Use of Sirt1 Activators or Inhibitors to Modulate an Immune Response

Abstract

The present disclosure provides a method of increasing an immune response in an individual, the method involving administering to an individual in need thereof an inhibitor of SIRT1. The present disclosure provides a method of reducing an immune response, e.g., to treat chronic immune hyperactivity, the method generally involving administering to an individual in need thereof an activator of SIRT1. The present disclosure provides a method of modulating activation and differentiation of CD4 + T cells.

1 .- 9 . (canceled) 
     
     
         10 . A method of modulating activation and differentiation of a CD4 +  T cell, the method comprising contacting the CD4 +  T cell with a SIRT1 inhibitor. 
     
     
         11 . The method of  claim 10 , wherein the CD4 +  T cell is a helper T cell, and wherein contacting results in reduced deacetylation of NF-κB in the helper T cell. 
     
     
         12 . The method of  claim 11 , wherein said contacting takes place in an individual in vivo and wherein said contacting results in increasing in an immune response to an antigen in the individual. 
     
     
         13 . The method of  claim 12 , wherein the individual is a human. 
     
     
         14 . The method of  claim 12 , further comprising administering the antigen to the individual. 
     
     
         15 . The method of  claim 12 , further comprising administering to the individual at least one additional agent that increases an immune response. 
     
     
         16 . The method of  claim 15 , wherein the at least one additional agent is a Toll-like receptor agonist, an immunostimulatory polynucleotide, an immunostimulatory polynucleotide-antigen conjugate, or an immunostimulatory cytokine. 
     
     
         17 . The method of  claim 10 , wherein the CD4 +  T cell is a CD4 + /CD25 + /FoxP3 +  T cell, and wherein said contacting results in reduced deacetylation of FoxP3 in the CD4 + /CD25 + /FoxP3 +  T cell. 
     
     
         18 . The method of  claim 17 , wherein said contacting takes place in an individual in vivo and wherein said contacting results in an increase in activity and/or levels of the CD4 + /CD25 + /FoxP3 +  T cell in the individual. 
     
     
         19 . The method of  claim 18 , wherein said increase in activity and/or levels of the CD4 + /CD25 + /FoxP3 +  T cell in the individual is effective to treat an autoimmune disorder or to reduce graft rejection. 
     
     
         20 . The method of  claim 18 , wherein the individual is a human. 
     
     
         21 . The method of  claim 10 , wherein the SIRT1 inhibitor is 7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole-3-carboxylic acid amide; 6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid amide; 1,2,3,4-tetrahydro-cyclopenta[b]indole-3-carboxylic acid amide; or 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid (5-chloro-pyridin-2-yl)-amide. 
     
     
         22 . The method of  claim 12 , wherein the SIRT1 inhibitor is administered orally. 
     
     
         23 . The method of  claim 18 , wherein the SIRT1 inhibitor is administered orally. 
     
     
         24 . A method of treating an autoimmune disorder in an individual, the method comprising administering to the individual an effective amount of a SIRT1 inhibitor. 
     
     
         25 . The method of  claim 24 , wherein the individual is a human. 
     
     
         26 . The method of  claim 24 , wherein the SIRT1 inhibitor is 7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole-3-carboxylic acid amide; 6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid amide; 1,2,3,4-tetrahydro-cyclopenta[b]indole-3-carboxylic acid amide; or 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid (5-chloro-pyridin-2-yl)-amide. 
     
     
         27 . The method of  claim 24 , wherein the SIRT1 inhibitor is administered orally. 
     
     
         28 . The method of  claim 24 , wherein the autoimmune disorder is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Type 1 diabetes, or autoimmune hemolytic anemia. 
     
     
         29 . The method of  claim 24 , wherein the SIRT1 inhibitor is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         30 . The method of  claim 24 , wherein the SIRT1 inhibitor is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of  claim 24 , further comprising administering to the individual at least one additional therapeutic agent. 
     
     
         32 . The method of  claim 31 , wherein the at least one additional therapeutic agent is selected from a corticosteroid drug, a non-steroidal anti-inflammatory drug, and an immunosuppressant drug. 
     
     
         33 . The method of  claim 31 , wherein the autoimmune disorder is Type 1 diabetes, and the at least one additional therapeutic agent is insulin or an insulin analog. 
     
     
         34 . The method of  claim 31 , wherein the autoimmune disorder is multiple sclerosis, and the at least one additional therapeutic agent is interferon-alpha. 
     
     
         35 . The method of  claim 24 , wherein the SIRT1 inhibitor is formulated with an enteric-soluble coating material.