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WO2017046734A1 - Lipopolysaccharide (lps) pour une utilisation dans le traitement d'affections ou de maladies associées à une réponse immunitaire excessive de l'organisme provoquée par des troubles du système digestif - Google Patents

Lipopolysaccharide (lps) pour une utilisation dans le traitement d'affections ou de maladies associées à une réponse immunitaire excessive de l'organisme provoquée par des troubles du système digestif Download PDF

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Publication number
WO2017046734A1
WO2017046734A1 PCT/IB2016/055500 IB2016055500W WO2017046734A1 WO 2017046734 A1 WO2017046734 A1 WO 2017046734A1 IB 2016055500 W IB2016055500 W IB 2016055500W WO 2017046734 A1 WO2017046734 A1 WO 2017046734A1
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Prior art keywords
lps
administered
tartaric acid
mice
cells
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English (en)
Inventor
Ewa KOZLOWSKA
Nadzieja DRELA
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Uniwersytet Warszawski
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Uniwersytet Warszawski
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/739—Lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/40—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum bacterial
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • LIPOPOLYSACCHARIDE LPS FOR USE IN THE TREATMENT OF CONDITIONS OR DISEASES ASSOCIATED WITH EXCESSIVE IMMUNE RESPONSE OF THE ORGANISM CAUSED BY DISORDERS OF THE DIGESTIVE SYSTEM
  • the subject of this invention relates to the use of lipopolysaccharide (LPS) in the treatment of conditions or diseases associated with an excessive immune response of an organism caused by gastrointestinal disorders, in particular selected from a group of nonspecific inflammatory bowel disease (IBD) and / or food allergies.
  • LPS lipopolysaccharide
  • Lipopolysaccharide is a heat-stable particle, an integral component of the outer membrane of the cell wall of Gram-negative bacteria.
  • LPS is an endotoxin of known biological activity.
  • IBD Inflammatory bowel diseases
  • IBD is a group of chronic inflammatory diseases of the gastrointestinal tract, especially the colon or intestine, such as Crohn's disease or ulcerative colitis. The etiology of IBD is not fully understood, but most often environmental factors and allergens are mentioned as determinants of the disease. It is also believed that food allergies can lead to the development of IBD.
  • CD4 + CD25 + FoxP3 + regulatory T cells have therapeutic applications in the maintenance of grafts, autoimmune suppression. Also their use in the treatment of allergies including food allergies and IBD has been proposed (Berin MC, Mayer L. Can we produce true tolerance in patients with food allergy? The Journal of allergy and clinical immunology. 2013;
  • US application US 20040228837 discloses a method of assessing the effectiveness of treatment of inflammatory bowel disease in mammals, as well as a kit for conducting such an assessment.
  • the method includes inter alia a step comprising a measurement of the level of at least one anti-inflammatory cytokine and at least one pro-inflammatory cytokine in a biological sample from a mammal, preferably a biological sample containing plasma, peripheral blood mononuclear cells after in vitro stimulation, and without in vitro stimulation.
  • the in vitro stimulation involves a use of a mitogen, wherein said mitogen may include preferably a lipopolysaccharide, lectin, superantigen or a mixture thereof.
  • US application US 20060216283 discloses a method for inhibiting secretion from non-neuronal inflammatory cells involving administration of an agent comprising at least a first and a second domain, wherein the first domain cleaves one or more proteins essential / indicated for exocytosis and a second domain for translocation of the first domain to an inflammatory cell.
  • the agent comprises a third domain that introduces an agent into the inflammatory non-neuronal cell.
  • the ligand comprises a third domain, which for macrophages, monocytes and neutrophils may be bacterial LPS and yeast ⁇ - glucans which bind to CR3.
  • US application US 2005238651 discloses a method of treating ulcerative colitis comprising, wherein a patient in need of such a treatment is administered a B7 antigen ligand that binds to the antigen presenting cells in the gastrointestinal tract of a patient, in an amount inducing immune - tolerance.
  • the B7 antigen ligand which is an inducer of indoleamine 2,3 - dioxygenase may be bacterial LPS.
  • the application also discloses a method of treating ulcerative colitis, comprising selecting of an agent based on a factor that is effective in the induction of indoleamine 2,3 -dioxygenase in cells containing an antigen, effective in blocking of the co- stimulation of T cell activity or effective in both induction of indoleamine 2,3 -dioxygenase and blocking the activation of T cells; administering an effective amount of an agent to the ill patient.
