US20090124573A1 - Immunomodulating compounds and related compositions and methods - Google Patents

Immunomodulating compounds and related compositions and methods Download PDF

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Publication number
US20090124573A1
US20090124573A1 US12/267,602 US26760208A US2009124573A1 US 20090124573 A1 US20090124573 A1 US 20090124573A1 US 26760208 A US26760208 A US 26760208A US 2009124573 A1 US2009124573 A1 US 2009124573A1
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Prior art keywords
psa
cells
mice
polysaccharide
animals
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Sarkis Mazmanian
June L. Round
Ryan Michael O'connell
Dennis L. Kasper
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Brigham and Womens Hospital Inc
California Institute of Technology CalTech
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Brigham and Womens Hospital Inc
California Institute of Technology CalTech
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Application filed by Brigham and Womens Hospital Inc, California Institute of Technology CalTech filed Critical Brigham and Womens Hospital Inc
Assigned to CALIFORNIA INSTITUTE OF TECHNOLOGY reassignment CALIFORNIA INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: O'CONNELL, RYAN MICHAEL, ROUND, JUNE L., MAZMANIAN, SARKIS
Assigned to BRIGHAM AND WOMEN'S HOSPITAL reassignment BRIGHAM AND WOMEN'S HOSPITAL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KASPER, DENNIS L.
Publication of US20090124573A1 publication Critical patent/US20090124573A1/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: BRIGHAM & WOMEN'S HOSPITAL, INC.
Priority to US12/831,131 priority patent/US20110002965A1/en
Priority to US13/464,876 priority patent/US20130039949A1/en
Priority to US14/631,760 priority patent/US20160022727A1/en
Priority to US14/660,827 priority patent/US20160030464A1/en
Priority to US15/706,604 priority patent/US20180264026A1/en
Priority to US16/151,793 priority patent/US11622973B2/en
Priority to US16/562,358 priority patent/US20200197436A1/en
Abandoned legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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

  • the present disclosure relates to the immune system, and, in particular, to an immunomodulating compound able to control T cell differentiation and/or cytokines production associated with an immunitary response in an individual.
  • T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity.
  • T helper cells also known as effector T cells or Th cells
  • Th cells are a sub-group of lymphocytes (a type of white blood cell or leukocyte) that plays an important role in establishing and maximizing the capabilities of the immune system and in particular in activating and directing other immune cells.
  • Th cells are essential in determining B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.
  • Th cells Different types have been identified that originate in outcome of a differentiation process and are associated with a specific phenotype. Following T cell development, matured, na ⁇ ve (meaning they have never been exposed to the antigen to which they can respond) T cells leave the thymus and begin to spread throughout the body. Once the na ⁇ ve T cells encounter antigens throughout the body, they can differentiate into a T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17) or regulatory T cell (Treg) phenotype.
  • Th1 T-helper 1
  • Th2 T-helper 2
  • Th17 regulatory T cell
  • Th1, Th2, and Th17 inflammatory T-helper or inflammatory Th
  • pro-inflammatory cytokines such as IL-1, IL-6, TNF-a, IL-17, IL21, IL23, and/or through activation and/or inhibition of other T cell including other Th cells (for example Th1 cell suppresses Th2 and Th17, Th2 suppresses Th1 and Th17).
  • Tregs instead, are a component of the immune system that suppresses biological activities of other cells associated to an immune response.
  • Tregs can secrete immunosuppressive cytokines TGF-beta and Interleukin 10, and are known to be able to limit or suppress inflammation.
  • An imbalance in the profile of any of the inflammatory T-helper cells is usually associated with a condition in an individual.
  • an increase profile for Th1 or Th17 leads to autoimmunity, whereas an increased Th2 cell profile leads to allergies and asthma.
  • imbalance of Th17 cell profile has been associated with several autoimmunitary conditions. Treg cells suppress inflammation induced by all 3 other T cell lineages, and thus are crucial for preventing uncontrolled inflammation, which leads to disease. Therefore, a balanced T-helper profile is critical for health in individuals.
  • immunomodulating compounds and related methods and compositions that are suitable to balance a T-helper cell profile, and in particular to balance the cell profile of at least one of Th1, Th2, Th17 and Treg cells in an individual. More particularly, provided herein are methods and compositions based on the surprising immunomodulating properties of PSA polysaccharide A (PSA) and other zwitterionic polysaccharides (ZPs) that make those polysaccharides suitable for treatment, prevention and control of inflammations and inflammatory conditions in an individual.
  • PSA PSA polysaccharide A
  • ZPs zwitterionic polysaccharides
  • a method to balance a T-helper cell profile in an individual comprises administering to the individual an effective amount of a zwitterionic polysaccharide.
  • a method to balance a cell profile of at least one Th cell selected from the group consisting of Th1, Th2, Th17 and Treg, in an individual comprises administering to the individual an effective amount of a zwitterionic polysaccharide.
  • a method to treat or prevent conditions associated with an imbalanced cell profile of at least one Th cell selected from the group consisting of Th1, Th2, Th17 and Treg in an individual comprises administering to the individual an effective amount of a zwitterionic polysaccharide.
  • a method to treat or prevent conditions associated with production of at least one of IL-1, IL-6, TNF-a, IL-17, IL21, IL23 cytokines in an individual comprises administering to the individual an effective amount of a zwitterionic polysaccharide.
  • an anti-inflammatory composition comprises a zwitterionic polysaccharide and a suitable vehicle, wherein the zwitterionic polysaccharide is comprised in an amount of from about 1 to about 100 ⁇ g.
  • FIG. 1 shows an exemplary ZP mediated protection from experimental colitis in individuals according to some embodiments herein disclosed.
  • Panel (a) shows diagrams summarizing the results of mono-association of germ-free mice with wild-type B. fragilis and B. fragilis DPSA (mean percentages ⁇ Standard Deviation (SD) for 3 experiments: conventional, 38.4% ⁇ 2.2; germ-free, 26.7% ⁇ 1.3; B. fragilis, 40.8% ⁇ 3.1; B. fragilis DPSA, 28.8% ⁇ 2.6). All cells gated on CD4 + splenocytes.
  • Panel (b) shows a diagram illustrating the results of co-colonization experiments of H. hepaticus with B. fragilis and B.
  • fragilis DPSA two-tailed p value, 0.004; Mann-Whitney U test). Combined data from 2 independent experiments are shown. Error bars show SD for triplicate samples.
  • Panel (c) shows a diagram illustrating the results of ELISA test of colon organ cultures to detect TNFa levels in animals co-colonized with H. hepaticus and wild-type B. fragilis or B. fragilis DPSA.
  • Panel (d) shows a diagram illustrating the results of a Q-PCR for IL-23p19 performed on splenocytes, normalized to L32 expression. Error bars show SD for triplicate samples.
  • FIG. 2 shows an exemplary ZP mediated cytokine control according to some embodiments herein disclosed.
  • FIG. 2 shows diagrams illustrating the results of ELISA tests for the detection of the pro-inflammatory cytokines IL-12p40 (left) and IL-1b (right) in animals co-colonized with H. hepaticus and wild-type B. fragilis or B. fragilis DPSA over those in control animals (C57BL/6). Results are from one trial of 2 independent experiments. Error bars indicate SD values from studies of colons recovered from 4 animals per group.
