The importance of T cells in the pathogenesis of human and animal insulin-dependent diabetes mellitus (IDDM) has been amply documented. T cell clonotypes expressing T cell receptor (TCR) genes reactive with islet cell autoantigens. Such putative autoreactive TCR genes might be detectable at the genomic or expression levels and thus reflected in the overall TCR repertoire, in the T cell clonotypes reactive with corresponding self-antigens, and/or those found infiltrating pancreatic islets in the disease process. The IDDM-like disease of the NOD mouse provides and excellent model system in which to assess these possibilities. In the proposed study, restriction fragment length polymorphisms (RFLPs) in the genes encoding the variable portion of the NOD mouse TCR will be utilized in genetic studies to assess the possible contribution of germline-encoded TCR V genes to disease manifestations. The phenotypic characteristics, and particularly the nature of the clonotypic TCR molecules expressed by pancreatic infiltrating T cells, will be assessed at the RNA level using V- specific molecular probes, and at the single-cell level using in situ hybridization and antibodies specific for relevant individual TCR V-gene subfamilies. If, as expected, a restricted pattern of TCR v. gene usage is identified in the infiltrating cell population, anti-clonotypic or variotypic (V subfamily-specific) monoclonal antibodies specific for the relevant TCR molecules will be prepared and administered in vivo to assess their effects on the disease process. These model studies will begin to define the role of putative autoreactive T cell clonotypes in murine diabetes at the molecular level, and might constitute the basis for similar studies in human autoimmune diabetes.
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