptides derived from casein represent the first: 2, 3, 5, 6, 7, 9, 11, 12, 16, 23, 24 and 26 amino acids of casein «SI stimulate the proliferation of dendritic cells, from 2.2% and up to 23% of the total cells compared with 0.1-0.2% dendritic cells in the samples of cells incubated without Synthetic peptides derived from casein (Figure 7). Synthetic peptides derived from casein that stimulates cell proliferation in Plasma in murine CFU-GEMM: The effect of Synthetic peptides derived from casein on plasma cell proliferation in primary murine bone marrow cells was demonstrated under the same delineated conditions for the stimulation of megakaryocytes. The synthetic peptides derived from casein representing the first: 2, 3, 5, 7, 11, 16, 17, 18, 19, 20, 21, 22, 23 and 24 and 26 amino acids of casein ocSl, significantly stimulate the proliferation of cells in plasma, of 1.5% and up to 12.3% of the total cell count, compared with 0.3% of the total without Synthetic peptides derived from casein (Figure 7). Synthetic peptides derived from casein that stimulate macrophage proliferation in CFU-GEMM: The effect of Synthetic peptides derived from casein on macrophage proliferation was demonstrated in murine primary bone marrow cells under the same conditions delineated by megakaryocyte stimulation. The incubation of cells with synthetic peptides derived from casein representing the first: 7, 9, 16 and 23 amino acids of casein ocSl significantly stimulate the proliferation of macrophages, from approximately 17% of the total cell count in controls, to almost 30% of the total in cells incubated with Synthetic peptides derived from casein (Figure 7). Synthetic peptides derived from casein that stimulates the proliferation of red blood cells in CFU-GEMM: The effect of synthetic peptides derived from casein proliferation of red blood cells in murine primary bone marrow cells was demonstrated under the same conditions delineated by the stimulation of megakaryocytes. Incubation of cells with casein-derived Synthetic peptides representing the first 4 amino acids of the N-terminal casein Sl significantly stimulates red blood cell proliferation, from 53% of the total cell count in controls, to 71% of the total in cells incubated with the synthetic peptide derived from casein (Figure 7). Synthetic peptides derived from casein that stimulates polymorphonuclear cell (PMN) proliferation in CFÜ-GEMM: The effect of casein-derived synthetic peptides on the proliferation of polymorphonuclear cells (PMN) in primary murine bone marrow cells under the same conditions was demonstrated delineated conditions for the stimulation of megacaricitos. Incubation of cells with synthetic peptides derived from casein representing the first: 3, 6, 7, 9, 16 and more, up to and including 26 amino acids of casein aSl significantly stimulates the proliferation of PMN, from 1.6% of total cell count in non-incubated controls, between 2.9% and 14.9% of the total in cells incubated with Synthetic peptides derived from casein (Figure 7). Peptides derived from natural casein that stimulate haematopoiesis in vivo after irradiation and bone marrow transplantation: Myeloablative therapy can lead to life-threatening reduction in thrombocytes and leukocytes, which may persist despite the administration of blood cells and blood factors. increase. The following demonstrates the effect of peptides derived from natural casein after irradiation and bone marrow transplantation. Peptides derived from natural casein that improves the reconstitution of leukocyte and plaque after bone marrow transplantation in mice: When BALB / c mice (n = 12) reconstituted with bone marrow minimally irradiated sub-lethally 600 cGy) received 1 mg per mouse of natural casein-derived peptides through intravenous injection one day after reconstitution of bone marrow cell, significant increases in peripheral white blood cell counts were observed on days 4, 6 and 15 after treatment, compared to controls receiving human serum albumin (Figure 8). Platelet counts in the peripheral blood of mice irradiated with bone marrow and treated with control were likewise reduced up to 8 days after treatment. However, on the thirteenth day a clear advantage was observed for the mice treated with peptides derived from natural casein, which shows a significant increase over the controls treated with human serum albumin which became even more pronounced by day 15 (Figure 9). ). In this way, the peptides derived from natural casein that improves the reconstitution of leukocyte and platelet after transplantation with limiting numbers of bone marrow cells. It is expected that this effect will also increase in the reconstitution with optimal numbers instead of bone marrow cell limitations. Synthetic peptides derived from casein that improve the reconstitution of leukocyte after transplantation of bone marrow syngeneic in mice: When BALB / c mice (n = 5 by synthetic peptide, n = 10 in the control group) reconstituted with bone marrow minimally, irradiated sub-lethally (600 cGy) received 1 mg per mouse of synthetic peptides (13-26 amino acids in length, see Table 3) casein derivatives through an intraperitoneal injection one day after bone marrow transplantation, a clear improvement was observed reconstitution of leukocyte. Significant increases in peripheral white blood cell counts over a period of 10 to 14 days were observed with peptides that are 15 (day 10: 1.72 x 106 cells per ml).; day 12: 6.54 x 106 cells per ml) and 17 (day 10: 2.74 cells x 106 per ml, day 12: 5.20 x 106 cells per ml) amino acids (see Table 3), compared to controls that receive human serum albumin ( day 10: 1.67 x 106 cells per ml, day 12: 4.64 x 106 cells per ml). In this way, the synthetic peptides derived from casein that improves the reconstitution of leukocyte after transplantation with limiting numbers of bone marrow cells. Synthetic peptides derived from casein that improve platelet reconstitution after bone marrow transplantation in mice: To confirm the. The observed ability of synthetic peptides derived from casein to enhance megakaryocyte proliferation in hematopoietic pluripotent cell cultures (see Figures 6 and 7), the effects of peptides on platelet reconstitution in vivo were investigated. When mice (n = 5 per group) reconstituted with bone marrow minimally, lethally irradiated (800 cGy), they received 100 pg per mouse of synthetic 4P and 3a peptides (6 and 12 amino acids in length, respectively - see Table 3) in 4 intraperitoneal injections daily (4-7 days post-transplant), a clear improvement of platelet reconstitution was observed over untreated controls. Significant increases in platelet counts at 10 and 12 days after transplantation were observed by both peptides. Treatment with 4P peptide increased the counts by 29% (872 X 103 / ml compared