  • FIG. 3 shows an example of ZP mediated control of TNFa expression by CD4 + T cells according to some embodiments herein disclosed.
  • CD4 + cells were purified from pooled splenocytes from each group (4 mice per group) and restimulated in vitro with PMA and ionomycin in the presence of brefeldin A for 4 hours. Cells were stained for intracellular TNF ⁇ . Cells within the lymphocyte gate were included in the analysis, and numbers indicate the percentage of cells producing TNF ⁇ . Purified cells were >90% CD4 + . Animals colonized with PSA-producing B. fragilis during protection displayed lower TNFa levels than diseased animals.
  • A Rag2 ⁇ / ⁇ animals with CD4 + CD45Rb high T cell transfer colonized with H. hepaticus and B. fragilis 9343 (wt).
  • B Rag2 ⁇ / ⁇ animals with CD4 + CD45Rb high T cell transfer colonized with H. hepaticus and B. fragilis DPSA.
  • C Rag2 ⁇ / ⁇ animals with CD4 + CD45Rb high T cell transfer colonized with H. hepaticus alone.
  • D C57BL/6 mice colonized with H. hepaticus alone.
  • E B. fragilis genomic DNA (positive control).
  • M Marker. Primers for B.
  • FIG. 5 effects associated to a ZP-mediated protection according to some embodiments herein disclosed.
  • FIG. 5 shows a diagram illustrating the results of Q-PCR experiments directed to quantitate H. hepaticus in animals co-colonized with H. hepaticus and wild-type B. fragilis or B. fragilis DPSA. The results was assessed according to Young et al., 2004 1 as log 10 number of copies of a known gene (cytolethal distending toxin). Animals contained equivalent levels of H. hepaticus at the end of the experiment.
  • Panel (c) shows the architecture of colonic sections from wild-type animals (left panel); following transfer of CD4 + CD45Rb high T cell into Helicobacter -colonized Rag2 ⁇ / ⁇ mice (middle panel); oral PSA treatment of Helicobacter -colonized animals (right panel). Images in each row are the same magnification.
  • FIG. 7 shows a ZP modulated immune response according to some embodiments herein disclosed.
  • Panel (a) shows a diagram illustrating the correlation between oral PSA administration and body weight related to TNBS-treated PBS controls. ANOVA values for all indicated groups (asterisks) are statistically significant. Error bars show SD between 4 animals per group.
  • Panel (b) shows colon sections from TNBS+PBS-treated groups, from TNBS+PSA-treated animals and from a control (representative sections from animals in 2 independent experiments).
  • Panels (c, d) show diagram illustrating the results of Q-PCR of purified CD4 + T cells from MLNs with IL-17A (Panel c) and TNFa (Panel d) in presence or absence of PSA during disease.
  • Error bars are from duplicate runs of 3 independent experiments.
  • Panels (e, f) show diagrams illustrating transcriptional expression of IL17A (Panel e) and TNF ⁇ (Panel f) from homogenized colons of TNBS+PBS-treated groups, from TNBS+PSA-treated animals and from a control. Error bars are from duplicate runs of 3 independent experiments.
  • FIG. 8 shows a ZP mediated control of cytokine expression according to some embodiments herein disclosed.
  • Panel (a) shows a diagram illustrating the results of Q-PCR assay of colons for IL-10 in wild type mice treated with ethanol (control), TNBS, or TNBS and PSA. Error bars show SD for triplicate samples.
  • Panel (b) shows a diagram illustrating Q-PCR results for IL-10 expression in CD4 + T cells purified from MLNs of TNBS-treated groups. Error bars show SD for triplicate samples.
  • Panel (c) shows a diagram illustrating the effects of incubation of BMDC/T cell co-cultures with purified PSA LPS and a-CD3/a-CD28 on IL-10 production.
  • Panel (d) shows a diagram illustrating the results of an infection of BMDC-T cell co-cultures with increasing concentrations of H. hepaticus (multiplicity of infection: 0.1, 1.0, and 10, as depicted by triangles) on TNFa release in presence (middle three bars) or absence (left three bars) of PSA and following the addition of aIL-10R right three bars. Error bars show SD values of experiments run in triplicate.
  • FIG. 9 shows a ZP mediated control of cytokine expression according to some embodiments herein disclosed.
  • FIG. 9 shows a diagram illustrating the results for an IL-10 ELISA of supernatants of primary BMDC-T cell co-cultures incubated for 48 hours with H. hepaticus alone or with H. hepaticus and B. fragilis (wild-type or ⁇ PSA) at a multiplicity of infection of 5. Error bars show SD values for samples run in duplicate and represent 3 independent experiments.
  • FIG. 10 shows a ZP mediated control of cytokine expression according to some embodiments herein disclosed.
  • FIG. 10 shows a diagram illustrating the results of an infection of BMDC-T cell co-cultures with increasing concentrations of live H. hepaticus (multiplicity of infection: 0.1, 1.0, and 10, as depicted by triangles) on release of the cytokine IL-1b in presence (middle three bars) or absence (left three bars) of PSA and following the addition of aIL-10R right three bars. Error bars show SD values for experiments run in triplicate.
  • FIG. 11 shows a ZP mediated protection from inflammation according to some embodiments herein disclosed.
  • Panels (a, b) show diagrams illustrating results of ELISA detection for pro-inflammatory cytokines TNF ⁇ (Panel a) and IL-17A (Panel b) in IL-10 ⁇ / ⁇ mice left uncolonized (control) or colonized with H. hepaticus (to induce inflammation) either alone or in combination with B. fragilis (wild-type or ⁇ PSA). Error bars show SD for triplicate samples.
  • Panel (c) shows a diagram illustrating the colitis scores in Rag ⁇ / ⁇ animals with CD4 + CD45Rb high T cell transfer colonized with H.
  • Panel (d) shows a diagram illustrating colitis scores in Rag ⁇ / ⁇ animals with CD4 + CD45Rb high T cell transferred from IL-10 ⁇ / ⁇ mice colonized with H. hepaticus with PSA or PBS. Results are shown for 1 representative trial of 2 independent experiments.
  • Panel (e) shows histologic colon sections Rag ⁇ / ⁇ animals with CD4 + CD45Rb high T cell transferred from IL-10 ⁇ / ⁇ mice colonized with H. hepaticus with PSA or PBS. All images are the same magnification.
  • FIG. 12 shows effect of a ZP administration supporting embodiments herein disclosed.
  • FIG. 12 shows a diagram illustrating the variation on body weight in groups of 4 C57BL/6 mice treated with PSA (or PBS) and then subjected to rectal administration of TNBS or vehicle (control). Mean body weights (shown as percentages of initial weight) are shown for each group; SD values indicate that, in the absence of IL-10, PSA cannot restore TNBS-induced weight loss. ANOVA demonstrates that weight loss in both TNBS-treated groups is statistically different from that in control animals.
  • FIG. 13 shows effects of a ZP administration supporting some embodiments herein disclosed.
