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Methods of modulating a mammalian cytokineRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Lymphokine, InterleukinMethods of modulating a mammalian cytokine description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070160579, Methods of modulating a mammalian cytokine. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This filing is a U.S. Patent Application which claims benefit of U.S. Provisional Patent Application No. 60/545,730, filed Feb. 17, 2004, which is incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention relates generally to uses of mammalian cytokines. More specifically, the invention discloses methods of using IL-33, and a receptor for IL-33. BACKGROUND OF THE INVENTION [0003] The immune system protects individuals from infective agents, e.g., bacteria, multi-cellular organisms, as well as cancers. This system includes several types of lymphoid and myeloid cells such as monocytes, macrophages, dendritic cells (DCs), eosinophils, T cells, B cells, and neutrophils. These lymphoid and myeloid cells often produce signaling proteins known as cytokines. Immune response includes inflammation, i.e., the accumulation of immune cells systemically or in a particular location of the body. In response to an infective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate immune cell proliferation, development, differentiation, or migration. Immune response sometimes results in pathological consequences, that is, inflammatory disorders. These inflammatory disorders, which involve immune cells and cytokines, include, e.g., psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, and atherosclerosis (see, e.g., Abbas, et al. (eds.) (2000) Cellular and Molecular Immunology, W.B. Saunders Co., Philadelphia, Pa.; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, Calif.; Kaufmann, et al. (2001) Immunobiol. 204:603-613; Saurez and Schultz-Cheery (2000) Dev. Comp. Immunol. 24:269-283; van Reeth and Nauwynck (2000) Vet. Res. 31:187-213; Garcia-Sastre (2001) Virology 279:375-384; Katze, et al. (2002) Nat. Rev. Immunol. 2:675-687; van Reeth (2000) Vet. Microbiol. 74:109-116; Tripp (2003) Curr. Pharm. Des. 9:51-59). [0004] The interleukin-1 (IL-1) family of cytokines contributes to the pathology of inflammatory disorders and proliferative conditions, e.g., arthritis and cancer. Cytokines of the IL-1 family include IL-1 alpha, IL-1beta, IL-1 delta, IL-1 epsilon, basic fibroblast growth factor, IL-18, CREG and CREG2. IL-1 alpha and IL-1beta are biosynthesized as 31 kDa polypeptides that are further processed to mature 17 kDa forms, while IL-1 delta and IL-1epsilon appear not to possess a distinct pro-form (see, e.g., Debets, et al. (2001) J. Immunol. 167:1440-1446; McMahon, et al. (1997) J. Biol. Chem. 272:28202-28205; Irikura, et al. (2002) New Engl. J. Med. 169:393-398; Kim, et al. (2002) J. Biol. Chem. 277:10998-11003). [0005] The IL-1 family also includes IL-1 receptors, i.e., IL-1RI, IL-1RII, and IL-1R accessory protein (a.k.a. IL-1R1, IL-1R2, and IL-1R3, respectively). IL-1alpha and IL-1beta trigger cell signaling by binding to IL-1R1, while IL-1 RII can function as a molecule that absorbs circulating ligand. IL-1 receptor antagonist (IL-1Ra), another IL-1 family protein, binds to IL-1 receptor without transmitting a signal and serves as an inhibitor of IL-1. IL-1ra and IL-1 delta play similar roles in antagonizing signaling through receptors, i.e., IL-1ra antagonizes IL-1alpha-mediated signaling via IL-1R1, while IL-1delta antagonizes IL-1epsilon-mediated signaling via IL-1R6 (see, e.g., You, et al. (2001) New Engl. J. Med. 193:101-109). Debets, et al. (2001) J. Immunol. 167:1440-1446; Apte and Voronov (2002) Sem. Cancer Biol. 12:277-290; Wong, et al. (1997) Proc. Natl. Acad. Sci. USA 94:227-232). [0006] IL-1 family members play a role in inflammatory conditions, e.g., rheumatoid arthritis, psoriasis, asthma, chronic obstructive pulmonary disorder (COPD), sepsis, and inflammatory bowel disorder (IBD). Rheumatoid arthritis (RA) is a common chronic inflammatory disorder characterized by degradation of joints, e.g., the synovial membrane, cartilage, and bone. The disorder strikes about 1% of the population and cannot be cured. IL-1 stimulates a number of cells involved in arthritic inflammation, e.g., fibroblasts, osteoclasts, chondrocytes, and neutrophils, which may show abnormal proliferation and release enzymes causing joint destruction (see, e.g., (Debets, et al. (1997) J. Immunol. 158:2955-2963; Lacey, et al. (2003) Arthritis Rheum. 48: 103-109; Chung (2001) Eur. Resp. J. Suppl. 34: 50s-59s; Freeman and Buchman (2001) Expert Opin. Biol. Ther. 1:301-308; Dinarello (2000) Chest 118:503-508). Krause, et al. (2002) J. Immunol. 169:6610-6616; Choy and Panayi (2001) New Engl. J. Med. 344:907-916; Woolley (2003) New Engl. J. Med. 348:1709-1711; Williams, et al. (2000) New Engl. J. Med. 164: 7240-7245; Feldmann and Maini (2001) Annu. Rev. Immunol. 19:163-196; Lacey, et al., supra; Niki, et al. (2001) J. Clin. Invest. 