The immunopathogenetic events underlying the development of Type 1 diabetes (TiD) in the NOD mouse have been the focus of this grant since its inception. We found that autoimmune diabetes in NOD mice is a hematopoietic stem cell disease associated with defects in the maturation of antigen presenting cells (APC). We identified a number of critical APC dysfunctions associated with failure to maintain central and peripheral T cell tolerance to pancreatic B cell autoantigens. During the last grant cycle, our attention has turned to the role of the pancreatic B cell itself in the autoimmune cascade culminating in diabetes, and it is this aspect that provides the focus for this request for a final three years of support. The ALR mouse is closely related to NOD as evidenced by genetic identity for markers at multiple """"""""Idd"""""""" (diabetes susceptibility) loci. This includes the H2gX MHC haplotype of ALR sharing many, but not all alleles with the NOD H2g7 haplotype. However, not only are ALR/Lt mice completely T1D-free, but they also exhibit remarkable systemic and B cell defenses against diabetogenic stress. This includes resistance to chemically mediated injury induced by toxins, cytokines, and killing affected by highly pathogenic NOD B cell autoreactive T cells. Importantly, an AIR locus on Chr. 3 identified as controlling a remarkable ability to dissipate oxidative free radicals contributed to T1D resistance. In addition, interval specific congenics have been developed to isolate and identify the protective allele (IddlO) li'-ked to the ALR H2gX MHC. Moreover, preliminary data are presented implicating an unusual interaction between ALR's nuclear and mitochondrial genomes to constitute their diabetes resistance phenotype. The 3 aims of the proposal are: (i) to identify the ALR diabetes-resistance locus on Chr. 3 linked both to high level dissipation of superoxide radicals and to resistance to autoimmune T1D; (2) to identify the protective allele (IddlO) linked to the H2gX MHC haplotype of ALR; and (3) to analyze whether the ALR maternal contribution to T1D resistance in outcross analysis with NOD mice reflects a contribution from their mitochondrial genome. Understanding the molecular genetic basis for systemically upregulated free radical defenses in the ALR mouse has important biomedical implications, especially for organ transplantation. Understanding the contributions of diabetes modifying genes in the extended mouse MIHC may identify human HLA orthologs whose presence has recently been established.
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