  • FIG. 13 shows results of histologic analysis of H&E-stained sections from a representative animal of groups of 4 C57BL/6 mice treated with PSA (or PBS) and then subjected to rectal administration of TNBS or vehicle (control). Results represent 2 independent experiments.
  • FIG. 14 shows inhibition of inflammation within extra-intestinal immune compartments following oral administration of ZPS according to some embodiments herein disclosed.
  • Panel (a) shows a diagram illustrating the colonic histological score detected in untreated mice (control) and in mice treated with TNBS or TNBS/PSA. Each dot represents an individual mouse and the line indicates the average score of the group.
  • Panel (c) shows an image of the spleen of untreated mice (control) and mice treated with TNBS or TNBS/PSA
  • Panel (d) shows a diagram illustrating the relative units of TNF- ⁇ , IL-6, IL-17A and IL-10 within CD4 + splenocytes in untreated mice (control) and in mice treated with TNBS or TNBS/PSA.
  • FIG. 15 shows protection from TNBS induced intestinal colitis following administration of ZPS to extra-intestinal sites according to some embodiments herein disclosed.
  • Panel (b) shows a diagram illustrating variation of the spleen weight in untreated mice (Etoh) and in mice treated with TNBS or TNBS/PSA systemically administered. The weight of the spleen was used as an indicator of size. Each diamond represents the weight of the spleen from an individual animal. The bar indicates the average weight of the group. P values were determined by students T test.
  • FIG. 16 shows inhibition of inflammatory cytokines at both intestinal and systemic immune compartments following systemic administration of ZPS during TNBS induced colitis according to some embodiments herein disclosed.
  • Panel (a) shows a diagram illustrating TNF- ⁇ production in CD4 + T lymphocytes residing within the mesenteric lymph nodes (MLN) splenocytes in untreated mice (control) and in mice treated with TNBS or TNBS/PSA. Cells were collected from the MLN and stained with antibodies recognizing CD4 or TNF-a. Numbers within quadrants represent the percentage of cells.
  • MN mesenteric lymph nodes
  • Panel (b) shows a diagram illustrating analysis of the expression of IL-12, IL-23, and IL-17 in colon of untreated mice (control) and mice treated with TNBS or TNBS/PSA.
  • Panel (c) show a diagram illustrating TNF- ⁇ production in CD4 + T lymphocytes residing within the spleen of untreated mice (control) and of mice treated with TNBS or TNBS/PSA. Numbers within quadrants represent the percentage of cells.
  • Panel (d) a diagram illustrating analysis of the expression of IL-12, IL-6, and IL-17 in spleen of untreated mice (control) and mice treated with TNBS or TNBS/PSA.
  • FIG. 17 shows inhibition of inflammation and death associated with systemic septic shock following administration of ZPS according to some embodiments herein disclosed.
  • Panel (a) shows a diagram illustrating TNF-a serum levels in mice 1 and 4 hours post-administration of 100 ⁇ g of LPS alone. Mice were either pre-treated with PBS or 50 ug of PSA three times every other day before LPS administration. * indicates statistical significance as determined by a students t test. SD was determined from the serum of individual mice. These data are representative of three independent experiments.
  • Panel (c) shows a diagram illustrating variation of the spleen weight in untreated mice (con) and in mice administered LPS within the intraperitoneal cavity (LPS) and pre-treated with PBS or PSA as in panel a. Each dot represents the weight of the spleen from an individual mouse. P values were determined by a students T test.
  • Panel (d): shows a diagram illustrating the survival rate of animals undergoing septic shock induced by high dose (500 ⁇ g) administration of LPS and pre-treated with PSA or PBS. N 12 mice in each group.
  • Panel (e) shows a diagram illustrating the serum concentrations of TNF-a in mice post-administration of 500 ⁇ g of LPS alone or pre-treated with PSA or PBS. p values were determined by students T test. Each dot represents an individual mouse.
  • Panel (f) shows a diagram illustrating the serum concentrations of IL-6 in mice post-administration of 500 g of LPS alone and pre-treated with PSA or PBS. p values were determined by students T test. Each dot represents an individual mouse.
  • FIG. 18 shows inhibition of inflammation and death associated with systemic septic shock following administration of ZPS according to some embodiments herein disclosed.
  • Panel (c): shows a diagram illustrating percent survival in mice post-administration of LPS alone or together with PSA in IL-10 31/ ⁇ mice. N 8 mice in each group.
  • FIG. 19 shows a diagram illustrating additional effects of ZPS administration on inflamed tissues according to some embodiments herein disclosed.
  • Methods and compositions are herein disclosed that allow balancing a T-helper cell profile in an individual, based on the use of PSA or another zwitterionic polysaccharide.
  • CD4 + T cells are also known as CD4 + T cells.
  • CD4 + T cells are generally treated as having a pre-defined role as helper T cells within the immune system, although there are known rare exceptions. For example, there are sub-groups of suppressor T cells, natural killer T cells, and cytotoxic T cells that are known to express CD4 (although cytotoxic examples have been observed in extremely low numbers in specific disease states, they are usually considered non-existent).
  • the wording “Th17 cell profile” as used herein indicates the detectable set of data, such as presence and amount, related to production of IL-17 in a certain organ or tissue of the individual wherein the presence and/or activity of Th1 cell is investigated. Similar definitions apply to the other Th cell types.
  • the wording “cell profile” is referred to a subset of Th cell including more then one Th cell type
  • the wording “T-helper cell profile” indicates a detectable set of data related to each marker cytokine that is produced by and characterizes each, of the T-helper cells of the subset.
  • balance indicates the activity of bringing the cell profile to a status associated with absence of an inflammatory response.
  • balanced Th profile indicates the Th cell profile status associated with absence of an inflammatory response and in particular to the detectable set of data related to a marker cytokine that is produced by the T helper cell and characterizes the T helper cell with respect to another in absence of an inflammatory response.
  • T-helper cell profile refers to a subset of Th cell including more then one Th cell type
  • the term “balanced Th profile” refers instead to the relative ratio between the detectable set of data related to each marker cytokine that is produced by and characterizes each, of the T-helper cells.
  • a “balanced Th cell profile” referred to a Th cells subset comprising Th1, Th2 and Th17 indicates the relative ratio of data related to Interferon-gamma, IL-4 and IL17 associated with absence of an inflammatory response.
  • zwitterionic polysaccharide indicates synthetic or natural polymers comprising one or more monosaccharides joined together by glicosidic bonds, and including at least one positively charged moiety and at least one negatively charged moiety.
  • Zwitterionic polysaccharides include but are not limited to polymers of any length, from a mono- or di-saccharide polymer to polymers including hundreds or thousands of monosaccharides.
  • a zwitterionic polysaccharide can include repeating units wherein each repeating unit includes from two to ten monosaccharides, a positively charged moiety (e.g.
  • a derivative polysaccharide indicates a second polysaccharide that is structurally related to the first polysaccharide and is derivable from the first polysaccharide by a modification that introduces a feature that is not present in the first polysaccharide while retaining functional properties of the first polysaccharide.