with 676 X 103 / ml in the control group) at 12 days after transplantation while treatment with peptide 3a increased the counts by up to 35.5% ( 229 X 103 / ml compared with 169 X 103 / ml in the control group, in 10 days, and up to 13.5¾ (622 X lCT / ml compared with 461 X 103 / ml in the control group) in 12 days after transplantation. Thus, the same synthetic peptides derived from casein that improves the proliferation of in vitro megakaryocyte and platelet reconstitution after bone marrow transplantation in vivo Peptides derived from natural casein that inhibits in vitro infection of lymphocytic T cell lines by virus. HIV-1 Penetration of peptides derived from natural casein in lymphocyte T cells: To investigate the mechanisms of immune stimulatory and antiviral effects, derived from natural casein, human T cells were treated s cultured with CE and Sup-Tl susceptible with peptides derived from natural casein before in vitro infection with HIV-1 virus. Fluorescent microscopy revealed that FITC-conjugated peptides derived from natural casein (100 pg per ml) penetrated the Sup-Tl cells when incubated with them as described above (Figures 10A-f). A small amount of label was observed in the cytoplasm of the cells after 15 minutes (Figures 10a-b). In 30 minutes (Figures lOc-d) more mark was observed in the cytoplasm, with limited nuclear incorporation. From 1 hour of incubation and in (Figures lOe-f), FITC-labeled peptides derived from natural casein were observed in the cytoplasm, but for the most part they were concentrated in the cell nucleus. Analysis of the Sup-Tl cells by flow cytometry confirmed the increased incorporation of the labeled peptides derived from natural casein at 5 minutes after incubation. Peptides derived from natural casein that improves the proliferation of human lymphocytes: The presence of peptides derived from natural casein in the culture medium resulted in the Sup-Tl cell counts increased during a period of 14 days. Larger increases in cell number were observed in 1 day for 50 μg per ml of peptides derived from natural casein (42%) for 1000 \ ig in 10 days (30%) and for 600 μ? (32%) in 14 days of incubation (data not shown). The measurement of [3H] -thymidine incorporation by the cultured cells, which provides a proliferation index, reflected the increase in cell number, with the most significant effect observed by 600 μg per ml of peptides derived from natural casein on day 10 and 50 per ml on day 14 (Figure 11). Proliferation rates reduced by 14 days probably reflect cellular overgrowth and nutrient reduction. Synthetic peptides derived from casein that enhance the proliferation of human lymphocytes: The presence of synthetic peptides derived from casein (all the peptides listed in Table 3) in the culture medium resulted in Sup-Tl cell counts increased over a period of 10 days. days. The increase was similar for all synthetic peptides. Larger increases in the number of lymphocyte cells were observed in infected cells for 250 μg and 500 μg per ml of peptide representing the first 9 amino acids (80% and 33%, respectively (data not shown). Peptides derived from natural casein that inhibit HIV-1 infection in human lymphocyte cells: The susceptible CEM lymphocyte cells pre-treated with peptides derived from natural casein (50-1000 μq per ml) 24 or 48 hours before incubation with HIV-1, or exposed to HIV-1 pre-treated 3 hours with natural casein peptides, exhibited improved cell proliferation and reduced levels of viral infection compared to untreated controls. Cell counts and HIV-1 34P antigen assay in 15 days after infection revealed 100% inhibition of viral infection after 3 hours of virus incubation with 600-1000 μs per ml of peptides derived from natural casein and 98% and 99% inhibition after 24 hours of incubation of cells with 50 and 600 pg per ml of peptides, respectively (comparing cell numbers with uninfected UIF controls). No longer incubation times were found to be more effective (Figure 12). Although the increased concentrations of peptides derived from natural casein enhances cell proliferation at 3 and 24 hours after infection, viral infection is more significantly inhibited in these faster growing cultures. An even more dramatic improvement of cell proliferation and inhibition of HIV-1 infection was observed in Sup-Tl cells pre-treated with peptides derived from natural casein before infection by HIV-1 (average inhibition of viral infection of 96.71, 88.7% and 95.7% during 3 hours of virus pre-treatment, and 24 hours and 48 hours of pre-treatment of cells, respectively) (not shown). Thus, peptides derived from natural casein penetrate human cultured lymphocyte cells and their nucleus, improve cell growth, and significantly reduce the susceptibility of CD4 cells to HIV-1 infection. As such, peptides derived from natural casein are expected to have been useful both for preventing HIV infection and for post-infection treatment of patients infected with HIV and AIDS. Synthetic peptides derived from casein. qrue inhibit HIV-1 infection in human lymphocyte cells: The ability of synthetic peptides derived from casein to inhibit HIV-1 infection in human lymphocyte cells was demonstrated using CEM lymphocyte cells under the same conditions outlined above. Three hours of pre-treatment of CEM lymphocytes with the synthetic peptide derived from casein representing the first 3 amino acids of casein aSl conferred a significant degree of resistance to infection after incubation with HIV-1. The cell numbers of lymphocytes were 1.29 x 106 (100 pg per ml) and 2.01 x 10G (500 pg per ml) in the treated cells when compared to the infected HIV-1 control of 1.06 x 1 O6 (Figure 13). Levels of HIV-1 infection in the same cells, measured by the HIV-P "antigen assay at 7 days after infection, were significantly reduced in peptide-treated cells (0.17 and 0.14 ng P 4 of Antigen). / ml with 100 pg / ml and 500 pg / ml respectively), when compared with untreated controls (C.52 p P24 Ag / ml). Likewise, significant inhibition of HIV-1 infection was observed in EC cells exposed to pre-treated viruses (3 hours) with synthetic casein which represents the first 5 amino acids of casein aSl. Cell counts in the cultures incubated with 10 and 25 pg of 3P peptide per ml were 1.17 x 106 and 1.26 x 106, respectively, when compared to the infected HIV-1 control of 1.06 x 106. The HIV-antigen test P24 in 7 days after infection, revealed significant reduction in levels of HIV-1 infection in treated cultures (0.26 and 0.18 ng P24 Ag per ml per 10 and 25 pg per ml respectively, when compared to the control of 0.52 ng Pi4 Ag for me). Also, 3 hours of pre-incubation of the virus with the synthetic peptide derived from casein 4P, which represents the first 6 amino acids of casein aSl had a significant effect on the