  • the agent effective in inducing of indoleamine 2,3-dioxygenase in cells containing the antigen is a bacterial lipopolysaccharide, interferon- ⁇ or a fusion protein comprising an antigen 4 present on cytotoxic T lymphocytes and immunoglobulins (CTLA-4-Ig).
  • the Australian application AU 2004237888 discloses an immunogenic composition comprising an immunogenic peptide fragment of the fibroblast growth factor and a pharmaceutically acceptable carrier.
  • the adjuvant is a component of the composition, which may be a lipopolysaccharide derived from gram-negative bacteria.
  • the document also discloses a method of treating cancer or hyperproliferative disorders in a human or animal comprising administering an effective amount of a composition comprising an immunogenic peptide fragment of fibroblast growth factor and a pharmaceutically acceptable carrier.
  • the condition to be treated with the fore mentioned composition is Crohn's disease.
  • Patent EP 1031347 discloses the use of a penetrating agent in the composition of a pharmaceutical active ingredient or an allergen or an antigen, wherein the composition is administered intranasally for the treatment of, for example, Crohn's disease.
  • the pharmaceutical composition is in the form of a vaccine and the adjuvant is lipopolysaccharide, such as lipid A or its derivative or modification.
  • the subject of this invention is LPS for the use in the treatment of conditions or diseases associated with excessive immune response of the body caused by disorders of the digestive system, in particular from the group of non-specific inflammatory bowel disease (IBD) and/or food allergy, characterized by the administration of LPS to a subject in a daily dose from 200 to 4000 ⁇ g / kg body weight for at least 3 consecutive days, or optionally by the administration of LPS in combination with D-tartaric acid.
  • IBD non-specific inflammatory bowel disease
  • LPS optionally in combination with D-tartaric acid
  • a daily dose from 200 to 4000 ⁇ g / kg body weight for a period from 3 to 14 consecutive days, preferably for a period from 3 to 10 consecutive days, more preferably for 3 to 7 consecutive days, even more preferably for 3 to 5 consecutive days, and most preferably for 3 days.
  • LPS or combinations of LPS with D-tartaric acid is administered intraperitoneally or orally as a solution in the physiological saline or other pharmaceutically acceptable carrier.
  • LPS is administered in the initial stage of the disease in combination with D-tartaric acid, wherein LPS is administered in a daily dose of 4000 ⁇ g / kg body weight and D-tartaric acid is administered in a daily dose of 300mg / kg body weight.
  • LPS is administered in the initial stage of the disease for a period from 3 to 14 consecutive days, more preferably for a period from 3 to 10 consecutive days, even more preferably for 3 to 7 consecutive days, also more preferably for 3 to 5 consecutive days, and most preferably for 3 days in combination with D-tartaric acid, wherein LPS is administered in a daily dose of 4000 ⁇ g / kg body weight and D-tartaric acid in a daily dose of 300 mg / kg body weight.
  • Treg cells as cells with suppressive activity, alleviate or prevent the development of excessive immune response of the body caused by gastrointestinal disease, particularly from the group of non-specific inflammatory bowel disease (IBD) and / or food allergies.
  • IBD non-specific inflammatory bowel disease
  • LPS can be administered in combination with D-tartaric acid.
  • D-tartaric acid is to lead to a temporary loss of containment of the intestine walls which is beneficial for early-stage disease IBD and food allergies.
  • the induction of the generation of CD4 + CD25 + FoxP3 + regulatory T cells in the thymus induces suppression or inhibition of excessive adverse immune response, including inflammatory bowel disease IBD.
  • LPS is administered in combination with D-tartaric acid, which unseals the intestinal walls and thus increases its permeability.
  • the administration for a period of 3 days of a daily dose of LPS up to 4000 ⁇ g / kg body weight of the subject, optionally in combination with D-tartaric acid at a daily dose of 300 mg / kg of subject's body weight results in targeted stimulation of the immune system which leads to the rapid attainment of immune suppression, which is particularly important in the case when an individual experiences exacerbation of conditions associated with IBD or of rapid allergic reactions.
