Methods for treating and preventing fibrosis

Abstract

The present invention provides methods of screening for compositions useful for treating, ameliorating, or preventing fibrosis and/or fibrosis-associated conditions by measuring changes in the level(s) of IL-21 and/or IL-21 receptor (IL-21R) (e.g., the level of expression of IL-21 and/or IL-21R protein and/or mRNA, the level of activity of IL-21 and/or IL-21R, the level of interaction of IL-21 with IL-21R). The invention further provides antagonists of IL-21 or IL-21R for the treatment of fibrosis and/or fibrosis-associated conditions. Further provided herein are methods of diagnosing, prognosing, and monitoring the progress (e.g., the course of treatment) of fibrosis and/or fibrosis-associated conditions by measuring the level of IL-21 and/or IL-21R (i.e., the level of activity of IL-21 and/or IL-21R, the level of expression of IL-21 and/or IL-21R (e.g., the level of IL-21 and/or IL-21R gene products), and/or the level of interaction of IL-21 with IL-21R).

1 . A method for treating, ameliorating, or preventing fibrosis or a fibrosis-associated disorder in a subject comprising administering to the subject a therapeutically effective amount of an agent that reduces the level of IL-21 and/or IL-21R in the subject. 
     
     
         2 . The method of  claim 1 , wherein the agent is a soluble fragment of an IL-21R. 
     
     
         3 . The method of  claim 2 , wherein the soluble fragment of the IL-21R comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of amino acids 1-538 of SEQ ID NO:2, amino acids 20-538 of SEQ ID NO:2, amino acids 1-235 of SEQ ID NO:2, amino acids 20-235 of SEQ ID NO:2, amino acids 1-236 of SEQ ID NO:2, amino acids 20-236 of SEQ ID NO:2, amino acids 1-529 of SEQ ID NO:5, amino acids 20-529 of SEQ ID NO:5, amino acids 1-236 of SEQ ID NO:5, and amino acid 20-236 of SEQ ID NO:5. 
     
     
         4 . The method of  claim 3 , wherein the soluble fragment of the IL-21R binds to an IL-21 polypeptide. 
     
     
         5 . The method of  claim 2 , wherein the soluble fragment of the IL-21R comprises an amino acid sequence that is substantially identical to the amino acid sequence set forth in SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, or SEQ ID NO:27. 
     
     
         6 . The method of  claim 5 , wherein the amino acid sequence of the soluble fragment of the IL-21R comprises an amino acid sequence that is substantially identical to the amino acid sequence set forth in SEQ ID NO:11 or SEQ ID NO:13. 
     
     
         7 . The method of  claim 2 , wherein the soluble fragment of the IL-21R is encoded by a nucleotide sequence that is substantially identical to the nucleic acid sequence set forth in SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, or SEQ ID NO:26. 
     
     
         8 . The method of  claim 7 , wherein the soluble fragment of the IL-21R is encoded by a nucleotide sequence that is substantially identical to the nucleic acid sequence set forth in SEQ ID NO:12 or SEQ ID NO:16. 
     
     
         9 . The method of  claim 2 , wherein the agent is a soluble fragment of an IL-21R, and wherein the soluble fragment of the IL-21R comprises an extracellular domain of IL-21R and an immunoglobulin Fc fragment. 
     
     
         10 . The method of  claim 9 , wherein the amino acid sequence of the extracellular domain of the IL-21R comprises an amino acid sequence that is at least 90% identical to amino acids 1-235 of SEQ ID NO:2 or amino acids 20-235 of SEQ ID NO:2. 
     
     
         11 . The method of  claim 9 , wherein the immunoglobulin Fc fragment has an altered function. 
     
     
         12 . The method of  claim 11 , wherein the immunoglobulin Fc fragment has the amino acid sequence of amino acids 244-467 of SEQ ID NO:17. 
     
     
         13 . The method of  claim 1 , wherein the fibrosis or fibrosis-associated disorder affects the liver, epidermis, endodermis, muscle, tendon, cartilage, heart, pancreas, lung, uterus, nervous system, testis, ovary, adrenal gland, artery, vein, colon, small intestine, biliary tract, or stomach. 
     
     
         14 . The method of  claim 13 , wherein the fibrosis or fibrosis-associated disorder affects the liver, epidermis, endodermis, or lung. 
     
     
         15 . The method of  claim 14 , wherein the fibrosis or fibrosis-associated disorder is interstitial lung fibrosis. 
     
     
         16 . The method of  claim 13 , wherein the fibrosis or fibrosis-associated disorder is the result of an infection with  schistosoma.    
     
     
         17 . The method of  claim 1 , wherein the fibrosis or fibrosis-associated disorder is the result of wound healing. 
     
     
         18 . The method of  claim 17 , wherein the wound healing results from a surgical incision. 
     
     
         19 . The method of  claim 1 , further comprising administering to the subject at least one additional therapeutic agent. 
     
     
         20 . The method of  claim 19 , wherein the at least one additional therapeutic agent is selected from the group consisting of cytokine inhibitors, growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, cytotoxic agents, and cytostatic agents. 
     
     
         21 . The method of  claim 19 , wherein the at least one additional therapeutic agent is selected from the group consisting of TNF antagonists, anti-TNF agents, IL-12 antagonists, IL-15 antagonists, IL-17 antagonists, IL-18 antagonists, IL-22 antagonists, T cell-depleting agents, B cell-depleting agents, cyclosporin, FK506, CCI-779, etanercept, infliximab, rituximab, adalimumab, prednisolone, azathioprine, gold, sulphasalazine, hydroxychloroquine, minocycline, anakinra, abatacept, methotrexate, leflunomide, rapamycin, rapamycin analogs, Cox-2 inhibitors, cPLA2 inhibitors, NSAIDs, p38 inhibitors, antagonists of B7.1, B7.2, ICOSL, ICOS and/or CD28, and agonists of CTLA4. 
     
     
         22 . The method of  claim 1 , wherein the subject is a human. 
     
     
         23 . A method for identifying a compound for treating, ameliorating or preventing fibrosis or a fibrosis-associated disorder in a subject, comprising: (a) measuring the level of IL-21 and/or IL-21R in a cell or sample of interest; (b) contacting the cell or sample of interest with a compound; and (c) measuring the level of IL-21 and/or IL-21R in the cell or sample of interest following contact with the compound, wherein a lower level of IL-21 and/or IL-21R in the contacted cell or sample of interest, in comparison to the level of IL-21 and/or IL-21R in a noncontacted cell or sample of interest, identifies the compound as a compound useful for treating, ameliorating, or preventing fibrosis or a fibrosis-associated condition in a subject. 
     
     
         24 . A method for identifying a compound for treating, ameliorating or preventing fibrosis or a fibrosis-associated disorder in a subject, comprising: (a) measuring the level of IL-21 and/or IL-21R in a cell or sample of interest; (b) contacting the cell or sample of interest with a compound; (c) measuring the level of IL-21 and/or IL-21R in the cell or sample of interest following contact with the compound; and (d) comparing the level of IL-21 and/or IL-21R in the contacted cell or sample of interest with a reference level of IL-21 and/or IL-21R, wherein a lower level of IL-21 and/or IL-21R in the contacted cell or sample of interest, in comparison to the reference level of IL-21 and/or IL-21R, identifies the compound as a compound useful for treating, ameliorating, or preventing fibrosis or a fibrosis-associated condition in a subject.