Lymphocyte surface receptor that binds caml and methods of use thereof

Abstract

A novel lymphocyte receptor protein, its DNA sequence, and its role in the calcium activation pathway is described. The protein, or genetically engineered constructs encoding it, is shown to increase lymphocyte response, and to identify ligands of the protein receptor. Antibodies to the proteins of the invention are generated for diagnostic therapeutics. The protein and DNA can also be used for diagnostic purposes and for identifying agents for modulating the calcium induced activation pathway. A particular advantage of the present invention is that it provides lymphocyte activation of receptor found on all B cells, but only on a subset of T cells. The receptor can thus be targeted to specifically regulate B cell responses without affecting mature T cell activity. Such targeting specificity is always advantageous, particularly where an increase or decrease of antibody production is desired, e.g., during an infection (increase) or to avoid immune complex deposition complications (rheumatoid arthritis, glomerulonephritis, and other auto immune conditions).

1 . A method of treating an undesirable immune response in a mammal, comprising administering to the mammal a composition that comprises a polypeptide comprising amino acid residues 70-104 of SEQ ID NO: 2, wherein the undesirable immune response is selected from the group consisting of an autoimmune and inflammatory disease, a transplantation rejection, and a graft-versus host disease. 
     
     
         2 . The method of  claim 1 , wherein the polypeptide further comprises amino acid residues 33-66 of SEQ ID NO: 2. 
     
     
         3 . The method of  claim 1 , wherein the polypeptide comprises a chimeric protein. 
     
     
         4 . The method of  claim 3 , wherein the chimeric protein comprises an Fc domain of an immunoglobulin. 
     
     
         5 . The method of  claim 4 , wherein the chimeric protein comprises an Fc domain of an immunoglobulin. 
     
     
         6 . The method of  claim 1 , wherein the autoimmune and inflammatory disease is selected from the group consisting of immune complex-induced vasculitis, glomerulonephritis, hemolytic anemia, myasthenia gravis, type II collagen-induced arthritis, experimental allergic xenograft rejection, hyperacute xenograft rejection, rheumatoid arthritis, and systemic lupus erythematosus. 
     
     
         7 . The method of  claim 6 , wherein the autoimmune and inflammatory disease is myasthenia gravis. 
     
     
         8 . The method of  claim 6 , wherein the autoimmune and inflammatory disease is type II collagen-induced arthritis. 
     
     
         9 . The method of  claim 6 , wherein the autoimmune and inflammatory disease is rheumatoid arthritis. 
     
     
         10 . The method of  claim 6 , wherein the autoimmune and inflammatory disease is systemic lupus erythematosus. 
     
     
         11 . The method of  claim 1 , wherein the mammal is human. 
     
     
         12 . A method of treating a lymphocyte cancer in a mammal, comprising administering to the mammal a composition comprising a polypeptide comprising amino acid residues 70-104 of SEQ ID NO: 2, wherein the lymphocyte cancer is selected from the group consisting of myeloma, lymphoma, and leukemia, and wherein administration of the soluble TACI extracellular domain or the chimeric protein suppresses cancer cell growth. 
     
     
         13 . The method of  claim 12 , wherein the polypeptide further comprises amino acid residues 33-66 of SEQ ID NO: 2. 
     
     
         14 . The method of  claim 12 , wherein the polypeptide comprises a chimeric protein. 
     
     
         15 . The method of  claim 14 , wherein the chimeric protein comprises an Fc domain of an immunoglobulin. 
     
     
         16 . The method of  claim 12 , wherein the lymphocyte cancer is myeloma. 
     
     
         17 . The method of  claim 12 , wherein the lymphocyte cancer is lymphoma. 
     
     
         18 . The method of  claim 12 , wherein the lymphocyte cancer is leukemia. 
     
     
         19 . The method of  claim 12 , wherein the mammal is human.