susceptibility of CEM lymphocyte cells to infection with HIV-1. The cell numbers were most affected at concentrations of 25 and 250 g per ml (1.26 x 10fa and 1.59 x 106 respectively, when compared to the infected control value of 1.06 x 106). The HIV-P24 antigen test in 7 days after infection revealed a dose-dependent reduction in viral particles when compared to infected, untreated control cultures (Figure 13). Thus, the protection of HIV-1 infection produced 1-infocyte cells by the casein-derived peptides representing as few as the first five N-terminal amino acids of casein aSl. Peptides derived from casein to prevent the development of glucosuria in non-obese diabetic (NOD) mice: Non-Obese Diabetic Mice (NOD) spontaneously developed Juvenile Diabetes (Type I, IDDM), an autoimmune condition that causes inflammation of pancreatic β cells and They ended in illness and death. NOD mice are extremely susceptible females, showing eevviiddeenncciiaa ooff ooff iinnvvaassiióónn mmaaccrróóffaaggoo PPoolliiccyy mmaattrriizz * ddee ppaannccrreeááttiiccaa iisslleettaa ttaann tteemmpprraannoo ccoorrrr..oo 55 sseemmaannaass ddee eeddaadd .. UUnnaa iinnyyeecccciióónn uunnaa oo ddooss vveecceess sseemmaannaallmmeennttee ddee 110000 gg ddee ppééppttiiddooss ddeerriivvaaddooss ddee ccaasseerínnaa nnaattuurraall dduurraannttee 55 sseemmaannaass ((55 oo 55 iinnyyeecccciioonneess ttoottaalleess 1100)) ssee eeffeeccttiivvaammeennttee ccoommpplleettaarroonn ttoo tthhee eevviittaarr wwiitthh tthhee gglluuccoossuurriiaa aassoocciiaaddaa iinniicciioo yy ooff tthhee ccuurrssoo eennffeerrmmeeddaadd .. PPoorr ddiíaass 220000 110000 ,, ooff tthhee %% rraattoonneess ccoonnttrrooll ddooeess ttrraattaaddooss ((nn == 55 )) hhaabbííaann lllleeggaaddoo aa sseerr ddiiaabbééttiiccooss ,, yy ssuubbsseeccuueenntteemmeennttee mmuurriieerroonn ,, mmiieennttrraass llooss rraattoo nneess ttrraattaaddooss 1 100 ((nn == 55)) ppeerrmmaanneecciieerroonn 110000 eeuugglliiccéémmiiccooss %% ,, iinn ttooddooss aaúúnn ssoobbrreevviivviieerroonn ddííaass 336655 ((FFiigguurraa 1144)) .. ooff tthhee ppééppttiiddooss TThhiiss MMOODDEE ,, ooff ddeerriivvaaddooss ccaasseeíínnaa nnaattuurraall eeffeeccttiivvaammeennttee pprrootteeggiieerroonn aa tthhee rraattoonneess ggeennééttiiccaammeennttee ssuusscceeppttiibblleess ccoonnttrraa ooff tthhee aattaaqquuee tthhiiss ccoonnddiicciióónn iinnffllaammaattoorriiaa aauuttoommmmuunnee .. 1155 PPééppttiiddooss ccaasseeíínnaa ttoo tthhee ssiinnttééttiiccooss ddeerriivvaaddooss eevviittaann development glucosuria in nonobese diabetic mice (NOD): preventive effect of Synthetic peptides derived from casein on the development of glucosuria in NOD mice 20 showed under the same conditions outlined above, except that the mice were injected only once a week for five (5) weeks with 100 μq d e Synthetic peptides derived from casein. The results of these experiments are presented in Table 5 below: Table 4 The effect of synthetic peptides in IDDM in NOD mice Negative 205 197 Negative 201 211 A 2/5 Negative 134 164 Negative 105 107 B 2/5 Negative 130 117 Negative 130 97 D 2/5 Negative 99 108 Negative 130 136 I 2/5 Negative 324 not tested Negative 124 138 J 3 / 5 Negative 166 not tested Negative 193 not tested Negative 186 not tested K 2/5 Negative 116 143 Negative 443 not tested Chay-13 2/5 Negative 123 130 Negative 1 1 1 11 1 Chay-13 2/5 Negative 128 116 Negative 1 13 125 Control 0/5 Blood was drawn from the paraorbital plexus at 0 minutes and 60 minutes after the intraperitoneal injection of glucose 1 g / kg body weight. Plasma glucose levels were determined with a Glucose Analyzer 2 (Beckman Instruments, Fullerton, CA) and expressed as mmoles / L. * Healthy and good = Sugar not detected in urine Glucosuria = > 1000 mg / dL. IPGTT performed with 6 healthy female control mice: 0 minutes - 11C mmoles / L; 60 minutes - 106 mmol / L of blood glucose. The synthetic peptides derived from casein representing the first 9 (X), 11 (2a) and 12 (3a) amino acids and the highest chain length of casein Sl, were highly effective in preventing glucosuria associated with the beginning and course of the disease. The effect of treatment with synthetic peptides derived from casein was evaluated after 25 weeks. At that time, all 5 mice in the untreated control group (n = 5) had become diabetic, as indicated by the presence of frank glycosuria (> 1000 mg / dl) (Table 4). No glucosuria was detected in three of the five (3/5) NOD mice treated with the synthetic peptide representing the first nine (9) amino acids of the N-terminal casein Sl. Of the group injected with the synthetic peptide of eleven (11) N-terminal amino acids of casein aSl, no glycosuria was detected in four out of five (4/5) of the NOD mice. In the groups of mice treated with peptide in which glucosuria was detected, the attack was generally significantly delayed (by 3-5 weeks) in relation to the attack of glucosuria in untreated controls (data not shown), indicating a clearly protective effect of the Peptides even when they are incomplete. The protective effects of shorter synthetic peptides derived from casein have also been studied in NOD mice. In a further series of experiments similar to those mentioned above, the administration of peptides representing the first 3 (1P) and 4 (2P) N-terminal amino acids of casein aSl effectively prevents the attack of glucosuria in the treated mice (evaluated in the week 16), while untreated controls had become all diabetic (100% glycosuria) (data not shown). Glucose test tolerance (IPGT) performed after 25 weeks with healthy and good NOD mice, of the group injected with the synthetic casein derived from the peptide of the first 9 amino acids, showed no evidence of abnormal glucose metabolism (normal glycemic values of pre charge and 60 minutes post glucose). In the group treated with synthetic peptide derived from casein representing the first 11 amino acids of the N-terminus of casein aSl (2a), subtracting plasma glucose levels rose a little more in two of the five mice (215 and 159 mmoles / L), and remained gently elevated at (183 and 204 mmoles / L) 60 minutes after loading, indicating mild diabetic tendencies. The other two mice remained within the normal glycemic range throughout the entire trial (Table 4). In general, the normal results of the IPGTT reflected the absence of glucosuria in mice treated with peptide, survivors, healthy (Table 4). Thus, synthetic peptides representing only a few amino acids of the N-terminus of casein aSl, as well as peptides derived from native casein dramatically reduced the susceptibility of NOD mice genetically predisposed to attack of diabetic autoimmune disease. Peptides derived from synthetic casein that significantly reduces blood levels of Total Cholesterol (TC), Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL): The