Methods for modulating il-33 activity

Abstract

Provided herein are methods of modulating IL-33 activity, e.g., for the purpose of treating immune diseases and conditions, as well as methods of screening for compounds capable antagonizing IL-33 signaling.

1 . A method of modulating an immune disorder or condition, comprising inhibiting IL-33 signal transduction through ST2 and IL-1RAcP by administering to a subject in need thereof an effective amount of:
 a) an antagonist of IL-33 binding to a complex of ST2 and IL-1RAcP; or   b) an antagonist of IL-1RAcP binding to a complex of IL-33 and ST2.   
     
     
         2 . The method of  claim 1 , wherein the immune disorder or condition is selected from the group consisting of an innate response, asthma, an allergy, multiple sclerosis, inflammatory bowel disorder, arthritis, an infection, cancer, and a tumor. 
     
     
         3 . The method of  claim 2 , wherein the infection is selected from the group consisting of an intracellular pathogen, a bacterium, a parasite and a virus. 
     
     
         4 . The method of  claim 3 , wherein the infection is an intracellular pathogen selected from the group consisting of  Leishmania  sp.,  Mycobacterium  sp.,  Listeria  sp.,  Toxoplasma  sp.,  Schistosoma  sp. 
     
     
         5 . The method of  claim 1 , wherein the immune disorder or condition comprises:
 a) a T H 1-type response; or   b) a T H 2-type response.   
     
     
         6 . The method of  claim 2 , wherein the arthritis is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and psoriatic arthritis. 
     
     
         7 . The method of  claim 1 , wherein the antagonist comprises an antibody or a fragment thereof that specifically binds to:
 a) IL-33;   b) IL-1RAcP;   c) ST2;   d) a complex of ST2 and IL-1RAcP;   e) a complex of IL-33 and ST2; or   f) a complex of IL-33, ST2 and IL-1RAcP.   
     
     
         8 . The method of  claim 7 , wherein the antibody or fragment thereof does not bind to ST2 alone and does not bind to IL-33 alone. 
     
     
         9 . The method of  claim 7 , wherein the antibody or fragment thereof is a humanized antibody or human antibody. 
     
     
         10 . The method of  claim 7 , wherein the antibody or fragment thereof is a fragment selected from the group consisting of a Fab, an Fv fragment, and an F(ab′) 2  fragment. 
     
     
         11 . A method of modulating blood cell counts, comprising inhibiting IL-33 signal transduction through ST2 and IL-1RAcP by administering to a subject in need thereof an effective amount of:
 a) an antagonist of IL-33 binding to a complex of ST2 and IL-1RAcP; or   b) an antagonist of IL-1RAcP binding to a complex of IL-33 and ST2.   
     
     
         12 . The method of  claim 11 , wherein the antagonist increases the count of platelets. 
     
     
         13 . The method of  claim 11 , wherein the antagonist decreases the count of one or more of total white blood cells, neutrophils, lymphocytes, and eosinophils. 
     
     
         14 . The method of  claim 11 , wherein the antagonist comprises an antibody or a fragment thereof that specifically binds to:
 a) IL-33;   b) IL-1RAcP;   c) ST2;   d) a complex of ST2 and IL-1RAcP;   e) a complex of IL-33 and ST2; or   f) a complex of IL-33, ST2 and IL-1RAcP.   
     
     
         15 . The method of  claim 14 , wherein the antibody or fragment thereof is a humanized antibody or human antibody. 
     
     
         16 . The method of  claim 14 , wherein the antibody or fragment thereof is a fragment selected from the group consisting of a Fab, an Fv fragment, and an F(ab′) 2  fragment. 
     
     
         17 . An isolated and purified complex of ST2 and IL-1RAcP. 
     
     
         18 . The isolated and purified complex of  claim 17 , wherein ST2 and IL-1RAcP are human ST2 and human IL-1RAcP, respectively. 
     
     
         19 . The isolated and purified complex of  claim 18 , further comprising human IL-33. 
     
     
         20 . An in vitro method of determining whether a test compound is an antagonist of i) IL-33 binding to a complex of ST2 and IL-1RAcP, or ii) IL-1RAcP binding to a complex of IL-33 and ST2, comprising an assay selected from the group consisting of:
 a) an NF-κB-dependent reporter gene expression assay;   b) an MyD88 IRAK, IRAK4 or TRAF6 recruitment assay;   c) an Erk1/2, p38, IκBα or JNK phosphorylation assay;   d) an NF-κB, Erk1/2 or p38 phosphorylation assay in cells that naturally express ST2;   e) an IL-13, IL-6 or IL-5 expression assay; and   f) an IL-6 production assay in mouse mast cell line WTMC;   wherein the test compound is determined to be an antagonist if it reduces the activity of IL-33 in the assay when compared to an assay run without the test compound.