Methods for the diagnosis and treatment of insulin-dependent diabetes mellitus

Abstract

Methods for detecting the status of an insulin-dependent diabetes mellitus (IDDM)-associated autoimmune response in a mammal are provided. Specifically, the ratio of the frequency of T helper 1 cells to T helper 2 cells specific for a pancreatic β-cell associated antigen is indicative of the status of the autoimmune response. The methods may be employed prior to the onset of the clinical symptoms of the disease, thereby allowing identification of those at risk for developing clinical symptoms of IDDM, or subsequent to pancreatic tissue transplantation, for example, to measure the efficacy of treatment directed to enhancing the lifetime of the tissue transplant. Methods for prolonging the survival of tissue transplants are also provided. Specifically, a tissue-associated antigen is administered to the mammal which serves to shift the pathogenic Th1 response associated with pathological immunity toward a protective Th2 response.

What is claimed is:  
     
         1 . A method for detecting the status of an IDDM-associated autoimmune response in a mammal, said method comprising determining the ratio of T helper 1 to T helper 2 cells in said mammal each of which are specific for a pancreatic β-cell-associated antigen, wherein said ratio is indicative of the status of said autoimmune response in said mammal.  
     
     
         2 . The method according to  claim 1 , wherein the number of T helper 1 cells specific for said pancreatic β-cell-associated antigen is determined by detecting the frequency of interferon-γ secreting T-cells in said mammal that are specific for said antigen.  
     
     
         3 . The method according to  claim 1 , wherein the number of T helper 2 cells specific for said pancreatic β-cell-associated antigen is determined by detecting the frequency of interleukin-4 and interleukin-5 secreting T-cells in said mammal that are specific for said antigen.  
     
     
         4 . The method according to  claim 3 , wherein the number of T helper 1 cells specific for said pancreatic β-cell-associated antigen is determined by detecting the frequency of interferon-γ secreting T-cells in said mammal that are specific for said antigen.  
     
     
         5 . The method according to  claim 1 , wherein said determining is performed prior to the onset of clinical symptoms of IDDM in said mammal.  
     
     
         6 . The method according to  claim 1 , wherein said determining is performed subsequent to a pancreatic tissue transplant in said mammal.  
     
     
         7 . The method according to  claim 6 , wherein said method measures the efficacy of a treatment for enhancing the lifetime of said transplant.  
     
     
         8 . The method according to  claim 1 , wherein said pancreatic β-cell-associated antigen is selected from the group consisting of GAD65, hsp65 and insulin B-chain.  
     
     
         9 . The method according to  claim 8 , wherein said pancreatic β-cell-associated antigen is GAD65.  
     
     
         10 . A method for detecting the status of an IDDM-associated autoimmune response in a mammal, said method comprising determining the isotype of antibodies in said mammal specifically directed against a pancreatic β-cell-associated antigen, wherein the ratio of the amount of said antibodies having an isotype which is associated with the presence of T helper 1 cells specific for said β-cell-associated antigen to the amount of said antibodies having an isotype which is associated with the presence of T helper 2 cells specific for said β-cell-associated antigen is indicative of the status of the IDDM-associated autoimmunity in said mammal.  
     
     
         11 . The method according to  claim 10 , wherein said determining is performed prior to the onset of clinical symptoms of IDDM in said mammal.  
     
     
         12 . The method according to  claim 10 , wherein said determining is performed subsequent to a pancreatic tissue transplant in said mammal.  
     
     
         13 . The method according to  claim 12 , wherein said method measures the efficacy of a treatment for enhancing the lifetime of said transplant.  
     
     
         14 . The method according to  claim 10 , wherein said pancreatic β-cell-associated antigen is selected from the group consisting of GAD65, hsp65 and insulin B-chain.  
     
     
         15 . The method according to  claim 14 , wherein said pancreatic β-cell-associated antigen is GAD65.  
     
     
         16 . A method for prolonging the survival of a tissue transplant in a mammal, said method comprising: 
 administering to said mammal a tissue transplant protecting amount of an antigen which is associated with the donor tissue, wherein said antigen administration results in an increase in the ratio of T helper 2 cells specific for said antigen to the number of T helper 1 cells specific for said antigen.    
     
     
         17 . The method according to  claim 16 , wherein said tissue transplant is a pancreatic tissue transplant.  
     
     
         18 . The method according to  claim 16 , wherein said administering is performed prior to transplantation of said tissue into said mammal.  
     
     
         19 . The method according to  claim 16 , wherein said administering is performed after transplantation of said tissue into said mammal.  
     
     
         20 . The method according to  claim 16 , wherein said antigen is an autoantigen.  
     
     
         21 . The method according to  claim 20 , wherein said autoantigen is a pancreatic β-cell-associated autoantigen.  
     
     
         22 . The method according to  claim 21 , wherein said pancreatic β-cell-associated autoantigen is GAD65.  
     
     
         23 . A method for reducing the severity of an IDDM-associated autoimmune response in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pancreatic β-cell-associated antigen, wherein said administering results in an increase in the ratio of the number of T helper 2 cells specific for said antigen to the number of T helper 1 cells specific for said antigen.  
     
     
         24 . The method according to  claim 23 , wherein said pancreatic β-cell-associated antigen is selected from the group consisting of GAD65, hsp65 and insulin B-chain.  
     
     
         25 . The method according to  claim 24 , wherein said pancreatic β-cell-associated antigen is GAD65.  
     
     
         26 . The method according to  claim 23 , wherein said pancreatic β-cell-associated antigen is administered in conjunction with an adjuvant.  
     
     
         27 . The method according to  claim 26 , wherein said adjuvant is selected from the group consisting of incomplete Freund's adjuvant, aluminum hydroxide, interleukin-4 and interleukin-10.  
     
     
         28 . The method according to  claim 23 , wherein said administration is parenteral.  
     
     
         29 . The method according to  claim 28 , wherein said parenteral administration is by subcutaneous, intramuscular, intraperitoneal, intracavity, transdermal, intranasal, or intravenous injection.  
     
     
         30 . The method according to  claim 23 , wherein said administration is at a dosage of about 0.01 mg/kg/dose to about 2000 mg/kg/dose.  
     
     
         31 . A method for increasing the frequency of T helper 2 cells specific for a tissue-associated antigen relative to T helper 1 cells specific for said tissue-associated antigen in a mammal comprising administering to said mammal said tissue-associated antigen in an amount sufficient to induce a T helper 2 cell response to said antigen.  
     
     
         32 . The method according to  claim 31 , wherein said tissue-associated antigen is a pancreatic β-cell-associated autoantigen.  
     
     
         33 . The method according to  claim 32 , wherein said pancreatic β-cell-associated autoantigen is selected from the group consisting of GAD65, hsp65 and insulin B-chain.  
     
     
         34 . The method according to  claim 32 , wherein said pancreatic β-cell-associated autoantigen is GAD65.  
     
     
         35 . The method according to  claim 31 , wherein said tissue-associated antigen is administered in conjunction with an adjuvant.