intraperitoneal administration of synthetic peptides derived from casein caused a significant reduction in the values of the blood lipid (HDL, LDL and TC) in experimentally hypercholesterolemic mice. After a week of the atherogenic Thomas Hartroft diet, the blood cholesterol levels of the mice had been raised to levels of 318 mg / dL. One week after treatment with 1 mg of synthetic peptides derived from casein per mouse, the group treated with synthetic peptides containing casein representing the first 5 (3P) and 11 (2a) amino acids of casein aSl, had significantly reduced the values TC, HDL and LDL to those of the control group [TC: 308 and 279 mg / dl respectively; HDL: 42.5 mg / dl and 41 mg / dl respectively and LDL: 247 mg / dl and 221 mg / dl respectively when compared with 393 mg / dl (TC), 54.5 mg / dl (HDL) and 326 mg / dl ( LDL) in the hypercholesterole / hyperlipidemic control group induced with diet] (Figure 15). Thus, synthetic peptides representing the first few N-terminal amino acids of casein aSl effectively reduce hyperlipidemia and hypercholesterolemia induced experimentally within one week after a single intraperitoneal administration. Clinical tests with peptides derived from natural casein: Patients who received intramuscular injections of 50 mg of peptides derived from natural casein, each divided into three deposits, as indicated. Peptides derived from natural casein that stimulates hematopoiesis in cancer patients: The hematological profiles of six cancer patients who had received and were receiving chemotherapy were examined before and after the administration of peptides derived from natural casein, as indicated. Special attention was paid to changes in the values of Platelet (PLT), Leukocyte (WBC), Erythrocyte (RBC) and Hemoglobin (HGB), which represent thrombocytopoiesis, leukocytopoiesis and erythrocytopoiesis, respectively. G.T., (Female Patient, Patient 1): The patient had ovarian cancer, underwent a hysterectomy followed by chemotherapy. This received two intramuscular injections of peptides derived from natural casein in two and then two and a half months after the operation. No chemotherapy was administered between the first and second administrations of peptides derived from natural casein. Blood tests 6 days after the first injection, 7 and 13 days after the second injection reflect a considerable increase in platelet and WBC components, also as RBC increases (Figure 16.} EC, (Female Patient, Patient 2): The patient underwent a radical mastectomy for lobular carcinoma in 1983, and six years later he suffered from gastric metastasis Three days before the start of chemotherapy, he received an intramuscular injection (in three deposits) of casein-derived peptides natural by injection, and a second 10 days after chemotherapy, although blood counts of 10 and 16 days after chemotherapy indicated an attenuation in the depressive hematological profile usually found after chemotherapy, the most significant effects of casein-derived peptides natural were observed 3 days after the first injection, before chemotherapy (Figure 16). ES, (Female Patient, Patient 3): The patient was suffering from dissemination of extended metastasis from a breast carcinoma first discovered in 1987. Two years later, she received a first intramuscular injection of peptides derived from natural casein, and a second one. days after. No additional therapy was administered during this period. Blood tests indicated a strong improvement of PLT seven days after the first treatment and a significant increase in BC and WBC seven days after the second treatment (Figure 16). J.R., (Female Patient, Patient 4): The patient's diagnosis is breast cancer with bone metastasis. She received an intramuscular injection of natural casein-derived peptides, 8 days before the start of chemotherapy, and another 14 days later. The most significant effect is clearly seen in the rapid return of WBC levels after depression induced by chemotherapy (Figure 16). D. M., (Female patient, Patient 5). The patient suffers from liver cancer with extended metastatic dissemination. She received three intramuscular injections of peptides derived from natural casein at 10, 8 and 6 days before receiving chemotherapy. A second series of injections was started 10, 12 and 14 days after treatment by chemotherapy. Although a significant effect on the hematological profile is observed following the first series of injections and before chemotherapy, the most dramatic improvements were seen in the rapid return of depressive post-chemotherapy values to normalize cell counts after the second series of peptides derived from natural casein injections (Figure 16). Thus, the administration of peptides derived from natural casein to cancer patients results in improved hematological profiles, specifically improved erythropoiesis, leukocypoidosis and thrombocytopoiesis, and is able to moderate and shorten the duration of depression induced by chemotherapy of blood components. Peptides derived from natural casein that stimulates thrombocytopoiesis in transplant recipients with resistant thrombocytopenia: Thrombocytopenia resistant to prolonged transfusion with severe bleeding episodes, can be a life-threatening complication of bone marrow transplantation, especially where traditional therapies are ineffective . Two patients with severe resistant thrombocytopenia were treated, with peptides derived from natural casein. M-l (Female Patient): A 32-year-old patient suffering from acute myeloid leukemia in complete remission, after autologous pluripotent cell transplantation. F. lia had experienced two episodes of life threatening bleeding, involving pulmonary hemorrhage and a large obstructive hematoma on the soft palate. In more than 114 days after transplantation, the platelet counts were refractive to rhIL-3, rhIL-6, intravenous gamma globulin, and recombinant erythropoietin. After two intramuscular treatments of 50 mg of peptides derived from natural casein (each treatment divided into three deposits), their condition improved immediately. Along with the rapid return of normal platelet counts (Figure 17), her distal extremity bleeds with excessive exertion and decreased patechiae, she was able to start walking again, and return to her home abroad without complications or side effects. M-2 (Male Patient): A 30-year-old patient who suffers from Acute Myeloid Leukemia in a second complete remission after autologous pluripotent cell transplantation, exhibiting fully resistant platelet counts and massive gastrointestinal bleeding episodes. He required daily transfusions of packed cells, had developed hypoalbuminia, and failed to respond to intensive therapy with rhIL-3, rhIL-ß and gamma globulin. After two intramuscular treatments, each of the peptides of 50 mg of natural casein