GENETICS AND PATHOLOGY OF NONOBESE DIABETIC (NOD) MICE

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Development of autoimmune insulin dependent diabetes mellitus (IDDM) in NOD mice entails a complex interaction between an inherently daibetogenic MHC and numerous non-MHC genes. Although chromosomal locations for a number of the non-MHC insulin dependent diabetes (Idd) genes have been established, their actual identities and precise functions remain unknown. The strategy employed to isolate these non-MHC Idd loci and to establish their contribution to immunopathogenesis has been to make congenic stocks of NOD mice carrying resistance alleles at Idd loci. The objectives of this proposal are to combined mouse genetics and function genomics to identify genes that control peripheral accumulation of autoreactive CD4 and CD8 T cells ("T-lymphoaccumulation") and to identify more precisely the nature of regulatory T cells capable of retarding the diabetogenic process. A targeted disruption of the L- selectin gene will be introduced into NOD/Lt mice to test the hypothesis that this marker identifies peripheral T-regulatory cells. To identify non-MHC genes that function either to regulate activation of islet- accumulation T cells or to limit their accumulation, studies are proposed to establish the genetic basis for IDDM resistance in the H2g7- identical NOR/Lt strain. NOR mice show a retarded activation of T- effector cells that may, in part, be a consequence of a more normal macrophage population. A genetically disrupted Caspase 1 (IL-1beta converting enzyme) gene will be introduced into diabetes-resistant Chr.2 congenic stocks expressing IL-1 alleles from NOR to test the candidacy of the IL-1 gene complex. NOD/Lt stocks congenic for NON/Lt-derived resistance loci on Chr 9 (exhibiting T-lymphoaccumulation, but retarded effector activation), and NOcCB-1, a new recombinant congenic strain, will be used to identify NOD genes controlling CD4 and CD4 T cell accumulation respectively. The combination of approaches proposed should permit not only molecular identification of major non-MHC associated IDDM susceptibility genes, but also establishment of their pathogenic contributions at a cellular level.