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WO2007104493A1 - Utilisation du peptide intestinal vaso-actif (piv) et cellules isolées stimulées par ce peptide - Google Patents

Utilisation du peptide intestinal vaso-actif (piv) et cellules isolées stimulées par ce peptide Download PDF

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Publication number
WO2007104493A1
WO2007104493A1 PCT/EP2007/002091 EP2007002091W WO2007104493A1 WO 2007104493 A1 WO2007104493 A1 WO 2007104493A1 EP 2007002091 W EP2007002091 W EP 2007002091W WO 2007104493 A1 WO2007104493 A1 WO 2007104493A1
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Prior art keywords
cells
antigen
vip
responsible
isolated
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PCT/EP2007/002091
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Inventor
Mario Delgado Mora
Elena Gonzalez Rey
Alejo Chorny
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GRUP D'AFECTATS D'ESCLEROSI MULTIPLE (GAEM)
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GRUP D'AFECTATS D'ESCLEROSI MULTIPLE (GAEM)
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/19—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/24—Antigen-presenting cells [APC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/421—Immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0639—Dendritic cells, e.g. Langherhans cells in the epidermis
    • C12N5/064—Immunosuppressive dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/50—Cellular immunotherapy characterised by the use of allogeneic cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/22—Colony stimulating factors (G-CSF, GM-CSF)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/30—Hormones
    • C12N2501/35—Vasoactive intestinal peptide [VIP]; Pituitary adenylate cyclase activating polypeptide [PACAP]

