Modulation of nkg2d

Abstract

The present invention relates to methods and compositions for treating and/or preventing autoimmune and/or inflammatory disease. In particular, the present invention provides therapeutics for impairing the expansion and function of autoreactive T cells, NK cells and/or NKT cells, by modulating NKG2D.

1 - 37 . (canceled) 
     
     
         38 . A method for treating or preventing inflammatory bowel disease, the method comprising contacting leukocytes expressing NKG2D with an agent that reduces ligand-induced NKG2D activation of the leukocytes under conditions suitable for treating or preventing the inflammatory bowel disease, wherein the agent is an antibody or fragment thereof that binds to NKG2D and reduces the amount of the NKG2D on the cell-surface of the leukocytes. 
     
     
         39 . The method of  claim 38 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         40 . The method of  claim 38 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         41 . The method of  claim 38 , wherein said contacting results in a reduction of at least 30% in ligand-induced NKG2D activation. 
     
     
         42 . The method of  claim 38 , wherein said antibody or fragment thereof reduces the interaction of NKG2D with DAP10. 
     
     
         43 . The method of  claim 38 , wherein said reduction in the amount of cell-surface NKG2D occurs under conditions in which one or more of MICA, MICB, ULBP1, ULBP2, ULBP3, or ULBP4 cannot decrease the amount of cell-surface NKG2D. 
     
     
         44 . The method of  claim 38 , wherein said antibody of fragment thereof increases the rate at which cell-surface NKG2D is internalized. 
     
     
         45 . The method of  claim 44 , wherein said increase in the rate of NKG2D internalization occurs under conditions in which one or more of MICA, MICB, ULBP1, ULBP2, ULBP3, or ULBP4 cannot increase the rate of NKG2D internalization. 
     
     
         46 . The method of  claim 38 , wherein said contacting reduces signaling through the NKG2D-NKG2D ligand complex. 
     
     
         47 . The method of  claim 38 , wherein the leukocytes are selected from the group consisting of NKG2D+CD8+ T cells, NKG2D+CD4+ T cells, NKG2D+gamma-delta T cells, NKG2D+NK cells, and macrophages. 
     
     
         48 . The method of  claim 38 , wherein said contacting results in less than about 10% reduction in the number of NKG2D-expressing leukocytes relative to a control. 
     
     
         49 . The method of  claim 38 , wherein said antibody is a monoclonal antibody. 
     
     
         50 . The method of  claim 49 , wherein said monoclonal antibody is a human antibody, a humanized antibody, or a chimeric antibody. 
     
     
         51 . The method of  claim 38 , wherein NKG2D ligand expression is elevated in cells of an organ or tissue affected by said inflammatory bowel disease. 
     
     
         52 . The method of  claim 51 , wherein said conditions result in a reduction in lymphocytes infiltrating an organ said organ or tissue affected by said inflammatory bowel disease. 
     
     
         53 . The method of  claim 51 , wherein said conditions result in a reduction in levels of interferon gamma in an organ said organ or tissue affected by said inflammatory bowel disease. 
     
     
         54 . The method of  claim 38 , wherein said antibody or fragment thereof reduces proliferation of said leukocytes. 
     
     
         55 . The method of  claim 38 , wherein the method comprises treating a human patient diagnosed as having the inflammatory bowel disease. 
     
     
         56 . A method of impairing expansion of NKG2D+ cells in a mammalian host suffering from or being at substantial risk of developing an inflammatory bowel disease, comprising delivering to a mammalian host an antibody or antibody fragment specific for NKG2D and capable of impairing the expansion of NKG2D+ T cells or NK cells without significantly depleting such cells, under conditions and in an amount effective to impair the expansion of the NKG2D+ cells in the mammalian host. 
     
     
         57 . The method of  claim 56 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         58 . The method of  claim 56 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         59 . The method of  claim 56 , wherein said mammalian host is a human host. 
     
     
         60 . The method of  claim 56 , wherein said antibody is a monoclonal antibody. 
     
     
         61 . The method of  claim 60 , wherein said monoclonal antibody is a human antibody, a humanized antibody, or a chimeric antibody. 
     
     
         62 . A method of stimulating cellular internalization of NKG2D in NKG2D-expressing cells in a mammalian host suffering from or at substantial risk of developing an inflammatory bowel disease, comprising delivering to the mammalian host an antibody or an antibody fragment that specifically binds NKG2D and is capable of stimulating cellular internalization of NKG2D without significant activation via NKG2D-mediated signaling pathway(s), under conditions and in an amount effective to stimulate cellular internalization of NKG2D in NKG2D-expressing cells. 
     
     
         63 . The method of  claim 62 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         64 . The method of  claim 62 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         65 . The method of  claim 62 , wherein said mammalian host is a human host. 
     
     
         66 . The method of  claim 62 , wherein said antibody is a monoclonal antibody. 
     
     
         67 . The method of  claim 66 , wherein said monoclonal antibody is a human antibody, a humanized antibody, or a chimeric antibody.