  • LPS optionally in the combination with D-tartaric acid can also be used for desensitization. Then, an allergen is administered in addition to LPS and D-tartaric acid.
  • LPS can be used for treatment of autoimmune diseases.
  • LPS is administered in a composition with an auto- antigen and D-tartaric acid.
  • LPS used in the method according to the present invention is of microbial origin
  • an appropriate carrier is selected, which may be, for example, saline, distilled water, or another pharmaceutically acceptable carrier.
  • the pharmaceutical composition as defined above may take the form of any conventional dosage form known in the field of pharmaceutical forms suitable for oral or intraperitoneal administration (injection into the abdominal wall). Examples of such pharmaceutical forms are solutions, suspensions, infusions etc.
  • the form of the preparation depends on the nature of the substrate (carrier).
  • IBD non-specific inflammatory bowel disease
  • the treatment of choice is the resection of the disease affected sections of the intestine.
  • an increased incidence of intestinal tumours has been observed.
  • the standard treatment of IBD or allergy includes anti-inflammatory drugs, immunosuppressive drugs, antibiotics, pain killers, etc., which can cause a variety of side effects. Therefore, the use of LPS according to the invention is a cheaper and more efficient alternative to the current treatment of conditions or diseases associated with excessive immune response of the organism.
  • LPS can be used in diseases manifested by excessive activity of the immune system, associated with chronic inflammation, e.g. autoimmune diseases and allergies.
  • Fig. 1 is a graph illustrating the percentage of CD4 + CD25 + FoxP3 + regulatory T cells in the thymus of mice treated with LPS (LPS) once a day, intraperitoneally in a dose of 200 ⁇ g / kg mouse body weight for 3 consecutive days and in the thymus control mice (receiving saline ) (K).
  • LPS LPS
  • Fig. 2 shows a comparison diagram of the amount of the CDl lb mid F4 / 80 mid myeloid cell (indicated by a rectangle) in the peritoneal cavity of mice treated with LPS (LPS) once a day, intraperitoneally in a dose of 200 ⁇ g / kg mouse body weight for 3 consecutive days and control mice (receiving physiological saline ) (K).
  • LPS LPS
  • Fig. 3 shows a confocal microscopy photograph of thymus sections form C57BL / 6 mice (recipient mice) after the i.p. adoptive transfer of peritoneal CD19 CDl lc l0 Cl lb + F4 / 80 + myeloid cells.
  • the donor CD19 CDl lc lo Cl lb + F4 / 80 + myeloid cells were from C57BL / 6 Tg (UBC-GFP) 30SchaGFP mice (transgenic mice of which all cells of the immune system express GFP - Green Fluorescent Protein) treated three consecutive days (once a day) with LPS at a dose of 200 ⁇ g / kg mouse body weight; (left panel) shows a confocal microscopy photograph of thymus sections of the form C57BL / 6 mice (recipient mice) after the i.p. adoptive transfer of peritoneal CD19 " CDl lc lo Cl lb + F4 / 80 + myeloid cells.
  • CD19 " CD1 lc lo Cl lb + F4 / 80 + myeloid cells were from C57BL / 6 Tg (UBC-GFP)30SchaGFP control mice treated for three consecutive days (once a day) with physiological saline;
  • Fig. 4 is a graph illustrating the percentage of CD4 + CD25 + FoxP3 + regulatory T cells in the thymus B6.Cg-Foxp3 tm2Tch 1 J mice (in these mice only cells expressing FoxP3 simultaneously express GFP) after the i.p. adoptive transfer of CD19 " CDl lc lo Cl lb + F4 / 80 + myeloid cell obtained from peritoneum of the LPS administered mice (after tree time administration once a day) in an amount of 200 ⁇ g / kg mouse body weight and the percentage of the regulatory T cells CD4 + CD25 + FoxP3 + in the thymus of C57BL/6 mice after the i.p. adoptive transfer of CD19 " CDl lc lo Cl lb + F4 / 80 + myeloid cells obtained from mice treated with physiological saline (K) in the same dosing regimen;
  • Fig. 5 is a graph illustrating the percentage of the CD4 + CD25 + FoxP3 + regulatory cells in the thymus of mice with the developed IBD, induced by DSS (1% in drinking water for 30 days) after intragastric application of LPS once a day for three consecutive days at a dose of 4000 ⁇ g / kg mouse body weight (LPS), and mice receiving water in the same dosing regimen (K).