in three tanks, 86 days after transplantation, rapid platelet reconstitution was observed (Figure 18) and gradual cessation of bleeding. No additional treatment was required and the patient was in fact asymptomatic completely with normal platelet count. Thus, a course of two intramuscular injections of peptides derived from natural casein at 0.7-1.0 mg per kg of body weight, each divided into three deposits, was effective in rapidly reconstituting platelet counts and decreasing associated clinical symptoms in patients suffering from of transfusion-resistant thrombocytopenia, prolonged with episodes of life-threatening bleeding. Peptides derived from natural casein that lowers triglycerides and Total Cholesterol in familial hyperlipidemia: M.S. (Female patient): A patient, a 38-year-old woman with a family history of hyperlipidemia. Before treatment with peptides derived from natural casein, the blood chemistry profile revealed total cholesterol (321 mg per day), triglycerides (213 mg per day).; normal range 45-185 mg per day) and high LDL cholesterol (236.4 mg per day, normal range 75-174 mg per day). One month after a single administration of 50 mg of peptides derived from natural casein (in three intramuscular reservoirs), hyperlipidemia was stabilized: total cholesterol was reduced to 270 mg per day; triglycerides were 165 mg per day and LDL-cholesterol was 201 mg per day, still higher than the normal range, but significantly reduced by the pre-treatment value. No additional treatment was administered. Thus, treatment with peptides derived from natural casein is effective in rapidly provoking a significant reduction in another hyperlipidemic way untreated in humans. Peptides derived from natural casein that stimulates normoglohinemia in a case of occult bleeding: D.G. (Male patient): The patient is a 75-year-old man who suffers from anemia and hypoglobinemia (RBC, HGB, CH and depressive MCHC) associated with intensive occult bleeding. One month after receiving an intramuscular injection of 50 mg of peptides derived from natural casein (in three deposits), a significant reduction in anemia was observed. After two months, the RBC values approached normal (4.32 instead of 3.44 M per μ?) The increased HGB (11.3 instead of 8.9 g per di) and HCT, MCH and MCHC all improved to almost normal values, despite the persistence of concealed bleeding. Thus, a peptide injection derived from natural casein appeared to be capable of stimulating erythropoiesis and reducing the anemia associated with blood loss in humans. It is appreciated that certain characteristics of the invention, which are, for clarity described in the context of the separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment may also be provided separately or in any suitable sub-combination. Although the invention has been described in conjunction with the specific embodiments, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to cover all alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents, patent applications and sequences identified by an access number, mentioned in this specification are hereby incorporated in their entirety for reference in the specification to the same extent as if each individual publication, patent, patent application or sequence will be specified specifically and individually to be incorporated herein by reference. In addition, the mention or identification of any reference in this application will not be constructed as an admission so that the reference is available as a prior art to the present invention.

] List of Sidelman Sequences, Zvi Peptides derived from casein and their uses in therapy 02/23922 25 Patentln version 3.1 1 2 PRT Artificial sequence Synthetic pepti 1 Arg Pro 1 < 210 > 2 < 211 > 3 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 2 Arg Pro Lys 1 < 210 > 3 < 2U > 4 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 3 Arg Pro Lys His 1 < 210 > 4 < 211 > 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 00 > 4 Arg Pro Lys His Pro 1 5 < 210 > S < 211 > 6 < 212 > FRT < 213 > Artificial sequence < 22 C > < 223 > Synt etic peptide < 400 > 5 Arg Pro Lys His Pro lie 1 5 < 210 > 6 < 211 > 7 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 6 Arg Pro Lys His Pro lie Lys 1 s < 210 > 7 < 211 > 8 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 7 Arg Pro Lys His Pro lie Lys His 1 5 < 210 > 8 < 211 > 9 < 212 > PPT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 8 Arg Pro Lys His Pro lie Lys His Gln 1 5 < 210 > 9 < 211 > 10 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 9 Arg Pro Lys His Pxo lie Lys His Gln Gly: 5 10 < 210 > 10 < 211 > ? < 212 > PRT < 223 > Artifice! sequence < 220 > < 223 > Synthetic peptide < 400 > 10 Arg Pro Lys His Pro lie Lys His Gln Gly Leu 1 b 10 < 210 > 11 < 211 > 12 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 11 Arg Pro Lys His Pro He Lys His Gln Gly Leu Pro J 5 10 < 210 > 12 < 211 > 13 < 212 > PRT < 213 > Artificial sequence < 22? > < 223 > Synthetic peptide < 400 > 12 Arg Pro Lys His Pro He Lys His Gln Gly Leu Pro Gln 1 6 10 < 210 > 13 < 211 > 14 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 13 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu 1 5 10 < 210 > 14 < 211 > 15 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 4O0 > 14 Arg Pro Lys His Pro He Lys His Gln Gly Leu Pro Gln Glu Val 3 5 10 15 < 230 > 15 < 211 > 16 < 212 > PRT < 213 > Artificial secuence < 220 > < 223 > Synthetic peptide < 400 > 15 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu Val 1 5 10 Ib < 210 > 16 < 211 > 17 < 212 > PP.T < 213i Artificial sequence < 220¡ > < 223 > Synthetic peptide < 400 > 16 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu the Leu 1 5 30 15 Asn < 210 > 17 < 211 > 18 < 212 > PBX < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > ? Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu Val Leu 3 5 30 15 Asn Glu < 210 > 38 < 211 > 19 < 232 > PPT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 18 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu Val Leu 1 5 30 35 Asn Glu Asn < 210 > 19 < 211 > 20 < 232 > PFT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide 5 < 400 > 19 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu Val Leu 1 5 10 15 Asn Glu Asn Leu 20 < 210 > 20 < 211 > 21 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synt etic peptide < 400 > 20 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu Val Leu 1 5 10 15 Asn Glu Asn Leu Leu 20 < 210 > 21 < 211 > 22 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 21 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu Val Leu 1 5 10 15 Asn Glu Asn Leu Leu Arg 20 < 210 > 22 < 211 > 23 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 22 Arg Pro Lvs His Pro lie Lvs Hjs Gln Glv Leu Pro Gln Glu Val Leu 1 '5' 10 15 Asn Glu Asn Leu Leu Arg Fhe 20 < 210 > 23 < 211 > 24 < 212 > PRT < 213 > Artificial sequence < 220 > -222 > Synthetic peptide 6 < 400 > 23 Arg Pro Lvs His Pro lie Lys His Gln Gly Leu Pro Gln Glu Val Leu 1 '5 10 15 Asn Glu Asn Leu Leu Arg Phe Phe 20 < 210 > 24 < 211 > 25 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synlhetic peptide < 400 > 24 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu Vel Leu 1 5 10 15 Asn Glu Asn Leu Leu Arg Phe Phe Val 20 < 210 > 25 < 211 > 26 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Synthetic peptide < 400 > 25 Arg Pro Lys His Pro lie Lys His Gln Gly Leu Pro Gln Glu Val Leu 1 5 10 15 Asn Glu Asn Leu Leu Arg Phe Phe VBI Wing 20 25

