Insulin dependent diabetes (IDD) is autoimmune disorder characterized by a T cell infiltration of the pancreatic islets. In addition, certain HLA class II genes are associated with susceptibility and resistance to the disease. A description of the T cell receptor (TCR) recognition of autoantigen in the context of Class II MHC molecules should give insights into the pathogenesis of IDD, as well as provide a guide to future intervention studies. A probable autoantigen involved in the initiation of IDD is glutamic acid decarboxylase (GAD). Autoantibodies to the GAD protein are early manifestations. For this proposal, we plan to analyze peripheral blood T cell responses to GAD in patients with IDD as well as those at low to high risks for the disease; to generate GAD reactive T cell clones; to phenotype (CD) the responding cells and clones; to identify the GAD protein epitopes responsible for T cell activation; to determine the HLA molecule responsible for antigenic epitope presentation; and to sequence the TCR variable region genes of GAD reactive T cell clones. These studies could provide the means to develope antigen specific therapies for the prevention of IDD.
