Methods of Treating Autoimmune Diseases

Abstract

Novel methods for treating patients with autoimmune diseases are disclosed. The methods of the invention include first depleting circulating lymphocytes in the mammal, e.g., by administering anti-thymocyte antibody, and then, during the course of repopulation, administering to the mammal a therapeutically effective amount of latent TGF-β and/or another agent that promotes expansion of regulatory T cells. In certain aspects, the disclosed process results in improved kidney function and survival rates.

1 . A method of treating a mammal with an autoimmune disease, the method comprising:
 (a) depleting circulating lymphocytes in the mammal,   (b) allowing the lymphocytes to begin repopulating, and   (c) during the repopulation phase of (b), administering to the mammal a therapeutically effective amount of latent TGF-β and/or another agent that promotes the expansion of regulatory T cells.   
     
     
         2 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         3 . The method of  claim 2 , wherein the autoimmune disease is systemic lupus erythematosus 
     
     
         4 . The method of  claim 2 , wherein the autoimmune disease is multiple sclerosis. 
     
     
         5 . The method of  claim 1 , wherein the lymphocytes depleted are predominantly T cells. 
     
     
         6 . The method of  claim 1 , wherein the lymphocytes are depleted by administering an agent chosen from the group consisting of anti-thymocyte antibody, anti-CD52 antibody, and anti-CD3 antibody. 
     
     
         7 . The method of  claim 6 , wherein the anti-thymocyte antibody is chosen from the group consisting of Thymoglobulin®, Atgam™, Fresenius™, and Tecelac™. 
     
     
         8 . The method of  claim 1 , wherein the regulatory T cells are CD4 +  CD25 +  T cells. 
     
     
         9 . The method of  claim 1 , wherein latent TGF-β comprises mature TGF-β and one or both of the following:
 (a) latency associated peptide (LAP); and   (b) latent TGF-β binding protein (LTBP).   
     
     
         10 . The method of  claim 1 , wherein latent TGF-β is TGF-β1. 
     
     
         11 . The method of  claim 1 , wherein latent TGF-β is administered systemically. 
     
     
         12 . The method of  claim 1 , wherein the agent that promotes expansion of regulatory T cells is one or more agents chosen from the group consisting of:
 (1) IL-10,   (2) IL-4,   (3) IFN-α,   (4) vitamin D3,   (5) dexamethasone, and   (6) mycophenolate mofetil.   
     
     
         13 . The method of  claim 1 , wherein the agent that promotes expansion of regulatory T cells is rapamycin. 
     
     
         14 . The method of  claim 1 , wherein the autoimmune disease is associated with a loss of kidney function and the treatment results in slowing of the loss of or improvement in kidney function of the mammal. 
     
     
         15 . The method of  claim 14 , wherein the slowing of loss or improvement in kidney function is indicated by a change in systemic blood pressure, proteinuria, albuminuria, glomerular filtration rate, and/or renal blood flow. 
     
     
         16 . The method of  claim 14 , wherein the autoimmune disease is systemic lupus erythematosus, Goodpasture's syndrome, Wegener's syndrome, IgA nephropathy, IgM nephropathy, or another autoimmune disease that impairs kidney function. 
     
     
         17 . A method of treating a mammal with an autoimmune disease comprising:
 (a) administering an anti-lymphocyte antibody to the mammal, thereby reducing the population of peripheral blood T cells; and   (b) administering latent TGF-β to the mammal in an amount effective to slow the progression of the disease and/or improve symptoms.   
     
     
         18 . Use of latent TGF-β in the preparation of a medicament for treatment of autoimmune disease. 
     
     
         19 . The use of  claim 18 , wherein the autoimmune disease is systemic lupus erythematosus, Goodpasture's syndrome, Wegener's syndrome, IgA nephropathy, IgM nephropathy, or another autoimmune disease that impairs kidney function. 
     
     
         20 . The use of  claim 18 , wherein said treatment includes administration of an anti-lymphocyte antibody. 
     
     
         21 . Use of an anti-lymphocyte antibody in the preparation of a medicament for treatment of an autoimmune disease, wherein said treatment includes administration of latent TGF-β and/or another agent that stimulates regulatory T cells.