Claims

182 CLAIMS 1. A method for preventing or treating an autoimmune or infectious disease or condition, the method is characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of caserne aSl. 2. The method according to l rei indication 1, characterized in that the autoimmune or infectious disease or condition is selected from the group consisting of a viral disease, a viral infection, AIDS and HIV infection. 3. A method for preventing or treating a disease or blood condition, the method is characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of an aSl casein. 4. The method according to claim 3, characterized in that the disease or blood condition is selected from the group consisting of thrombocytopenia, pancytopenia, granulocytopenia, and a condition treatable with erythropoietin, and a condition treatable with thrombopoietin. 5. A method for modulating blood cell formation, the method is characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a peptide derived from a N-terminal portion of caseinSS aSl. 6. The method according to the rei indication 5, characterized in that the formation by modulation of the blood cell is selected from the group consisting of inducing hematopoiesis, inducing proliferation of hematopoietic stem cells, inducing proliferation and differentiation of hematopoietic stem cells, inducing megaraciotopoyesi s, induce erythropoiesis, induce leukocytopoiesis, induce tromboc topoisis, induce cell proliferation in plasma, induce dendritic cell proliferation and induce macrophage proliferation. 7. The method according to claim 5, further characterized in that it comprises administering to the subject in need thereof an effective amount of thrombopoietin. 8. A method for preventing or treating a diabetic disease or condition, the method is characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. 9. The method according to claim 8, characterized in that the disease or metabolic condition is selected from the group consisting of NIDDM, IDDM, glycosuria, hyperglycemia, hyperlipidemia and hypercholesterolemia. 184 10. A method for preventing or treating conditions associated with myeloablative doses of chemoradiotherapy supported by autologous bone marrow transplantation or peripheral cell pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT), the method is characterized in that it comprises administering to a subject with need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of ocsl casein. 11. The method according to claim 10, characterized in that it comprises administering to a subject in need thereof an effective amount of thrombopoietin. 12. A method for increasing the effect of erythropoietin, the method is characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein Sl. The method according to claim 12, further characterized in that it comprises administering to the subject in need thereof an effective amount of thrombopoietin. 14. A method for increasing the effect of thrombopoietin, the method is characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a peptide derived from a thrombopoietin. N-terminal portion of casein ocSl. 15. A pharmaceutical composition for preventing or treating an autoimmune or infectious disease or condition, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from an N-terminal portion of ctSl casein and a pharmaceutically acceptable carrier. 16. The pharmaceutical composition according to claim 15, characterized in that the autoimmune or infectious disease or condition is selected from the group consisting of a viral disease, a viral infection, AIDS and HIV infection. 17. A pharmaceutical composition for preventing or treating a disease or blood condition, the pharmaceutical composition is characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier. 18. The pharmaceutical composition according to claim 17, characterized in that the disease or blood condition is selected from the group consisting of thrombocytopenia, pancytopenia, granulocytopenia, a condition treatable with erythropoietin, and a condition treatable with thrombopoietin. 19. The pharmaceutical composition according to claim 17, further characterized in that it comprises 186 as an active ingredient, thrombopoietin. 20. A pharmaceutical composition for modulating blood cell formation, the pharmaceutical composition is characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 20, characterized in that the formation for modulating the blood cell is selected from the group consisting of inducing hematopoiesis, inducing proliferation of hematopoietic stem cells, inducing proliferation and differentiation of hematopoietic cells, inducing megakaryocytopoiesis, inducing erythropoiesis, induce leukocytopoiesis, induce thrombocytopoiesis, induce cell proliferation in plasma, induce dendritic cell proliferation and induce macrophage proliferation. 22. The pharmaceutical composition according to claim 20, further characterized in that it comprises, as an active ingredient, thrombopoietin. 23. A pharmaceutical composition for preventing or treating a diabetic disease or condition, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier. 24. The pharmaceutical composition in accordance with 187 Claim 23, characterized in that the disease or metabolic condition is selected from the group consisting of NIDDM, IDDM, glycosuria, hyperglycemia, hyperlipidemia and hypercholesterolemia. 25. A pharmaceutical composition for preventing or treating conditions associated with myeloablative doses of chemoradiotherapy supported by autologous bone marrow transplantation or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT), the pharmaceutical composition is characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier. 26. The pharmaceutical composition according to claim 25, further characterized in that it comprises, as an active ingredient, thrombopoietin. 27. A pharmaceutical composition for increasing the effect of erythropoietin, the pharmaceutical composition is characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. 28. The pharmaceutical composition according to claim 27, further characterized in that it comprises, as an active ingredient, thrombopoietin. 