Definitions

  • the present invention relates to a new use for vasoactive intestinal peptide (VIP) and to isolated cells stimulated by said peptide.
  • VIP vasoactive intestinal peptide
  • the invention also relates to new pharmaceutical compositions.
  • Vasoactive intestinal peptide is a protein released by cells of the immune system, particularly by T helper or Th cells when they are stimulated by an antigen and in conditions of inflammation or autoimmune reactions.
  • the immune system must act against any foreign body in the organism or pathogen, but it must tolerate or recognise the organism's own antigens in order to avoid reacting against the organism itself. The induction of antigen- specific tolerance therefore makes it possible to keep the immune system under control in order to prevent autoimmune diseases and to ensure minimum tolerance to transplants.
  • immune tolerance This phenomenon whereby cells of the immune system are able not to react against certain autoantigens or foreign antigens is known as immune tolerance.
  • T cells responsible for immune tolerance are called regulatory T cells (Treg). These regulatory T cells are activated by dendritic cells (DC), which are a type of antigen-presenting cells (APC).
  • DC dendritic cells
  • APC antigen-presenting cells
  • Antigen-presenting cells are the cells of the immune system that are responsible for processing and presenting antigens to the other cells of the system that will be capable of acting against foreign agents.
  • Dendritic cells are capable of stimulating T cells or lymphocytes known as naive T cells, i.e. which have not previously been in contact with an antigen. The interaction between T cells and dendritic cells causes a number of biochemical reactions or cascades inside the naive T cell, which enable it to start a process of cell proliferation and differentiation that will result in the appearance of mature T cells that will modulate the type of immune response that will be carried out against a certain antigen.
  • dendritic cells are cells that promote immunity by activating T cells, whilst immature dendritic cells (DCi) induce T-cell tolerance.
  • DCm mature dendritic cells
  • DCi immature dendritic cells
  • MS Multiple Sclerosis
  • CNS Central Nervous System
  • MS is a disease that affects young and old people alike, as it can begin be- tween the ages of 20 and 40.
  • the symptoms of MS are very varied and take different forms depending on the person affected. However, the most common symptoms are abnormal sensitivity, weakness (fatigue), sight disorders (double vision), numbness and tingling of the limbs, dizziness, etc. All these symptoms are experienced for unpredictable periods of time and when they recur, they can be more serious with muscle spasms, paralysis, intestinal disorders, etc.
  • MS Being a young person's disease that is chronic and potentially incapacitating, MS can have a strong impact on family, social, economic and working life but it does not essentially alter the life expectancy of the people that suffer from it.
  • corticosteroids tend to be applied in order to reduce the seriousness and duration of the attack.
  • interferon beta is used, blocking the expression of membrane proteins known as human lymphocyte antigens (HLA), which are the proteins of the cells of the nervous system recognised by the cells of the immune system.
  • HLA human lymphocyte antigens
  • glatiramer acetate is a mixture of polypeptides synthesised from four different amino acids. Its structure is similar to that of myelin, although its exact mechanism of action is not yet known. Glatiramer acetate is indicated for reducing the frequency of relapses in patients with recurrent-remitting MS of the type that has involved two attacks of neurological dysfunction during the two previous years.
  • CD4 antigen is a molecule present in the membrane of a type of T cells or lymphocytes.
  • EP 1165125 B1 relates to an alternative therapy based on the induction of antigen-specific peripheral immune tolerance.
  • This document discloses the use of nucleic acids that encode a first and a second protein, where the first protein induces apoptosis or inactivation of T cells and the second protein is a pathogenic antigen, for producing a composition to transfect mammal cells in order to reduce the immune response to the antigen.
  • Said antigen can consist, among other proteins, of myelin basic protein.
  • EP1165125 B1 also discloses a composition based on nanospheres comprising at least these nucleic acids that encode a first apop- tosis-inducing protein and a second pathogenic antigen.
  • MBP myelin basic protein
  • PGP proteolipid protein
  • MOG myelin oligodendrocyte glycoprotein
  • DC dendritic cells
  • This aspect opens up promising prospects for the treatment of most autoimmune diseases, such as Multiple Sclerosis, Rheumatoid Arthritis, Graves' disease, systemic lupus erythematosus, etc., as well as for improving the induction of tolerance to allogenic transplants.
  • autoimmune diseases such as Multiple Sclerosis, Rheumatoid Arthritis, Graves' disease, systemic lupus erythematosus, etc.
  • the object of the present invention is the use of vasoactive intestinal peptide (VIP) for preparing a medicinal product for cell therapy in autoimmune diseases and/or transplant rejection in mammals.
  • VIP vasoactive intestinal peptide
  • the cell therapy is based on regulatory T cells and/or tolerogenic dendritic cells.
  • the vasoactive intesti- nal peptide corresponds to a part or a derivative of vasoactive intestinal peptide.
  • the medicinal product for treating autoimmune diseases and/or transplant rejection comprises dendritic cells previously subjected to a maturation process in the presence of vasoactive intestinal peptide (VIP) and stimulated with at least one antigen that is responsible for the autoimmune response and/or with T cells isolated from the blood of a transplant donor.
  • VIP vasoactive intestinal peptide
  • vasoactive intestinal peptide is for preparing a medicinal product to treat autoimmune diseases and/or transplant rejection that comprises regulatory T cells induced from naive CD4 T cells stimulated with dendritic cells, said dendritic cells previously having been subjected to a maturation process in the presence of vasoactive intestinal peptide (VIP) and stimulated with at least one antigen that is responsible for the autoimmune response and/or with T cells isolated from the blood of a transplant donor.
  • VIP vasoactive intestinal peptide
  • antigens responsible for the autoimmune response are components of myelin sheaths.
