Methods of modulating immune responses by modulating tim-1, tim-2 and tim-4 function

Abstract

The invention relates to methods of modulating immune responses in a subject, such as by administering to the subject agents which modulate tim-1, tim-2 or tim-4 activity, or which modulate the physical interaction between tim-1 and tim-4 or between tim-2 and a tim-2 ligand. Immune responses include, but are not limited to, autoimmune disorders, transplantation tolerance, and Th1 and Th2-mediated responses and disorders. The invention also relates to novel assays for identifying agents which modulate the physical interaction between tim-1 and tim-4. In addition, the invention relates to novel soluble tim-4 polypeptides and to nucleic acids which encode them.

1 . A method of increasing immune tolerance in a subject in need thereof, the method comprising administering to such subject a therapeutically effective amount of a polypeptide agent that inhibits the activity or expression of tim-4, whereby immune tolerance in said subject is increased. 
     
     
         2 . The method of  claim 1 , wherein said subject suffers from an autoimmune disease, and wherein said increase in immune tolerance treats said autoimmune disease. 
     
     
         3 . The method of  claim 1 , wherein said subject is a transplant recipient, and whereby said increase in immune tolerance increases transplant tolerance. 
     
     
         4 . The method of  claim 1 , wherein said polypeptide agent comprises an antibody or antigen-binding fragment thereof that specifically binds to tim-4. 
     
     
         5 . The method of  claim 1 , wherein the polypeptide agent reduces binding of tim-4 to tim-1. 
     
     
         6 . The method of  claim 1 , wherein said polypeptide agent comprises a soluble tim-1 molecule. 
     
     
         7 . The method of  claim 6 , wherein the soluble tim-1 polypeptide comprises (i) amino acids 21-126 of SEQ ID NO: 1 or (ii) amino acids 21-129 of SEQ ID NO: 2. 
     
     
         8 . The method of  claim 1 , wherein the polypeptide agent further comprises (a) human serum albumin; or (b) an Fc domain of an immunoglobulin. 
     
     
         9 . The method of  claim 2 , wherein said autoimmune disease is selected from the group consisting of type-I diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and Crohn's disease. 
     
     
         10 . A method of increasing immune tolerance in a subject in need thereof, the method comprising administering to such subject a therapeutically effective amount of a polypeptide agent that inhibits the activity or expression of tim-1, whereby immune tolerance in said subject is increased. 
     
     
         11 . The method of  claim 10 , wherein said subject suffers from an autoimmune disease, and wherein said increase in immune tolerance treats said autoimmune disease. 
     
     
         12 . The method of  claim 10 , wherein said subject is a transplant recipient, and whereby said increase in immune tolerance increases transplant tolerance. 
     
     
         13 . The method of  claim 10 , wherein said polypeptide agent comprises an antibody or antigen-binding fragment thereof that specifically binds to and blocks the activity of tim-1. 
     
     
         14 . The method of  claim 10 , wherein the polypeptide agent reduces binding of tim-1 to tim-4. 
     
     
         15 . The method of  claim 10 , wherein said polypeptide agent comprises a soluble tim-1 molecule. 
     
     
         16 . The method of  claim 15 , wherein the soluble tim-1 polypeptide comprises (i) amino acids 21-126 of SEQ ID NO: 1 or (ii) amino acids 21-129 of SEQ ID NO: 2. 
     
     
         17 . The method of  claim 10 , wherein the polypeptide agent further comprises (a) human serum albumin; or (b) an Fc domain of an immunoglobulin. 
     
     
         18 . The method of  claim 11 , wherein said autoimmune disease is selected from the group consisting of type-I diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and Crohn's disease. 
     
     
         19 . A method of decreasing, inhibiting, suppressing, ameliorating, or delaying a Th1-mediated immune response in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a tim-1 or tim-4 antagonist that binds tim-1 or tim-4 in an amount sufficient to decrease, inhibit, suppress, ameliorate, or delay a Th1-mediated response in the subject by reducing the expression or activity of tim-1 or tim-4. 
     
     
         20 . The method of  claim 19 , wherein the tim-1 or tim-4 antagonist is selected from the group consisting of an antibody or antigen-binding fragment thereof that binds the tim-1 or tim-4 extracellular domain, and a soluble tim-1 polypeptide.