29. A pharmaceutical composition to increase the 188 As a thrombopoietin effect, the pharmaceutical composition is characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. 30. The pharmaceutical composition according to claim 29, further characterized in that it comprises, as an active ingredient, thrombopoietin. 31. A pharmaceutical composition for enhancing peripheral pluripotent cell mobilization, the pharmaceutical composition comprising, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. 32. The pharmaceutical composition according to claim 31, characterized in that it comprises, as an active ingredient, thrombopoietin. 33. A pharmaceutical composition for treating or preventing an indication selected from the group consisting of an autoimmune disease or condition, viral disease, viral infection, hematological disease, haematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, hyperlipidemia, hypercholesterolemia, glycosuria, hyperglycemia, diabetes , AIDS, HIV-1, T helper cell disorders, dendritic cell deficiencies, macrophage deficiencies, hematopoietic pluripotential cell disorders including disorders of platelet, lymphocyte, plasma and neutrophil cell, pre-leukemic conditions, leukemic conditions, disorders or the immune system resulting from the treatment of diseases of immune deficiency and bacterial infections, the pharmaceutical composition comprises, as an active ingredient, a peptide derived from a N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier. 34. The pharmaceutical composition according to claim 33, further characterized in that it comprises, as an active ingredient, thrombopoietin. 35. A pharmaceutical composition for treating or preventing an indication selected from the group consisting of hematologic disease, haematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, dendritic cell deficiencies, macrophage deficiencies, hematopoietic pluripotential cell disorders, including platelet disorders, lymphocyte , plasma and neutrophil cell, pre-leukemic conditions, leukemic conditions, myelodysplastic syndrome, aplastic anemia and bone marrow failure, the pharmaceutical composition is characterized in that it comprises, as active ingredients, thrombopoietin and a peptide derived from an N-terminal portion. of casein to Sl and a pharmaceutically acceptable carrier. 36. The pharmaceutical composition in accordance with 190 claim 35, further characterized in that it comprises, as an active ingredient, thrombopoietin. 37. A purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25. 38. A pharmaceutical composition, characterized in that it comprises a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25 and a pharmaceutically acceptable carrier. 39. A pharmaceutical composition characterized in that it comprises thrombopoietin and a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25 and a pharmaceutically acceptable carrier. 40. A method for improving the colonization of pluripotential cells of donated blood, in a myeloablative vessel, the method is characterized in that it comprises treating a donor of pluripotent blood cells donated with a peptide derived from an N-terminal portion of ocsl casein before the donation and implantation of pluripotent blood cells donated in the recipient. 41. The method according to claim 40, characterized in that it comprises, as an active ingredient, thrombopoietin. 191 42. A method to improve the colonization of pluripotent cells from donated blood in a myeloablative receptor, the method is characterized in that it comprises treating the pluripotent cells of donated blood with a peptide derived from an N-terminal portion of ocsl casein before implanting the pluripotent cells of donated blood in the recipient. 43. A method for improving the colonization of blood pluripotent cells in a myeloablative receptor, the method is characterized in that it comprises treating the blood pluripotent cells with a peptide derived from an N-terminal portion of ocsl casein before implanting the blood pluripotent cells in the blood. receiver . 44. The method according to claim 43, further characterized in that it comprises treating the blood pluripotent cells with thrombopoietin before implanting the blood pluripotent cells into the recipient. 45. A pharmaceutical composition for preventing or treating a condition associated with an infective agent SARS, the pharmaceutical composition is characterized in that it comprises as an active ingredient, a peptide derived from an N-terminal portion of cxSl casein and a pharmaceutically acceptable carrier. 192 46. The pharmaceutical composition according to claim 45, characterized in that the infective agent SARS is a coronavirus. 47. The pharmaceutical composition according to claim 46, characterized in that the coronavirus is SARS-CoV. 48. A method for preventing or treating a condition associated with an infectious agent SARS, the method is characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein aSl. 49. The method according to claim 48, characterized in that the infective agent SARS is a coronavirus. 50. The method of compliance with the claim 48, characterized in that the coronavirus is SARS-CoV. 51. The use of a peptide derived from an N-terminal portion of casein aSl, to prevent or treat an autoimmune or infectious disease or condition. 52. The use according to claim 51, characterized in that the autoimmune or infectious disease or condition is selected from the group consisting of a viral disease, a viral infection, AIDS, and HIV infection. 53. The use of a peptide derived from a N-193 portion casein terminal ocSl, to prevent or treat a disease or blood condition. 54. The use according to claim 53, characterized in that the disease or blood condition is selected from the group consisting of thrombocytopenia, pancytopenia, granulocytopenia, a condition treatable with erythropoietin, and a condition treatable with thrombopoietin. 55. The use of a peptide derived from an N-terminal portion of ocSl casein to modulate blood cell formation. 56. The use according to claim 55, characterized in that the formation for modulating the blood cell is selected from the group consisting of inducing hematopoiesis, inducing proliferation of hematopoietic stem cells, inducing proliferation and differentiation of hematopoietic stem cells, inducing megakaryocytopoiesis, inducing erythropoiesis, induce leukocytopoiesis, induce thrombocytopoiesis, induce cell proliferation in plasma, induce dendritic cell proliferation and induce macrophage proliferation. 57. The use of a peptide derived from an N-terminal portion of ocsl casein to prevent or treat a diabetic disease or condition. 