  • the antigen is selected from the group consisting of the myelin basic protein epitopes, the proteolipid protein epitopes and the myelin oligodendrocyte glycoprotein epitopes.
  • epitope it must be understood any antigenic zone with any structure or sequence which is recognized by an antibody.
  • a protein, as any macromolecule can have multiple epitopes.
  • the epitopes can be sequentially epitopes, i.e. formed by a known aminoacide sequence, or conformational epitopes, i.e established when the peptidic chain is folded adopting its final three-dimensional conformation.
  • the antigen is selected from the group constituted of peptides of 12 to 40 aminoacides of the myelin basic protein epitopes, the proteolipid protein epitopes and the myelin oligodendrocyte glycoprotein epitopes.
  • the antigen is an epitope of the myelin basic protein selected from the group consisting of SEQ ID NO 1 , SEQ ID NO 2, SEQ ID NO 3 and SEQ ID NO 7.
  • the peptide of SEQ ID NO 4 is preferred.
  • the peptide derived from epi- topes of the myelin oligodendrocyte glycoprotein is selected from the group consisting of SEQ ID NO 5 and SEQ ID NO 6.
  • autoimmune disease is Multiple Sclerosis (MS).
  • the medicinal product is for treating autoimmune diseases and/or transplant rejection in humans.
  • Another object of the present invention is an isolated dendritic cell generated from bone marrow cells or from monocytes, which can be produced by: a) incubating bone marrow cells or monocytes in complete medium with the granulocyte-macrophage colony-stimulating factor (GM-CSF) agent and in the pres- ence of vasoactive intestinal peptide (VIP); b) harvesting the non-adherent cells from step a); c) stimulating and maturing the cells from step b) with at least one antigen that is responsible for the autoimmune response and/or with T cells isolated from the blood of a transplant donor.
  • the isolated dendritic cell is characterised in that the antigen responsible for the immune response is myelin or one of its components.
  • the isolated dendritic cell has been stimulated by at least an antigen of those disclosed in claims 7 to 11.
  • Another object of the invention is an isolated regulatory T cell that can be produced by incubating naive CD4 T cells with dendritic cells subjected to a maturation process in the presence of vasoactive intestinal peptide (VIP) and stimulated with at least one antigen that is responsible for the autoimmune response and/or with T cells isolated from the blood of a transplant donor.
  • VIP vasoactive intestinal peptide
  • the isolated regulatory T cell according to the invention is characterised in that the antigen responsible for the immune response is myelin or one of its components.
  • the isolated regulating T cell has been incubated with dendritic cells stimulated with at least an antigen of those disclosed in claims 7 to 11.
  • the object of the present invention is a pharmaceutical composition that comprises, in addition to pharmaceutically acceptable excipients, dendritic cells previously subjected to a maturation process in the presence of vasoactive intestinal peptide (VIP) and stimulated with at least one antigen that is responsible for the autoimmune response and/or with T cells isolated from the blood of a transplant donor.
  • VIP vasoactive intestinal peptide
  • said pharmaceutical composition comprises dendritic cells previously subjected to a maturation process in the presence of vasoactive intestinal peptide (VIP) and stimulated with myelin components.
  • VIP vasoactive intestinal peptide
  • the pharmaceutical composition comprises dendritic cells stimu- lated with at least an antigen of those disclosed in claims 7 to 11.
  • Another object of the invention is a pharmaceutical composition that comprises, in addition to pharmaceutically acceptable excipients, regulatory T cells induced from naive CD4 T cells stimulated with dendritic cells, said dendritic cells having been previously subjected to a maturation process in the presence of vasoactive intestinal peptide (VIP) and stimulated with at least one antigen that is responsible for the autoimmune response and/or with T cells isolated from the blood of a transplant donor.
  • VIP vasoactive intestinal peptide
  • the pharmaceutical composition comprises regulatory T cells induced from naive CD4 T cells stimulated with dendritic cells, said dendritic calls hav- ing been previously subjected to a maturation process in the presence of vasoactive intestinal peptide (VIP) and stimulated with myelin or one of its components.
  • VIP vasoactive intestinal peptide
  • the pharmaceutical composition comprises T cells incubated with dendritic cells stimulated with at least an antigen of those disclosed in claims 7 to 11.
  • compositions according to the invention are characterised in that they take the form of injectable compositions.
  • FIG. 1 is a graph showing the degree of T cell proliferation in the lymph nodes and the production of interferon Y (IFN ⁇ ) and antibodies against a myelin component found in mice with a model of Multiple Sclerosis that have received the medicinal product comprising mature dendritic cells in the presence or absence of
  • IFN ⁇ interferon Y
  • FIG. 2 is a graph showing that the administration of a medicinal product con- taining regulatory T cells stimulated with dendritic cells that had matured in the presence of VIP leads to an improvement in Experimental Autoimmune Encephalomyelitis (EAE);
  • EAE Experimental Autoimmune Encephalomyelitis
  • FIG. 3 is another diagram illustrating the effect of administering dendritic cells differentiated in the presence of VIP in cases of bone marrow transplant rejec- tion.
  • FIG. 4 illustrates the effect of administering regulatory T cells in patients or animal models where transplanted bone marrow is expected to be rejected.
  • VIP vasoactive intestinal peptide
  • maturation of dendritic cells refers to the stage of maturity reached by said cells when they are stimulated by an antigen of interest, e.g. an antigen that causes the immune response.
  • Study 1 Production of dendritic cells that are capable of promoting the proliferation of regulatory T cells and inducing peripheral immune tolerance.
  • dendritic cells deriving from bone marrow were obtained from bone marrow cells of C57BL/6(H-2 b ) mice.
  • the bone marrow cells were incubated in a complete medium (RPMI medium 1640 supplemented with 100 units/ml penicillin/streptomycin, 2 mM L-glutamine, 50 ⁇ M 2- mercaptoethanol and 10% heat-inactivated foetal calf serum), which contained 20 ng/ml of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the pres- ence of 10 "8 M of vasoactive intestinal peptide (VIP).