  • Fig. 6 is a graph illustrating the percentage of CD4 + CD25 + FoxP3 + regulatory T cells in the thymus of healthy mice after intragastric application of LPS once a day for three consecutive days at a dose of 4000 ⁇ g / kg mouse body weight in combination with tartaric acid at a dose of 300 ⁇ g / kg mouse body weight (LPS KW) and mice receiving tartaric acid alone in the same dosing regimen (KW) at a dose of 300 ⁇ g / kg mouse body weight or water (K).
  • LPS KW ⁇ g / kg mouse body weight
  • K dosing regimen
  • LPS LPS
  • LPS derived from E. coli Olll: B4
  • concentration of 1 ⁇ g / ⁇ was prepared in distilled water.
  • the prepared solution was stored at temperature below 10 °C in the refrigerator. Prior to each administration, the solution was heated to 36 °C and vigorously stirred.
  • mice were divided into two groups. One group was i.p. treated with LPS at a dose of 200 ⁇ g / kg mouse body weight (100 ⁇ of the stock solution mixed with 400 ⁇ of physiological saline) for three consecutive days, while the control group received physiological saline. Then, the quantity of the CDl lb mid F4 / 80 mid myeloid cells in the peritoneal cavity and the percentage of Treg in the thymus was estimated in both groups of mice. For this purpose, cells from the peritoneal cavity and thymus of mice were labelled with monoclonal antibodies labelled with different fluorochromes.
  • the percentage of the chosen population of cells was estimated based on the measurement performed in a flow cytometer (BD FACSAria).
  • BD FACSAria flow cytometer
  • CD4 + CD25 + FoxP3 + cells Treg
  • FoxP3 transcription factor was not stained, because B6.Cg-Foxp3 tm2Tch n mice were used (in which FoxP3 expressing cells simultaneously express GFP).
  • the cells from the peritoneal cavity were stained with the antibody biding to following surface markers: CD19,CDl lc,CDl lb, F4/80.
  • mice in which all cells of the immune system express GFP
  • C57BL / 6 mice Tg (UBC-GFP) 30SchaGFP were divided into two groups. One group was intraperitoneally administered with LPS at a dose of 200 ⁇ g / kg body weight/day for 3 consecutive days, while the control group received physiological saline. Then, after 24 hours of the last administration of LPS or physiological saline, cells from mice peritoneal cavity were isolated and CD19 " CDl lc lo Cl lb + F4 / 80 + myeloid cells were sorted using BD FACSAria sorter.
  • mice which received adoptive transfer of the CD19 CD1 lc l0 Cl lb + F4 / 80 + peritoneal myeloid cells from mice treated with LPS, the presence of cells expressing GFP (showing green fluorescence) was observed.
  • Treg cells The percentage of Treg cells was determined by flow cytometry after labelling of the thymic cells with monoclonal antibodies binding surface markers: CD4, CD8, CD25. The results are presented in Fig. 4.
  • DSS dextran sulfate sodium
  • the inflammation of intestine was induced by treatment of C57BL / 6 mice with DSS (a standard technique of 1% solution of DSS in the drinking water for a month). The inflammation of the intestine was confirmed by the presence of blood in the stool (evaluation using Hemoccult SENSA test, Beckman Coulter).
  • mice were divided into two groups.
  • One group received LPS by gavage at a dose of 200 ⁇ g / kg mouse body weight (100 ⁇ of stock solution mixed with 400 ⁇ of physiological saline) for a three consecutive days, while the second group (control) received physiological saline.
  • tartaric acid to LPS is intended to transiently increase the permeability of the intestinal wall of a subject, resulting in LPS induced Treg cells development in the thymus, in a situations where the intestinal wall is not affected enough by the disease to allow LPS to penetrate it.
  • LPSKW D-tartaric acid
  • a fresh solution of D-tartaric acid was also obtained by mixing with 100 ⁇ of the stock solution of D-tartaric acid and with 400 ⁇ sterile water.
  • One mouse weighing 28-30g received 0,5 ml of this solution thereby a dose of 300 mg / kg body weight (hereinafter referred to as KW) was obtained.
  • the LPS solution was prepared by mixing 100 ⁇ of the LPS stock solution with 400 ⁇ of sterile water (LPS), or 0,5 ml of water (K) was administered.