107:1127-1135; Attur, et al. (2000) J. Biol. Chem. 51:40307-40315). [0007] Proliferative disorders are the second most common cause of death in the United States (Anderson (2002) National Vital Statistics Reports 50:1-86; Toribara and Sleisenger (2003) New Engl. J. Med. 332:861-867; Janne and Mayer (2000) New Engl. J. Med. 342:1960-1968; Fuchs and Mayer (1995) New Engl. J. Med. 333:32-41). Cytokines of the IL-1 family have been implicated in the control and pathology of proliferative disorders, i.e., cancer. IL-1 modulates progression through the cell cycle, e.g., by changing expression of cyclin-dependent kinases and cyclin-dependent kinase inhibitors. High doses of IL-1beta promote tumor invasiveness, while low doses can promote immune eradication of tumors (see, e.g., Zeisler, et al. (1998) Eur. J. Cancer 34:931-933; Yoshida, et al. (2002) Brit. J. Cancer 86:1396-1400; Nesbit, et al. (1999) Oncogene 18:6469-6476; Dinarello, et al. (1998) J. Leuko. Biol. 63:658-664; Apte and Voronov, supra; Saijo, et al. (2002) New Engl. J. Med. 169: 469-475; Murai, et al. (2001) J. Biol. Chem. 276:6797-6806; Koudssi, et al. (1998) J. Biol. Chem. 273: 25796-25803; Zeki, et al. (1999) J. Endocrinol. 160:67-73; Osawa, et al. (2000) J. Biochem. 127:883-893). [0008] There is an unmet need to treat inflammatory and immune disorders. The present invention fulfils this need by providing methods of using agonists and antagonists of IL-33 or IL-33 receptor. SUMMARY OF THE INVENTION [0009] The present invention is based, in part, upon the discovery that an agonist or antagonist of IL-33 or IL-33 receptor (previously known as IL-100 and IL-100 receptor) modulates response to a number of immune and inflammatory conditions. [0010] The present invention provides a method of modulating an immune disorder or condition, comprising administering an effective amount of an agonist or antagonist of IL-33 or IL-33R complex. Also provided is the above method wherein the disorder or condition comprises: a) innate response; b) asthma or allergy; c) multiple sclerosis; d) an inflammatory bowel disorder; e) arthritis; f) infection; g) a cancer or tumor. Further provided is the above method wherein the infection comprises: a) an intracellular pathogen; b) a bacterium; c) a parasite; or d) a virus; and the above method wherein the intracellular pathogen is: a) Leishmania sp.; b) Mycobacterium sp.; c) Listeria sp.; d) Toxoplasma sp.; e) Schistosoma; or f) a respiratory virus. Moreover, the present invention provides the above method wherein the immune disorder or conditions comprises TH1-type response or TH2-type response; and the above method wherein the TH2-type response comprises an early event in TH2-type response; as well as the above method wherein the arthritis comprises rheumatoid arthritis; osteoarthritis; or psoriatic arthritis. [0011] In another embodiment, the present invention provides the above method wherein the agonist comprises IL-33 or a nucleic acid; as well as the above method wherein the nucleic acid encodes IL-33; and the above method wherein the antagonist comprises a binding composition from an antibody that specifically binds IL-33 or a complex of IL-33, T1/ST2 and SIGIRR (IL-33R). In yet another embodiment, the present invention provides the above method wherein the binding composition from an antibody comprises a polyclonal antibody; a monoclonal antibody; a humanized antibody, or a fragment thereof; an Fab, Fv, or F(ab').sub.2 fragment; a peptide mimetic of an antibody; or a detectable label. Also provided is the above method, wherein the antagonist comprises: a) a soluble IL-33R; b) a small molecule; or c) a nucleic acid; and the above method wherein the nucleic acid specifically hybridizes with a polynucleotide encoding IL-33; as well as the above method wherein the nucleic acid comprises anti-sense nucleic acid or small interference RNA (siRNA). [0012] In another aspect, the present invention provides a method of modulating blood cell counts comprising administering an effective amount of an agonist or antagonist of L-33; and the above method wherein the IL-33 agonist increases the counts of total white blood cells; neutrophils; lymphocytes; or eosinophils; as well as the above method wherein the IL-33 antagonist increases the count of platelets; and the above method wherein the IL-33 antagonist decreases the counts of total white blood cells; neutrophils; lymphocytes; or eosinophils. [0013] Yet another aspect of the present invention provides a method of diagnosing the immune condition or disorder noted above, comprising contacting a binding composition to a biological sample, wherein the binding composition specifically binds to IL-33, and measuring or determining the specific binding of the binding composition to the biological sample. Also provided is a kit for the diagnosis of the immune condition or disorder of claim 1, comprising a compartment and a binding composition that specifically binds to: IL-33; an IL-33R complex; a complex of IL-33 and IL-33R; or a nucleic acid encoding IL-33. BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 shows IL-5 production in IL-33+anti-IL-33 antibody treated mice versus IL-33 alone and isotype control antibody treated mice. [0015] FIG. 2 shows CIA disease scores for anti-IL-33 and isotype control treated mice. [0016] FIG. 3 shows the incidence of CIA in anti-IL-33 and isotype control treated mice. [0017] FIG. 4 shows the mean number of arthritic paws in mice treated with anti-IL-33 antibody or isotype control antibody. [0018] FIG. 5 shows the EAE disease scores of anti-IL-33 and isotype control treated mice. [0019] FIG. 6 shows the incidence of EAE in anti-IL-33 and isotype control treated mice. 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