  • a complete medium RPMI medium 1640 supplemented with 100 units/ml penicillin/streptomycin, 2 mM L-glutamine, 50 ⁇ M 2- mercaptoethanol and 10% heat-inactivated foetal calf serum
  • GM-CSF granulocyte-macrophage colony-stimul
  • the non-adherent cells were harvested and were stimulated with myelin (20 ⁇ g/ml) for 12 hours. This step is called dendritic cell pulsation.
  • Naive CD4 T cells (2 x 10 s ) were cultured with dendritic cells that had matured in the presence of VIP (CDw). lnterleukin-2 (IL-2) (100 units/ml) was added to the culture medium and it was left for three days. To generate myelin-specific regulatory T cells, the dendritic cells that were later put in contact with the naive CD4 T cells were pulsed with myelin components and they were cultured with syngeneic CD4 T cells.
  • VIP lnterleukin-2
  • IL-2 lnterleukin-2
  • MS Multiple Sclerosis
  • Test 1 Administration of dendritic cells matured in the presence of VIP:
  • mice of the same experimental model were also inoculated with dendritic cells that had not matured in the presence of VIP, i.e. that had only been stimulated with GM-CSF and pulsed with myelin, hereafter referred to as CDco ntr oi-
  • the data extracted for mice that had not received any type of treatment were used as a blank.
  • mice treated with CDV I P both the proliferation of T cells in the lymph nodes and the production of interferon y (IFN ⁇ ) in response to autoantigens were low compared to their equivalents in mice inoculated with CD 00n- tr oi. It can also be inferred from FIG. 1 that the levels of anti-MOG antibodies were lower in the mice treated with CDVIP than in the mice treated with CDco n t r oi-
  • Test 2 Administration of regulatory T cells induced in vitro by dendritic cells matured in the presence of VIP.
  • antigen-specific regulatory T cells induced by CDvip were generated in vitro. These regulatory cells were inoculated into mice of the same experimental model as in the previous test. The generation of MOG-specific regulatory T cells that had been induced by
  • T ⁇ VI P CDVIP (hereafter referred to as T ⁇ VI P) was achieved using CD4 cells stimulated with dendritic cells pulsed with MOG and matured in the presence of VIP, as has been described in Study 2.
  • Regulatory T cells were also generated as a control (Trcomroi) by inducing CD4 T cells with dendritic cells that had not been subjected to cell maturation in the presence of VIP.
  • T ⁇ V IP mice with Experimental Autoimmune Encephalomyelitis
  • EAE Experimental Autoimmune Encephalomyelitis
  • Tr ⁇ tr oi white circles
  • the data extracted for mice that had not received any type of treatment black circles
  • the effect of inoculation with T ⁇ V IP was antigen specific, i.e. that if the mice were inoculated with Tr V ⁇ P that had been induced by CD V ⁇ P pulsed with an antigen other than myelin, e.g. with ovalbumin (OVA), the inoculation of these regulatory T cells did not depress autoimmune responses against myelin, therefore applicable to the treatment of Multiple Sclerosis.
  • OVA ovalbumin
  • results achieved for tests 1 and 2 show that if immature dendritic cells are subjected to a maturation process according to the usual protocols, including the presence of VIP in the medium, the resulting mature dendritic cells act in vivo, inducing peripheral immune tolerance. Dendritic cells matured in the presence of VIP and pulsed or exposed to an antigen that is responsible for the autoimmune response induce differentiation of regulatory T cells that promote immune tolerance to this antigen.
  • Example 1 Example of peptides derived from myelin components useful for the preparation of medicaments for the treatment of Multiple Sclerosis in cell therapy.
  • RRMS Recurrent Remittent Multiple Sclerosis
  • GM-CSF granulocytes macrophage colony stimulating factor
  • IL-4 interleukin 4
  • VIP vasoactive intestinal peptide
  • the culture medium used comprises X-Alive-15 Medium (Cambrex) + 1% autologous serum; GM-CSF of GMP grade (800 U/ml, CellGenix); IL-4 of GMP grade (500U/ml, CellGenix); VIP (10 "8 M, Calbiochem); and antibiotic prophylaxis (penicillin/streptomicin/fungizone).
  • GM-CSF GMP grade
  • IL-4 GMP grade
  • VIP penicillin/streptomicin/fungizone
  • the maduration and/or activation step is carried out during 48 hours with the alfa tumoral necrosis factor (alfa TNF) (10 ng/ml, CellGenix).
  • Test 3 Administration of dendritic cells matured in the presence of VIP to induce protection against transplant rejections.
  • GVHD acute graft-versus-host disease
  • the recipient animals were injected with medium (not treated) or with Balb/c (H-2 d ) dendritic cells generated in the absence (DCcontroi) or presence (DCVIP) of VIP.
  • FIG. 3 shows the survival rate in relation to the number of days after the transplant operation
  • the animals that were not treated black circles
  • those that received dendritic cells as a control white circles
  • CDvip In order to determine whether the regulatory T cells induced in vitro that had been in contact with dendritric cells CDvip could be useful when injected together with other excipients into mammals that can reject a transplant, they were injected according to the same scheme as in test 3, i.e. in the same animal model and transplanted with the same type of bone marrow cells, CD4Trco n t r oi or CD4Tr V) p cells, or only medium (usual excipients in this type of procedures), and the survival rate of the transplanted mice was observed. These results are shown in FIG.
  • vasoactive intestinal peptide can be highlighted as an essential component for preparing a medicinal product that can be applied by cell therapy to patients with autoimmune dis- eases such as Multiple Sclerosis or to patients who must undergo a transplant operation, e.g. a bone marrow transplant.
  • the medicinal product for cell therapy can comprise dendritic cells that can be produced by maturation and stimulation in the presence of said vasoactive intestinal peptide or a part or derivative thereof, or regu- latory T cells that are capable of inducing peripheral immune tolerance, which have been produced by maturation and stimulation of CD4T cells with dendritic cells that have matured in the presence of vasoactive intestinal peptide.
  • compositions used to carry out the tests are characterised by the pres- ence of said tolerogenic dendritic cells or regulatory T cells (capable of inducing tolerance), which will obviously be accompanied by the usual excipients that are known by a person skilled in the art to give them the desired formulation, preferably injectable.