  • a derivative polysaccharide of PSA usually differs from the original polysaccharide by modification of the repeating units or of the saccharidic component of one or more of the repeating units that might or might not be associated with an additional function not present in the original polysaccharide.
  • a derivative polysaccharide of PSA retains however one or more functional activities that are herein described in connection with PSA in association with the anti-inflammatory activity of PSA.
  • the zwitterionic polysaccharide can be PSA and/or PSB.
  • the effective amount of ZP and in particular PSA and/or PSB is from about 1-100 micrograms to about 25 grams of body weight and the T-helper cell profile is balanced by balancing at least one of Th1, Th2, Th17 and Treg, in particular at least one of Th1, Th 2 and Treg and Th17. More particularly, in some embodiments, balance Th cell profile can be performed by balancing the Th17 cell profile
  • control indicates the activity of affecting and in particular inhibiting a biological reaction or process, which include but are not limited to biological and in particular biochemical events occurring in a biological system, such as an organism (e.g. animal, plant, fungus, or micro-organism) or a portion thereof (e.g. a cell, a tissue, an organ, an apparatus).
  • a biological system such as an organism (e.g. animal, plant, fungus, or micro-organism) or a portion thereof (e.g. a cell, a tissue, an organ, an apparatus).
  • a substance “inhibits” a certain biological reaction or process if it is capable of decreasing that biological reaction or process by interfering with said reaction or process.
  • a substance can inhibit a certain biological reaction or process by reducing or suppressing the activity of another substance (e.g. an enzyme) associated to the biological reaction or process, e.g. by binding, (in some cases specifically), said other substance.
  • Inhibition of the biological reaction or process can be detected by detection of an analyte associated with the biological reaction or process.
  • detect indicates the determination of the existence, presence or fact of an analyte or related signal in a limited portion of space, including but not limited to a sample, a reaction mixture, a molecular complex and a substrate.
  • a detection is “quantitative” when it refers, relates to, or involves the measurement of quantity or amount of the analyte or related signal (also referred as quantitation), which includes but is not limited to any analysis designed to determine the amounts or proportions of the analyte or related signal.
  • a detection is “qualitative” when it refers, relates to, or involves identification of a quality or kind of the analyte or related signal in terms of relative abundance to another analyte or related signal, which is not quantified.
  • cytokine indicates a category of signaling proteins and glycoproteins extensively used in cellular communication that are produced by a wide variety of hematopoietic and non-hematopoietic cell types and can have autocrine, paracrine and endocrine effects, sometimes strongly dependent on the presence of other chemicals.
  • the cytokine family consists mainly of smaller, water-soluble proteins and glycoproteins with a mass between 8 and 30 kDa. Cytokines are critical to the development and functioning of both the innate and adaptive immune response. They are often secreted by immune cells that have encountered a pathogen, thereby activating and recruiting further immune cells to increase the system's response to the pathogen.
  • Detection of inhibition of cytokine production can be performed by methods known to a skilled person including but not limited to ELISA, Q-PCR and intracellular cytokine staining detected by FACs and any other methods identifiable by a skilled person upon reading of the present disclosure.
  • a ZP can be administered to inhibit production of at least one of TNF-a, IL-6, IL-17, IL-21 and IL-23.
  • ZP can be administered systemically and in particular, orally, sub cutaneously, intra peritoneally, and intravenously.
  • ZP can be administered in an amount between about 1 and about 100 micrograms/25 grams of body weight.
  • Methods and compositions are herein disclosed that allow control of an inflammation associated with an imbalanced Th cell profile and or to production of at least one of the pro-inflammatory cytokines IL-1, IL-6, TNF-a, IL-17, IL21, IL23, and TGF- ⁇ in an individual.
  • acute inflammation indicates a short-term process characterized by the classic signs of inflammation (swelling, redness, pain, heat, and loss of function) due to the infiltration of the tissues by plasma and leukocytes.
  • An acute inflammation typically occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring (fibrosis).
  • chronic inflammation indicates a condition characterized by concurrent active inflammation, tissue destruction, and attempts at repair. Chronic inflammation is not characterized by the classic signs of acute inflammation listed above.
  • chronically inflamed tissue is characterized by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
  • An inflammation can be controlled in the sense of the present disclosure by affecting and in particular inhibiting anyone of the events that form the complex biological response associated with an inflammation in an individual.
  • an inflammation can be controlled by affecting and in particular inhibiting cytokine production, and more particularly production of pro-inflammatory cytokines, following administration of a zwitterionic polysaccharide.
  • a ZP can be used to control an inflammation associated with IL-1, IL-6, TNF-a, IL-17, IL21, IL23, and/or TGF- ⁇ mediated inflammation in an individual.
  • cytokine mediated inflammation indicates an inflammation wherein the complex biological response to a harmful stimulus is controlled by cytokine molecules, such as pro-inflammatory cytokine molecules (e.g. TNF-a, IL1 and/or IL-6) and anti-inflammatory cytokine molecules (e.g. IL-10).
  • Exemplary cytokine mediated inflammation include but are not limited to conditions mediated by IL-1, IL-6, TNF- ⁇ , IL-12p35, IL-17A, IL-21, IL-22, IFN- ⁇ and/or IL-23p19.
  • the cytokine is at least one of TNF-a, IL-17, IL-21, and IL-23 and the cytokine mediated inflammation is a IBD, asthma, type I diabetes, multiple sclerosis, obesity, type 2 diabetes, hay fever, food allergies, skin allergies, or rheumatoid arthritis.
  • the inflammation is a systemic inflammation.
  • Systemic inflammations include but are not limited to an inflammatory response in the circulatory system, an inflammatory response which is not confined in a specific organ, and an inflammatory response that extends to a plurality (up to all) tissues and organs in an individual.
  • a ZP can be used to control an inflammation associated with an imbalance of T-helper cell profile and in particular to a Th17 cell profile, including but not limited to rheumatoid arthritis, respiratory diseases, allograft rejection, systemic lupus erythematosis, tumorgenesis, multiple sclerosis, systemic sclerosis and chronic inflammatory bowel disease.
  • PSA can be administered systemically to the individual.
  • systemic administration indicates a route of administration by which PSA is brought in contact with the body of the individual, so that the desired effect is systemic (i.e. non limited to the specific tissue where the inflammation occurs).
  • Systemic administration includes enteral and parenteral administration.
  • Enteral administration is a systemic route of administration where the substance is given via the digestive tract, and includes but is not limited to oral administration, administration by gastric feeding tube, administration by duodenal feeding tube, gastrostomy, enteral nutrition, and rectal administration.
  • Parenteral administration is a systemic route of administration where the substance is given by route other than the digestive tract and includes but is not limited to intravenous administration, intra-arterial administration, intramuscular administration, subcutaneous administration, intradermal, administration, intraperitoneal administration, and intravesical infusion.
  • administration is performed intravenously by introducing a liquid formulation including a ZP in a vein of an individual using intravenous access methods identifiable by a skilled person, including access through the skin into a peripheral vein.
  • administration of a ZP is performed intraperitoneally, by injecting a ZP in the peritoneum of an individual, and in particular of animals or humans. Intraperitoneal administration is generally preferred when large amounts of blood replacement fluids are needed, or when low blood pressure or other problems prevent the use of a suitable blood vessel for intravenous injection.