58. The use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat conditions 194 associated with myeloablative doses of chemoradiotherapy supported by autologous bone marrow transplantation or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT). 59. The use of a peptide derived from an N-terminal portion of casein aSl to increase the effect of erythropoietin. 60. the use of a peptide derived from an N-terminal portion of casein aSl to increase the effect of thrombopoieme. 61. The use of a pharmaceutical composition characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl and a pharmaceutically acceptable carrier to prevent or treat an autoimmune or infectious disease or condition. 62. The use according to claim 61, characterized in that the autoimmune or infectious disease or condition is selected from the group consisting of a viral disease, a viral infection, AIDS and HIV infection. 63. The use of a pharmaceutical composition characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein a Sl and a pharmaceutically acceptable carrier to prevent or treat a disease or blood condition. 195 64. The use according to claim 63, characterized in that the disease or blood condition is selected from the group consisting of thrombocytopenia, pancytopenia, granulocytopenia, a condition treatable with erythropoietin, and a condition treatable with thrombopoietin. 65. The use of a pharmaceutical composition, characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier to prevent or treat by modulation the formation of the blood cell. 66. The use according to claim 65, characterized in that the modulation of blood cell formation is selected from the group consisting of inducing hematopoiesis, inducing proliferation of hematopoietic stem cells, inducing proliferation and differentiation of hematopoietic stem cells, inducing megakaryocytopoiesis, inducing erythropoiesis, inducing leukocytopoiesis, inducing thrombocytopoiesis, induce cell proliferation in plasma, induce dendritic cell proliferation and induce macrophage proliferation. 67. The use of a pharmaceutical composition, characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier to prevent or eradicate a diabetic disease or condition. 196 68. The use according to claim 67, characterized in that the disease or metabolic condition is selected from the group consisting of NIDD, IDDM, glycosuria, hyperglycemia, hyperlipidemia and hypercholesterolemi. 69. The use of a pharmaceutical composition, characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier to prevent or treat conditions associated with myeloablative doses of chemoradiotherapy supported by transplantation of autologous bone marrow or peripheral blood pluripotent cell (ASCT) or allogeneic bone marrow transplantation (BMT). 70. The use of a pharmaceutical composition characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier to increase the effect of erythropoietin. 71. The use of a pharmaceutical composition, characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier to increase the effect of thrombopoietin. 72. The use of a pharmaceutical composition, characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl 197 and a pharmaceutically acceptable carrier to improve peripheral pluripotent cell mobilization. 73. The use of a pharmaceutical composition, characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocsl casein and a pharmaceutically acceptable carrier to prevent or treat an indication selected from the group consisting of disease or condition autoimmune, viral disease, viral infection, hematological disease, hematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, hyperlipidemia, hypercholesterolemia, glycosuria, hyperglycemia, diabetes, AIDS, HIV-l, T cell disorders, dendritic cell deficiencies, macrophage deficiencies , hematopoietic pluripotential cell disorders, including platelet, lymphocyte, plasma and neutrophil cell disorders, pre-leukemic conditions, leukemic conditions, immune system disorders resulting from chemotherapy or radiation therapy, immune system disorders resulting from the treatment of. diseases of immune deficiency and bacterial infections. 74. The use of a pharmaceutical composition characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of ocSl casein and a pharmaceutically acceptable carrier for preventing or treat a selected indication of the group consisting of hematologic disease, hematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, dendritic cell deficiencies, macrophage deficiencies, hematopoietic pluripotential cell disorders, including platelet disorders, lymphocyte, plasma and neutrophil cell, pre-leukemic conditions, leukemic conditions, myelodysplastic syndrome, aplastic anemia and bone marrow failure. 75. The use of a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25. 76. The use of a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25 and a pharmaceutically acceptable carrier. 77. The use of a pharmaceutical composition, characterized in that it comprises thrombopoietin and a purified peptide having an amino acid sequence selected from the group consisting of SEQ. FROM IDENT. NOs: 1-25 and a pharmaceutically acceptable carrier. 78. The use of a peptide derived from an N-terminal portion of ccSl casein to improve the colonization of pluripotent cells from donated blood in a myeloablative receptor. 199 79. The use of a peptide derived from an N-terminal portion of casein aSl to improve the colonization of blood pluripotent cells in a myeloablate receptor. 80. The use of a peptide derived from an N-terminal portion of casein aSl to prevent or treat a condition associated with an infective agent SARS. 81. The use according to claim 80, characterized in that the infective agent SARS is a coronavirus. 82. The use according to claim 81, characterized in that the coronavxrus is SARS-CoV. 83. The use of a pharmaceutical composition, characterized in that it comprises, as an active ingredient, a peptide derived from an N-terminal portion of casein aSl, and a pharmaceutically acceptable carrier to prevent or treat a condition associated with an infective agent SARS, the The method comprises administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N-terminal portion of casein to Sl. 84. The use according to claim 83, characterized in that the infective agent SARS is a coronavirus. 85. The use according to claim 84, characterized in that the coronavirus is SARS-CoV. 200 Active bi peptides that are derived from or are similar to sequences identical to the N-terminus of the SI fraction of milk casein. These peptides are capable of stimulating and improving the immune response, protecting against viral infection, normalizing serum cholesterol levels, and stimulating hematopoiesis. Casein-derived peptides are non-toxic and can be used to treat and prevent immune pathologies, hypercholesterolemia, hematological disorders and virus-related diseases.