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Abstract

L'invention concerne l'utilisation de peptide intestinal vaso-actif (PIV) pour préparer un produit médicamenteux destiné au traitement de maladies auto-immunes et/ou du rejet de greffe chez des mammifères. Elle concerne également des compositions comprenant des cellules dendritiques et/ou des lymphocytes T régulateurs qui sont capables de générer une tolérance immunitaire périphérique, ainsi que des cellules isolées contenues dans ces compositions.
PCT/EP2007/002091 2006-03-15 2007-03-09 Utilisation du peptide intestinal vaso-actif (piv) et cellules isolées stimulées par ce peptide Ceased WO2007104493A1 (fr)

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Application Number Priority Date Filing Date Title
ES200600656A ES2315081B1 (es) 2006-03-15 2006-03-15 Nuevo uso del peptido intestinal vasoactivo (vip) y de las celulas aisladas estimuladas con dicho peptido.
ESP200600656 2006-03-15

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WO2007104493A1 true WO2007104493A1 (fr) 2007-09-20

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US8729018B2 (en) 2005-12-20 2014-05-20 Duke University Therapeutic agents comprising elastic peptides
US9458217B2 (en) 2013-12-05 2016-10-04 Emory University Methods of managing graft versus host disease
US9821036B2 (en) 2008-06-27 2017-11-21 Duke University Therapeutic agents comprising a GLP-2 peptide and elastin-like peptides
US10258700B2 (en) 2005-12-20 2019-04-16 Duke University Methods and compositions for delivering active agents with enhanced pharmacological properties

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