  • administration is performed intragastrically, including administration through a feeding tube.
  • administration of a ZP is performed intracranially.
  • a ZP can be administered topically by applying the ZP usually included in an appropriate formulation directly where its action is desired.
  • Topical administration include but is not limited to epicutaneous administration, inhalational administration (e.g. in asthma medications), enema, eye drops (E.G. onto the conjunctiva), ear drops, intranasal route (e.g. decongestant nasal sprays), and vaginal administration.
  • the inflammation is an inflammation of in a tissue and in particular in pancreas, lungs, joints, skin, brains and central nervous system, and eyes.
  • PSA is used in a method of treating or preventing a condition associated with inflammation in an individual. The method comprises administering to the individual a therapeutically effective amount of the PSA.
  • the term “individual” as used herein includes a single biological organism wherein inflammation can occur including but not limited to animals and in particular higher animals and in particular vertebrates such as mammals and in particular human beings.
  • condition indicates a usually the physical status of the body of an individual, as a whole or of one or more of its parts, that does not conform to a physical status of the individual, as a whole or of one or more of its parts, that is associated with a state of complete physical, mental and possibly social well-being.
  • Conditions herein described include but are not limited disorders and diseases wherein the term “disorder” indicates a condition of the living individual that is associated to a functional abnormality of the body or of any of its parts, and the term “disease” indicates a condition of the living individual that impairs normal functioning of the body or of any of its parts and is typically manifested by distinguishing signs and symptoms.
  • Exemplary conditions include but are not limited to injuries, disabilities, disorders (including mental and physical disorders), syndromes, infections, deviant behaviors of the individual and atypical variations of structure and functions of the body of an individual or parts thereof.
  • the wording “associated to” as used herein with reference to two items indicates a relation between the two items such that the occurrence of a first item is accompanied by the occurrence of the second item, which includes but is not limited to a cause-effect relation and sign/symptoms-disease relation.
  • Conditions associated with an inflammation include but are not limited to inflammatory bowel disease, including but not limited to Chron's disease and ulcerative colitis, asthma, dermatitis, arthritis, myasthenia gravis, Grave's disease, sclerosis, psoriasis.
  • treatment indicates any activity that is part of a medical care for or deals with a condition medically or surgically.
  • prevention indicates any activity, which reduces the burden of mortality or morbidity from a condition in an individual. This takes place at primary, secondary and tertiary prevention levels, wherein: a) primary prevention avoids the development of a disease; b) secondary prevention activities are aimed at early disease treatment, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms; and c) tertiary prevention reduces the negative impact of an already established disease by restoring function and reducing disease-related complications.
  • An effective amount and in particular a therapeutically effective amount of PSA is for example in the range of between about 1 ⁇ g to about 100 ⁇ g of PSA per 0.025 kilograms of body weight. In some embodiments, the effective amount is in a range from about 001 to about 1,000 ⁇ g per 25 grams of body weight.
  • PSA is comprised in a composition together with a suitable vehicle.
  • vehicle indicates any of various media acting usually as solvents, carriers, binders or diluents for PSA comprised in the composition as an active ingredient.
  • composition where the composition is to be administered to an individual the composition can be a pharmaceutical anti-inflammatory composition, and comprises PSA and a pharmaceutically acceptable vehicle.
  • PSA can be included in pharmaceutical compositions together with an excipient or diluent.
  • pharmaceutical compositions which contain PSA, in combination with one or more compatible and pharmaceutically acceptable vehicle, and in particular with pharmaceutically acceptable diluents or excipients.
  • excipient indicates an inactive substance used as a carrier for the active ingredients of a medication.
  • Suitable excipients for the pharmaceutical compositions herein disclosed include any substance that enhances the ability of the body of an individual to absorb PSA. Suitable excipients also include any substance that can be used to bulk up formulations with PSA to allow for convenient and accurate dosage. In addition to their use in the single-dosage quantity, excipients can be used in the manufacturing process to aid in the handling of PSA. Depending on the route of administration, and form of medication, different excipients may be used. Exemplary excipients include but are not limited to antiadherents, binders, coatings disintegrants, fillers, flavors (such as sweeteners) and colors, glidants, lubricants, preservatives, sorbents.
  • diluent indicates a diluting agent which is issued to dilute or carry an active ingredient of a composition.
  • Suitable diluent include any substance that can decrease the viscosity of a medicinal preparation.
  • compositions and, in particular, pharmaceutical compositions can be formulated for systemic administration, which includes enteral and parenteral administration.
  • compositions for parenteral administration include but are not limited to sterile aqueous solutions, injectable solutions or suspensions including PSA.
  • a composition for parenteral administration can be prepared at the time of use by dissolving a powdered composition, previously prepared in lyophilized form, in a biologically compatible aqueous liquid (distilled water, physiological solution or other aqueous solution).
  • compositions for enteral administration include but are not limited to a tablet, a capsule, drops, and suppositories.
  • B. fragilis NCTC9343 and H. hepaticus ATCC51149 were obtained from the American Type Culture Collection. Conventionally reared SPF mice of strains C57BL/6NTac, C57BL/6NTac IL-10 ⁇ / ⁇ , and B6.129S6-Rag2 tm/Fwa N12 (Rag2 ⁇ / ⁇ ) were purchased from Taconic Farms (Germantown, N.Y.) and screened negative for B. fragilis and H. hepaticus . Swiss-Webster germ-free (SWGF) mice were purchased from Taconic Farms.
  • SWGF Swiss-Webster germ-free mice
  • mice Upon delivery in sterile shipping containers, the mice were transferred to sterile isolators (Class Biologically Clean, Madison, Wis.) in our animal facility. Animals were screened weekly for bacterial, viral, and fungal contamination as previously described 40 . All animals were cared for under established protocols and the IACUC guidelines of Harvard Medical School and the California Institute of Technology.
  • Model of inflammation Three models of intestinal inflammation were used: 1) CD4 + CD45Rb high T cells were purified from the spleens of wild-type or IL-10 ⁇ / ⁇ donor mice by flow cytometry and transferred into Rag ⁇ / ⁇ (C57B1/6) recipients as described. 2) TNBS colitis was induced by pre-sensitization of wild-type (C57B1/6) mice on the skin with a TNBS/acetone mix. Seven days after sensitization, 2.5% TNBS in ethanol was administered rectally; mice were sacrificed 3-6 days later. 3) IL10 ⁇ / ⁇ mice were colonized (by oral gavage) with H. hepaticus alone or in combination with wild-type B. fragilis or B. fragilis ⁇ PSA.
  • CD4 + T cells were purified by negative selection over a magnetic column (Miltenyi or R& D Systems).
  • Lymphocytes were isolated from mouse spleens that were mechanically disrupted into single-cell preparations. Red blood cells were lysed, and splenocytes (1 ⁇ 10 6 ) were incubated with various combinations of antibodies (BD Pharmingen, San Diego, Calif.) at 2 mg/mL for 30 min at 4° C. Cells were then washed and either fixed or used directly.
