Methods of modulating hvem, btla and cd160 cis complex response or signaling activity with soluble light polypeptide sequences

Abstract

The invention provides HVEM cis complexes which include, for example, HVEM/BTLA, HVEM/CD160 and HVEM/gD cis complexes. The invention provides ligands and agents that bind to HVEM cis complexes, such as antibodies. The invention further provides methods of use of the HVEM cis complexes, and the ligands and agents (e.g., LIGHT polypeptide sequence) that bind to the HVEM cis complexes.

1 . A method of modulating a HVEM, BTLA or CD160 response or signaling activity, comprising contacting a cis complex comprising a herpes virus entry mediator (HVEM) polypeptide binding to B- and T-lymphocyte attenuator (BTLA) polypeptide, or a cis complex comprising a herpes virus entry mediator (HVEM) polypeptide binding CD160 polypeptide with a soluble LIGHT polypeptide sequence that binds to the cis complex, thereby modulating a HVEM, BTLA or CD160 response or signaling activity. 
   
   
       2 . The method of  claim 1 , wherein the response comprises lymphocyte or hematopoetic cell proliferation or inflammation. 
   
   
       3 . The method of  claim 2 , wherein the response comprises proliferation, survival, differentiation, death, or activity of T cells, antigen presenting cells or B cells. 
   
   
       4 . The method of  claim 3 , wherein the activity comprises one or more of secretion of a cytokine, chemokine, interleukin, or interferon. 
   
   
       5 . The method of  claim 4 , wherein the cytokine comprises TNF, lymphotoxin (LT)-alpha, LT-beta, LIGHT, or a ligand for CD27, OX40, 41BB; wherein the chemokine comprises CCL21, 19, or CXCL13; wherein the interleukin comprises IL10, IL2, IL7, or IL15; or wherein the interferon comprises type 1, or Interferon-gamma. 
   
   
       6 . The method of  claim 3 , wherein the activity comprises cytotoxic or helper activity of activated T cells, or B cell production of antibody. 
   
   
       7 . The method of any of  claim 3 , wherein the soluble LIGHT polypeptide sequence is administered to a subject. 
   
   
       8 . The method of  claim 7 , wherein the subject is a mammal. 
   
   
       9 . The method of  claim 7 , wherein the subject is a human. 
   
   
       10 . The method of  claim 7 , wherein the subject has an undesirable or aberrant immune response, immune disorder or an immune disease. 
   
   
       11 . The method of  claim 10 , wherein the immune disorder or immune disease comprises an autoimmune disorder or an autoimmune disease. 
   
   
       12 . The method of  claim 10 , wherein the immune disorder or immune disease comprises undesirable or aberrant acute or chronic inflammatory response or inflammation, or autoimmune disease. 
   
   
       13 . The method of  claim 10 , wherein the immune disorder or immune disease is selected from type I or type II diabetes, systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease or graft vs. host disease. 
   
   
       14 . The method of  claim 10 , wherein the immune disorder or immune disease comprises undesirable or aberrant proliferation, survival, differentiation, death, or activity of a T cell, antigen presenting cell or B cell. 
   
   
       15 . A method of inhibiting, reducing, decreasing, attenuating, preventing or blocking proliferation, survival, differentiation, death, activity or signaling of T cells, antigen presenting cells or B cells, comprising contacting said cells with a soluble LIGHT polypeptide sequence that binds to a cis complex comprising a herpes virus entry mediator (HVEM) polypeptide binding to B- and T-lymphocyte attenuator (BTLA) polypeptide, or a cis complex comprising a herpes virus entry mediator (HVEM) polypeptide binding CD160 polypeptide, in an amount sufficient to inhibit, reduce, decrease, attenuate, prevent or block proliferation, survival, differentiation, death, or activity of T cells, antigen presenting cells or B cells. 
   
   
       16 . The method of  claim 15 , wherein said contacting is in vitro or in vivo. 
   
   
       17 . The method of  claim 15 , wherein said contacting is in a subject in need of inhibiting, reducing, decreasing, attenuating, preventing or blocking proliferation, survival, differentiation, death, or activity of T cells, antigen presenting cells or B cells. 
   
   
       18 . The method of  claim 17 , wherein said subject has or is at risk of having undesirable inflammation. 
   
   
       19 . The method of  claim 17 , wherein said subject has or is at risk of having an undesirable or aberrant immune response, immune disorder, immune disease or autoimmune disease. 
   
   
       20 . The method of  claim 17 , wherein said subject has or is at risk of having graft vs. host disease. 
   
   
       21 . The method of  claim 17 , wherein said subject has or is at risk of having type I or type II diabetes, systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, or Crohn's disease. 
   
   
       22 . A method of inhibiting, reducing, decreasing, attenuating, preventing or blocking an immune response or inflammatory response, comprising administering to a subject an amount of soluble LIGHT polypeptide sequence that binds to a cis complex comprising herpes virus entry mediator (HVEM) polypeptide binding to B- and T-lymphocyte attenuator (BTLA) polypeptide, sufficient to inhibit, reduce, decrease, attenuate, prevent or block an immune response or inflammatory response. 
   
   
       23 . The method of  claim 22 , wherein the immune response or inflammatory response comprises an acute or chronic inflammatory response or inflammation, or an inflammatory or autoimmune disease. 
   
   
       24 . The method of  claim 23 , wherein the inflammatory or autoimmune disease is selected from type I or type II diabetes, systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease or graft vs. host disease.