EXCEED THE SPACE PROVIDED. Our hypothesis for aim 1 is that unresponsiveness to a non-tolerant [3-cell autoantigen is lost, if it is presented by antigen resenting cells in the pancreatic draining lymph node. This can occur, even if only lower numbers of autoaggressive T cells with reduced avidity are present. The ensuing autoimmune process develops slowly and also contains a (counter)-regulatory component in addition to the aggressive driver clones directed to the non-tolerant antigen. We hypothesize that this regulatory response is directed to other islet antigens and is capable of controlling the autoaggressive response. This notion will be tested in a novel model of spontaneous autoimmune diabetes, where tolerance to a [3-cell antigen is lost without external triggers or addition of T cell receptor transgenic autoaggressive lymphocytes. We postulate that this is one of the most physiological autoimmune models developed to date. The hypothesis to be evaluated in aim 2 is that the initiating autoantigen needs to be expressed throughout the autoimmune process in order to maintain activated autoaggressive driver T-cells. Conversely, the addition of a non-tolerant autoantigen late into an already established autoimmune process will only marginally accelerate the disease course, since a sufficient number of 'driver clones' seeing other autoantigens has already been established. These studies will use a tetracycline-dependent promoter system and directly address the pathogenetic importance of antigenic spreading in autoimmunity. We believe that these two goals will greatly improve our understanding of how antigens are driving an autoaggressive process and will clarify the central role antigen presenting cells and regulatory lymphocytes play in breaking or maintaining unresponsiveness. Our approach is carefully designed to avoid the creation of experimentally artificial non-physiological conditions in order to provide in vivo scenarios that are as close as possible to the situations that we find in human individuals. Thus, no T cell receptor transgenic models or viral triggers as they have been established previously in RIP-LCMV models will be utilized to address our hypotheses. PERFORMANCE SITE ========================================Section End===========================================
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