  • FACS fluorescence-activated cell sorting
  • cytokine flow cytometry samples were analyzed on a model FC500 cytometer (Beckman Coulter, Fullerton, Calif.) or a FacsCalibur (Becton Dickson), and data were analyzed with RXP Analysis Software (Beckman Coulter) or FlowJO. FACS was performed on a BD FACSAria, and cell purity was always >99%.
  • CD4 + T cells were purified from splenic lymphocytes (prepared as described above) with a CD4 + T Cell Subset Kit (R&D Systems, Minneapolis, Minn.) used as instructed by the manufacturer. Cell purity was always >95%.
  • BMDCs were purified from femurs of mice after extraction and washing in PBS. Cells were cultured for 8 days in C—RPMI-10 in the presence of GM-CSF (20 ng/mL; Biosource, Camarillo, Calif.).
  • mice Induction of intestinal inflammation-TNBS colitis.
  • pre-sensitization solution 150 ⁇ L; acetone with olive oil in a 4:1 ratio mixed with 5% TNBS in a 4:1 ratio
  • mice Seven days after sensitization, mice were anesthetized with isofluorene and TNBS solution (100 ⁇ L; 1:1 5% TNBS with absolute ethanol) administered rectally through a 3.5 F catheter (Instech Solomon; SIL-C35). Mice were analyzed 4-6 days after TNBS administration.
  • T H 1 and T H 2 are defined by expression of the cytokines interferon g (IFNg) and interleukin 4 (IL-4), respectively (Janeway et al., 2001).
  • IFNg interferon g
  • IL-4 interleukin 4
  • PSA induces CD4 + T cell expansion in B. fragilis -colonized mice and in vitro.
  • cytokine profiles using purified cellular components. Co-culture of DCs and CD4 + T cells in the presence of PSA yields dose-dependent up-expression of the T H 1 cytokine IFNg.
  • the level of IFNg production associated with PSA is comparable to that associated with several known potent IFNg inducers (a-CD3, LPS, and staphylococcal enterotoxin A [SEA]) and requires both DCs and T cells. Specificity is evidenced by the lack of T H 1 cytokine production after NAc-PSA treatment.
  • T H 1 cytokine production suppresses T H 2 responses; conversely, T H 2 cytokine expression inhibits T H 1 responses.
  • Normal immune responses require a controlled balance of these opposing signals.
  • Examination of IL-4 expression in response to PSA treatment reveals no cytokine production by purified CD4 + T cells.
  • a-CD3 and the superantigen SEA are potent stimulators of both classes of cytokine.
  • T H 2 cytokine production is a “default pathway” in many systems (Kidd, 2003; Amsen et al.
  • T H 1 cytokine production is antagonistic to T H 2 expression
  • the specific stimulation of IFNg by PSA in vitro may provide a mechanism for establishing commensal-mediated homeostasis of the host immune system by balancing T H 1/T H 2 responses.
  • PSA is Required for Appropriate CD4 + T-Helper Cytokine Production During Colonization
  • T H 1/T H 2 balance is critical for human and animal health; over- or underproduction of either response is associated with immunologic disorders.
  • PSA protein kinase
  • CD4 + T cells from mouse spleens were purified and tested by ELISA for cytokine production.
  • Overproduction of the T H 2 cytokine IL-4 in spleens of germ-free mice compared with levels in conventional mice.
  • T H 2-skewed profile of mice devoid of bacterial contamination reflects the human neonatal (precolonization) cytokine profile (Kirjavainen and Gibson, 1999; Prescott et al., 1998; Adkins, 2000; Kidd, 2003).
  • This “default” T H 2-bias in the absence of bacterial colonization again highlights the profound contributions of the microflora to immune development and provides a model to test the effects of symbiotic bacteria on the establishment of appropriate host cytokine production.
  • mice colonized with wild-type B. fragilis alone display a level of IL-4 production similar to that in conventional mice with a complex microflora; this similarity shows the organism's sufficiency to correct systemic immune defects.
  • mice colonized with B. fragilis DPSA produce T H 2 cytokines at elevated levels similar to those in germ-free mice.
  • T H 2 cytokines at elevated levels similar to those in germ-free mice.
  • mice result from an initial inflammatory response that—lacking repression—advances in an uncontrolled fashion and ultimately leads to intestinal pathology and disease.
  • PSA trinitrobenzene sulphonic acid
  • Applicants employed an animal model of chemically induced colonic inflammation. Rectal administration of trinitrobenzene sulphonic acid (TNBS) to wild-type mice mimics the initiation of colitis by eliciting inflammatory T cell responses. Disease was induced by administration of TNBS (or vehicle, as a negative control), and oral treatment of PSA was evaluated.
  • TNBS trinitrobenzene sulphonic acid
  • results illustrated in FIG. 7 show that the intestinal immune response are beneficially modulated by PSA.
  • results illustrated in FIG. 7 a show that TNBS-treated animals display weight loss that is statistically significant relative to figures for vehicle-treated and PSA-treated animals, although partial weight loss is observed in the PSA group ( FIG. 7 a ).
  • Histological analysis confirmed PSA protection of colonic tissues against the massive epithelial hyperplasia and loss of colonocyte organization seen after TNBS treatment ( FIG. 7 b ).
  • pathogenic T H 17 cells which produce IL-17, mediate the induction of experimental colitis 30 .
  • IL-17 levels are increased among purified CD4 + T cells from mesenteric lymph nodes (MLNs; FIG.
  • FIGS. 7 e and 7 f Transcriptional analysis of TNBS-treated colons revealed that expression of both IL-17 and TNFa is highly elevated in diseased but not in PSA-protected animals.
  • IL-10 ⁇ / ⁇ Interleukin-10-deficient mice develop colitis 31 .
  • IL-10 one of the most potent anti-inflammatory cytokines, is required for protection in many animal models of inflammation 21,27,32 .
  • FIG. 8 The results of a series of experiments directed to test the effect of PSA on IL-10 production are illustrated in FIG. 8 , and show that PSA induces IL-10 expression in TNBS-treated animals and inhibits pro-inflammatory cytokine production in primary cultured cells through IL-10 production.
  • transcriptional levels of IL-10 within colons of PSA-treated mice are significantly higher than those in control and TNBS-treated mice ( FIG. 8 a ).
  • IL-10 is produced by many cell types. However, since CD4 + T cells that express IL-10 display immunosuppressive activities that inhibit inflammation during experimental colitis 33 , Applicants tested the IL-10 production in CD4 + T.
  • FIG. 8 b When fresh CD4 + T cells were purified from MLNs of PSA-treated mice (in which inflammation is reduced), highly elevated levels of the IL-10 transcript were observed ( FIG. 8 b ). Applicants then assessed whether PSA is sufficient to induce IL-10 in vitro; when bone marrow-derived dendritic cells (BMDCs) and na ⁇ ve CD4 + T cells were treated with purified PSA, a specific increase in IL-10 production was observed ( FIG. 8 c ).
  • BMDCs bone marrow-derived dendritic cells
  • FIG. 9 A further series of experiments illustrated in FIG. 9 , shows that PSA from B. fragilis induces expression of IL-10 in vitro.
