The Non-Obese Diabetic (NOD) mouse presents an excellent model for analyzing pathogenetic mechanisms underlying autoimmune destruction of pancreatic beta (B) cells. We have established that expression of NOD diabetogenic genes at the level of bone marrow derived effector cells is sufficient to adoptively transfer diabetes into otherwise diabetes-resistant F1 radiation chimeras. Immunoregulatory defects in signaling between accessory cells and T cells have been identified in NOD mice, and include defective activation of T suppressor cells accompanied by impaired IL-1 and IL-2 release. Proposed transplantation experiments will assess the pathogenic role of thylmocyte interactions with cells in the thymic microenvironment expressing the unique NOD H-2 gene products. A new NOD congenic strain carrying the recessive mutation """"""""severe combined immunodeficiency"""""""" (scid) has been created to allow evaluation of the pathogenic contributions of defined subsets of NOD T cells. The scid mutation prevents development of endogenous T and B lymphocytes such that these mice will be ideal for the T cell adoptive transfer studies proposed. NOD-scid mice will also permit testing whether defects in cytokine release cascades and failure to actively suppress autoreactive T cells are consequences of the unique I-AB gene product on accessory cells. Transplantation into reconstituted NOD-scid mice of NOD islets cultured in the presence or absence of gamma interferon (to induce Class I and Class II MHC antigens on B cells) will permit critical testing of the pathogenic significance of expression of the Ia antigen on B cells. Finally, to test the pathogenic consequences of high levels of retrovirus (intracisternal type A) expression in B cells, transgenic mice will be constructed to target this retroviral gene coupled with an insulin gene promoter into B cells of C57BL/6J mice that normally cannot express this endogenous retroviral genome.
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