Methods and Compositions for Modulating TH-GM Cell Function

Abstract

Disclosed herein is a T-helper cell (“TH-GM” cell) that is regulated by IL-7/STAT5 and which secrete GM-CSF/IL-3. Also disclosed are methods and compositions for modulating TH-GM function for the treatment of, e.g., inflammatory disorders. Diagnostic and prognostic methods for specifically identifying TH-GM-mediated inflammatory disorders (e.g., rheumatoid arthritis), as distinct from and/or in addition to non-TH-GM-mediated (e.g., TNF-α-mediated) inflammatory disorders, are also provided.

1 .- 33 . (canceled) 
     
     
         34 . A method of treating an inflammatory disease associated with a TNF-α-independent inflammatory pathway, comprising administering to a subject in need thereof an effective amount of a signal transducer and activator of transcription 5 (STAT5) inhibitor, wherein the inflammatory disease is mediated by granulocyte macrophage colony-stimulating factor (GM-CSF)-secreting T-helper (Th-GM) cells, wherein the STAT5 inhibitor reduces serum level of GM-CSF in the subject and thereby providing a therapeutic benefit to the subject in a TNF-α-independent manner. 
     
     
         35 . The method of  claim 34 , wherein the inflammatory disease is rheumatoid arthritis. 
     
     
         36 . The method of  claim 34 , wherein the inflammatory disease is multiple sclerosis. 
     
     
         37 . The method of  claim 34 , wherein the T H -GM cells are differentiated from precursor CD4 +  cells in the presence of activated STAT5 and IL-7. 
     
     
         38 . The method of  claim 34 , wherein the STAT5 inhibitor is pimozide. 
     
     
         39 . The method of  claim 34 , wherein the STAT5 inhibitor is CAS 285986-31-4. 
     
     
         40 . The method of  claim 34 , wherein the STAT5 inhibitor is an antibody that specifically binds to STAT5. 
     
     
         41 . The method of  claim 34 , wherein the STAT5 inhibitor is an antisense nucleic acid, small interfering RNA, short hairpin RNA, or microRNA. 
     
     
         42 . A method of treating rheumatoid arthritis, comprising administering to a subject in need thereof an effective amount of (A) a STAT5 inhibitor and (B) a therapeutic agent that inhibits the TNF-α inflammatory pathway. 
     
     
         43 . The method of  claim 42 , wherein the STAT5 inhibitor is pimozide. 
     
     
         44 . The method of  claim 42 , wherein the STAT5 inhibitor is CAS 285986-31-4. 
     
     
         45 . The method of  claim 42 , wherein the STAT5 inhibitor is an antibody that specifically binds to STAT5. 
     
     
         46 . The method of  claim 42 , wherein the STAT5 inhibitor is an antisense nucleic acid, small interfering RNA, short hairpin RNA, or microRNA. 
     
     
         47 . The method of  claim 42 , wherein the therapeutic agent that inhibits the TNF-α inflammatory pathway is an etanercept, adalimumab, infliximab, golimumab, or certolizumab pegol. 
     
     
         48 . The method of  claim 42 , wherein the therapeutic agent that inhibits the TNF-α inflammatory pathway is prednisone, methotrexate, or tofacitinib. 
     
     
         49 . The method of  claim 42 , Wherein the therapeutic agent that inhibits the TNF-α inflammatory pathway is anakinra, abatacept, rituximab, or tocilizumab. 
     
     
         50 . The method of  claim 42 , wherein (A) and (B) are administered sequentially. 
     
     
         51 . The method of  claim 42 , wherein (A) and (B) are administered simultaneously. 
     
     
         52 . The method of  claim 42 , wherein (A) and (B) are administered in a single dose.