  • BMDCs and na ⁇ ve CD4 + T cells were infected with H. hepaticus co-cultured with B. fragilis , and a specific expression of IL-10 from culture supernatants was observed; co-culture with B. fragilis DPSA induces significantly lower levels of IL-10 ( FIG. 9 ). Since PSA induces expression of IL-10 in vitro, to test whether this molecule is required for inhibition of inflammatory responses to H. hepaticus , BMDC-T cell co-cultures were infected with live H.
  • hepaticus and measured expression of the critical pro-inflammatory cytokine TNFa Addition of increasing concentrations of the pathogenic commensal causes a dose-dependent increase in TNFa production, as measured by ELISA of culture supernatants ( FIG. 8 d ; left three bars). Treatment of cells with purified PSA markedly decreases TNFa production in response to H. hepaticus ( FIG. 8 d ; middle three bars). Most importantly, co-incubation of cell cultures with H. hepaticus and PSA in the presence of a neutralizing IL-10 receptor antibody (aIL-10R) completely reverses this phenotypic effect and increases expression of TNFa ( FIG. 8 d ; right three bars).
  • aIL-10R neutralizing IL-10 receptor antibody
  • results are similar for the related pro-inflammatory cytokine IL-1b, as shown by the results of experiments illustrated in FIG. 10 .
  • infection of BMDC-T cell co-cultures with increasing concentrations of live H. hepaticus results in release of the cytokine IL-1b
  • Treatment of infected cells with PSA reduces IL-1b levels, as shown in the middle three bars.
  • Neutralization of IL-10 signaling by addition of an IL-10 receptor antibody (aIL-10R) alleviates suppression of in vitro inflammatory responses, resulting in increased levels of IL-1b FIG. 10 left three bars.
  • results illustrated in the present example support the conclusion that IL-10 produced in response to PSA is required for inhibition of inflammatory reactions in cell cultures.
  • MLNs from experimental groups were pooled and re-stimulated with soluble Helicobacter antigen (5 ⁇ g/ml) for 48 hours.
  • Secretion of pro-inflammatory cytokines TNF ⁇ (a) and IL-17A (b) was analyzed by ELISA
  • FIGS. 12 and 13 weight and histology data illustrated in FIGS. 12 and 13 , indicated that IL-10 production is required for PSA-elicited reduction of intestinal immune responses.
  • groups of 4 C57BL/6 mice were treated with PSA (or PBS) and then subjected to rectal administration of TNBS or vehicle (control).
  • SD values illustrated in FIG. 12 indicate that, in the absence of IL-10, PSA cannot restore TNBS-induced weight loss.
  • ANOVA demonstrates that weight loss in both TNBS-treated groups is statistically different from that in control animals and that PSA does not prevent weight loss in TNBS-treated IL-10 ⁇ / ⁇ animals ( FIG. 12 ).
  • mice were treated with PSA (or PBS) and then subjected to rectal administration of TNBS or vehicle (control). Histologic analysis of H&E-stained sections from a representative animal from each group is shown in FIG. 13 . Thickening of the colon and epithelial hyperplasia are noted in both TNBS-treated groups of IL-10 ⁇ / ⁇ animals, regardless of PSA treatment. Thus, the results illustrated in FIG. 13 show that in the absence of IL-10, PSA does not reduce intestinal injury in TNBS-treated IL-10 ⁇ / ⁇ mice.
  • FIGS. 11 d - 11 f show that, as expected, groups of mice receiving IL-10 ⁇ / ⁇ T cells along with H. hepaticus develop severe colitis ( FIG. 11 d ; left bar) and are not protected by PSA ( FIG. 11 d ; middle bar).
  • This result supported by histological findings in colons, indicates that PSA induces protection from “previously pathogenic” CD4 + CD45Rb high T cells in an IL-10-dependent manner (FIG. 11 e ).
  • Weight analysis at sacrifice shows that colitic PBS- and PSA-treated animals receiving IL-10 ⁇ / ⁇ CD4 + CD45Rb high T cells (unlike control animals receiving no transferred cells) develop wasting disease ( FIG. 11 f ).
  • CD4 + T cells of the mammalian immune system can be generally divided into a na ⁇ ve (‘uneducated’) CD4 + CD45Rb high population and an antigen-experienced (‘educated’) CD4 CD45Rb low population 16 .
  • fragilis DPSA does not generate an expansion of the CD4 + CD45Rb low T cell population ( FIG. 1 a ; lower right). It is well established that the latter population possesses potent anti-inflammatory properties and confers protection in animal models of inflammation 17 . These results suggested that PSA mediate protection from inflammation.
  • CD4 + CD45Rb transfer model of experimental colitis 18 was employed to investigate whether B. fragilis colonization protects animals from inflammatory disease.
  • pathogenic CD4 + CD45Rb high T cells are separated from protective CD4 + CD45Rb low cells and transferred into specific pathogen-free (SPF) Rag ⁇ / ⁇ mice.
  • SPF pathogen-free
  • mice are colonized with Helicobacter hepaticus 8,19 , a pathobiont that is a benign commensal in wild-type animals but an opportunistic pathogen causing colitis in immuncompromised mice. After 8 weeks, animals are sacrificed and colitis is assessed with a standard scoring system 20 .
  • FIG. 1 b The pathology scores illustrated in FIG. 1 b , show that H. hepaticus colonization and CD4 + CD45Rb high T cell transfer are sufficient to induce severe colitis in Rag ⁇ / ⁇ mice ( FIG. 1 b ; first column), as previously reported 19,21 .
  • Co-colonization with wild-type B. fragilis results in significant protection from disease ( FIG. 1 b ; second column), whereas co-colonization with B. fragilis DPSA does not ( FIG. 1 b ; third column).
  • Tissue damage in colitis is widely believed to result from production of inflammatory cytokines in response to commensal bacteria 22 .
  • the pro-inflammatory cytokines tumor necrosis factor a (TNFa, interleukin-1b (IL-1b and IL-23 are central to disease initiation and progression in this experimental model of colitis 23 .
  • levels of these cytokines are elevated in patients with IBD 24 , and therapies neutralizing TNFa have yielded promising results in clinical trials in patients with Crohn's disease 25 .
  • Applicants decided to test the inflammatory cytokine levels during disease by directly culturing intestinal tissues of T cell recipient colonized animals 26 .
  • the results illustrated in FIGS. 1 c , 1 d , 2 and 3 show that PSA alters cytokine levels in affected tissue.
  • results of ELISA experiments of colon organ cultures illustrated in FIG. 1 c show an increased expression of pro-inflammatory cytokine TNFa in diseased colons, with significant reductions in animals co-colonized with wild-type B. fragilis but not with B. fragilis DPSA.
  • ELISA results for the pro-inflammatory cytokines IL-12p40 and IL-1b in colon and small intestines shown in FIG. 2 show a specific increase in pro-inflammatory cytokines in diseased colons but not in small intestines. This increase is significantly reduced in animals co-colonized with PSA-producing B. fragilis . Conversely, animals colonized with B. fragilis DPSA express greatly increased pro-inflammatory cytokine levels over those in control animals (C57BL/6) ( FIG. 2 ).
