Type I diabetes (T1D) is a spontaneous autoimmune disease in which the insulin-producing beta cells of the islets of langerhans are destroyed as a consequence of inflammatory reactions triggered by genetic and environmental factors. Transfer of T helper type 1 (Th1) lymphocytes specific for p cell-associated antigens such as insulin beta (INSbeta) chain or glutamic acid decarboxylase (GAD) can confer disease into healthy animals suggesting that the immune system plays a primordial role in T1D. Modulation of diabetogenic Th1 cells offers a viable antigen-specific strategy against T1D. The objective in this proposal is to test a new antigen-specific approach for modulation of diabetogenic T cells in young mice prior to insulitis where The T cells remain peripheral to the islets and in older animals with ongoing insulitis where the T cells have become islet-residents. These studies should yield information useful for the development of a regimen suitable for intervention against the disease in susceptible subjects before progression to hyperglycemia. The new approach will use immunoglobulins (Igs) to vehicle diabetogenic peptides for presentation to autoreactive T cells in a tolerogenic fashion. Accordingly, select peptides will be genetically engineered into Igs and the resulting Ig peptide chimeras will be injected into animals in a soluble (sol) or aggregated (agg) form but while free of adjuvant. In vivo, the Ig-peptide chimeras will be internalized into antigen presenting cells (APCs) mainly via FcgammaR leading to endosomai processing, and access of the peptide to newly synthesized MHC molecules. Additionally agg chimeras will induce the production of IL-10 by APCs and augment the tolerogenic functions of the approach. Efficient loading of the peptide onto MHC molecules will occur, yet due to the autologous nature of Igs, peptide presentation will lack costimulation. Furthermore, the T cells will be exposed to IL-10, a cytokine defined to be suppressive for Th1 cells. Consequently, the approach should drive effective down-regulation of diabetogenic T cells and suppress diabetes. The driving hypothesis in this proposal postulates that diabetogenic T cells residing within the pancreatic islets are subject to different regulatory mechanisms from those located peripheral to the islets. In this case antigen-specific suppression of diabetes would require discrete modulatory mechanisms in young versus older insulitis-positive mice. To test this hypothesis, we propose to express INSp and GAD peptides on Igs and utilize the resulting Ig-INSp and Ig- GAD to define the requirements for restoration of T cell tolerance and suppression of diabetes. The NOD mouse, which develops spontaneous T1D, as well as mutant NOD strains, will be the animal model of choice for these investigations.
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