  • mice For the experiment healthy B6.Cg-Foxp3tm2 Tch 1 J mice were used. The mice were divided into 4 groups. For three consecutive days, one group was administered LPSKW by gavage, the second group was administered KW by gavage, the third group was administered with LPS by gavage and the fourth group was administered water (K).

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Abstract

L'invention concerne l'utilisation du LPS pour l'induction des cellules T régulatrices CD4+ CD25+ FoxP3+ dans des affections ou des maladies associées à une réponse immunitaire excessive de l'organisme provoquée par des troubles gastrointestinaux, en particulier sélectionnés à partir d'un groupe de maladies inflammatoires intestinales non-spécifiques (IBD) et/ou d'allergies alimentaires, dans le cadre d'un schéma thérapeutique particulier et, éventuellement, en combinaison avec l'acide D-tartrique.
PCT/IB2016/055500 2015-09-16 2016-09-15 Lipopolysaccharide (lps) pour une utilisation dans le traitement d'affections ou de maladies associées à une réponse immunitaire excessive de l'organisme provoquée par des troubles du système digestif Ceased WO2017046734A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLPL414020 2015-09-16
PL41402015A PL233566B1 (pl) 2015-09-16 2015-09-16 Zastosowanie lipopolisacharydu (LPS) w leczeniu stanów lub chorób związanych z nadmierną odpowiedzią odpornościową organizmu wywołanych schorzeniami układu pokarmowego zwłaszcza z grupy nieswoistych stanów zapalnych jelit (IBD) i/lub alergii pokarmowych

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040033550A1 (en) * 2002-06-26 2004-02-19 Petr Aparin Method of isolating biologically active fraction containing clinically acceptable native S-lipopolysaccharides obtained from bacteria producing endotoxic lipopolysaccharides
WO2010025542A1 (fr) * 2008-09-05 2010-03-11 National Research Council Of Canada Vaccins lipopolyosidiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040033550A1 (en) * 2002-06-26 2004-02-19 Petr Aparin Method of isolating biologically active fraction containing clinically acceptable native S-lipopolysaccharides obtained from bacteria producing endotoxic lipopolysaccharides
WO2010025542A1 (fr) * 2008-09-05 2010-03-11 National Research Council Of Canada Vaccins lipopolyosidiques

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ABDULLAH ALANGARI ET AL: "LPS-responsive beige-like anchor () gene mutation in a family with inflammatory bowel disease and combined immunodeficiency", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 130, no. 2, 29 May 2012 (2012-05-29), pages 481 - 488.e2, XP028431303, ISSN: 0091-6749, [retrieved on 20120602], DOI: 10.1016/J.JACI.2012.05.043 *
ABREU MARIA TERESA ET AL: "Regulation of TLR4 and MD-2 in the intestinal epithelium: Evidence for dysregulated LPS signaling in human inflammatory bowel disease (IBD)", THE FASEB JOU, FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY, US, vol. 17, no. 7, 14 April 2003 (2003-04-14), pages C57, XP009192794, ISSN: 0892-6638 *
D QUARCOO ET AL: "Oral administration of endotoxins modulates allergen-induced immune reactions in a rat model of food allergy*1", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 113, no. 2, 1 February 2004 (2004-02-01), AMSTERDAM, NL, pages S238, XP055328898, ISSN: 0091-6749, DOI: 10.1016/j.jaci.2004.01.315 *
MARIA T. ABREU ET AL: "TLR4 and MD-2 are up-regulated in inflammatory bowel disease (IBD): Mechanisms for dysregulated LPS signaling", GASTROENTEROLOGY, vol. 124, no. 4, 1 April 2003 (2003-04-01), AMSTERDAM, NL, pages A338, XP055328892, ISSN: 0016-5085, DOI: 10.1016/S0016-5085(03)81704-3 *
SPILLER GENE A ET AL: "Effect of tartaric acid and dietary fibre from sun-dried raisins on colonic function and on bile acid and volatile fatty acid excretion in healthy adults.", BRITISH JOURNAL OF NUTRITION, vol. 90, no. 4, October 2003 (2003-10-01), pages 803 - 807, XP055330679, ISSN: 0007-1145 *

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PL233566B1 (pl) 2019-10-31

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