  • CD4 + T cells were purified from pooled splenocytes from each group (4 mice per group) and restimulated in vitro with PMA and ionomycin in the presence of brefeldin A for 4 hours. Cells were stained for intracellular TNF ⁇ . Cells within the lymphocyte gate were included in the analysis, and numbers indicate the percentage of cells producing TNF ⁇ . Purified cells were >90% CD4 + . Animals colonized with PSA-producing B. fragilis during protection displayed lower TNFa levels than diseased animals.
  • fragilis DPSA results in increased colonic cytokine production similar to that seen in Rag ⁇ / ⁇ animals colonized with H. hepaticus alone.
  • purified splenic CD4 + T cells from H. hepaticus -colonized animals display increased TNFa production; this condition is corrected by colonization with wild-type B. fragilis but not with the PSA deletion strain ( FIG. 3 ).
  • Expression of IL-23 is critical in the cascade of events leading to experimental colitis 27,28 . Applicants found that increases in IL-23 production by splenocytes following disease induction are completely suppressed by intestinal colonization with PSA-producing B. fragilis ( FIG. 1 d ).
  • results shown in FIG. 4 show that experimental animals remain colonized with H. hepaticus and B. fragilis throughout the course of disease. More particularly, the ethidium bromide-stained gel electrophoresis of H. hepaticus -specific Q-PCR of FIG. 4 a shows that co-colonization with B. fragilis does not induce clearance of bacteria after 8 weeks.
  • the primers used for H. hepaticus 16S rDNA were: (HB-15) 5′-GAAACTGTTACTCTG-3′ (SEQ ID NO: 1) and (HB-17) 5′-TCAAGCTCCCCGAAGGG-3′ (SEQ ID NO: 2). Ethidium bromide-stained gel electrophoresis of B.
  • fragilis -specific Q-PCR of FIG. 4 b show stable bacterial colonization after 8 weeks; the primers used for B. fragilis ssr3 (finB) gene were: (ssr3-F) 5′-TATTTGCGAGAAGGTGAT-3′ (SEQ ID NO: 3) and (ssr3-r) 5′-TAAACGCTTTGCTGCTAT-3′ (SEQ ID NO: 4).
  • PSA is a specific immunomodulatory molecule that orchestrates beneficial immune responses to prevent B. Fragilis host from developing experimental colitis.
  • PSA Suppresses Inflammation Associated with CD4 + CD45Rb high T Cells
  • H. hepaticus provides the necessary antigens for inflammation induction; no pathology is observed in uncolonized animals (PBS ⁇ Hh) or in animals without cell transfer. Therefore these experiments show that oral administration of PSA protects animals against wasting (PSA+Hh).
  • hepaticus colonization results in infiltration of affected tissues by leukocytes—a hallmark of inflammation and disease ( FIG. 6 c second panel, bottom) 19,21 .
  • oral administration of PSA to H. hepaticus -colonized cell transfer recipients confers complete protection against experimentally induced colonic hyperplasia ( FIG. 6 c ; third panel); furthermore, PSA-treated animals display no leukocyte infiltration in colonic tissues ( FIG. 6 c third panel, bottom)—a result indicating protection against inflammation.
  • mice were treated with TNBS or TNB/PSA, orally administered to the mice.
  • the relevant colonic sections were subsequently analyzed by a blinded pathologist who provided a histological score.
  • the results illustrated in FIG. 14 a provide further evidence that oral PSA administration reduces colitis.
  • mice were orally administered purified PSA before induction of colitis. Indeed, oral treatment of PSA protected from weight loss associated with experimental colitis and inflammation within the intestine (not shown).
  • FIG. 15 show that delivery of ZPS to extra-intestinal sites is able to protect from induced intestinal colitis.
  • systemic administration of PSA enhances the survival of diseased animals and protects from splenomegaly (60% survival vs. 90%) ( FIGS. 15 a and 15 b ).
  • colons of animals that treated with PSA systemically have significantly less hyperplasia and inflammatory infiltrate.
  • systemic administration of ZPS reduces the production of TNF- ⁇ from CD4+ T lymphocytes within the spleen as shown by the results illustrated in FIG. 16 c .
  • systemic administration of ZPS reduces expression of the transcripts IL-17, and IL-6 within the spleen as shown by the results illustrated in FIG. 16 d.
  • the data illustrated in this example also show that systemic administration of PSA during TNBS induced colitis suppresses inflammatory cytokines at both intestinal and systemic immune compartments.
  • Endotoxic shock occurs during severe gram-negative bacterial infections and is characterized by hypotension, multi-organ failure and potentially death.
  • This syndrome results from the production of multiple inflammatory cytokines, including TNF-a and IL-6, in response to the lipopolysaccharides (LPS) found in the cell wall of gram negative bacteria.
  • LPS lipopolysaccharides
  • IL-10 has been demonstrated to be a central regulator of the inflammatory response to LPS, indeed a single dose of IL-10 prevents death in murine models of endotoxic shock 42 .
  • the dramatic effects of PSA within the systemic immune compartments lead us to investigate whether PSA could ameliorate systemic inflammation.
  • mice injected Balb/c mice with a low dose (100) ug) of LPS and monitored serum levels of the cytokines TNF- ⁇ and IL-6.
  • serum was collected from mice 1 and 4 hours post-administration of 100 ⁇ g or 500 ⁇ g of LPS and TNF- ⁇ and IL-6 protein levels in the serum were determined by ELISA.
  • FIGS. 17 d and 17 e show that while animals that were administered PBS all die within 60 hours of administration of LPS, those animals that received PSA treatment have a significantly increased survival rate ( FIG. 17 d ).
  • PBS animals have an over 3000 fold induction of TNF- ⁇ when administered LPS, those mice receiving PSA have very little TNF-a induction ( FIG. 17 e ).
  • PSA mediated protection from IBD is reliant on IL-10 production from a CD4 + T lymphocyte.
  • IL-10 is required for protection from LPS induced death
  • Applicants pretreated IL10 deficient animals with PBS or purified PSA and administer levels of LPS that would result in septic shock. The cytokine level and percentage survival were monitored.
  • FIG. 18 show that consistent with previous data IL10-deficient animals were more sensitive to lower doses of LPS and TNF alpha levels continue increase ( FIG. 18 a ).
  • PSA treated animals have a drastic decrease in the levels of serum TNF-a in response to LPS that drops to negligible levels by 4 hours post LPS administration ( FIG. 18 a ), indicating that decreased TNF-a levels by PSA is not dependent on the ability of PSA to induce IL-10.
  • FIG. 18 b decreased IL-6 production by PSA is IL-10 dependent as levels are similar to PBS treated animals, indicating multiple mechanisms are employed by PSA to alleviate endotoxic shock.
  • FIG. 18 c IL10 deficient mice receiving PSA are completely protected from LPS induced death

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WO2009062132A2 (fr) 2009-05-14
JP2011503104A (ja) 2011-01-27
WO2009062132A3 (fr) 2009-08-13
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US11622973B2 (en) 2023-04-11
US20130039949A1 (en) 2013-02-14

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