The hallmark of insulin dependent diabetes mellitus is the activation of autoreactive T ells and, as a consequence, the destruction of the islets of Langerhans. Most individuals do to develop this disease from which we conclude that normal mechanisms exist which prevent autoimmunity and that these are circumvented in autoimmune predisposed individuals. We hypothesize that in normal mice and humans peripheral tolerance mechanisms prevent the destruction of islets, although the level at which this prevention occurs is not yet established. We further hypothesize that in autoimmune predisposed NOD mice, that these mechanisms fail and, as a consequence, autoimmunity results. Our previous studies have established that sch peripheral tolerance mechanisms exist in mice of the B6 genetic background, though the mechanisms have not been elucidated. In this grant we will use covalently linked MHC-peptide complexes in conjunction with T cells from TCR transgenic mice to elucidate the mechanisms of peripheral tolerance of CD4 T cells in congenic mice of the B6B10 background. We will also determine the nature of the defects in peripheral tolerance in autoimmune predisposed NOD mice. We will elucidate which cells mediate peripheral tolerance mechanisms and specifically we will test the hypothesis that tissue cells and/or tolerogenic antigen presenting cells mediate peripheral tolerance.
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