Genetic regulation of contingent macrophage- and T-cell-dependent steps in islet inflammation

grantor: University of TorontoInsulin dependent diabetes mellitus (IDDM) is a complex disease that is conferred by at least nineteen susceptibility genes ('Idd1-19') in the nonobese, diabetic (NOD) mouse, of which only 'Idd1' has been identified. Although NOD and nonobese, diabetes resistant (NOR) mice are 88% genetically-identical, C57BLKS/J-derived alleles at 'Idd4, 5, 9, 11' and '13' protect NOR animals from destructive islet inflammation. In an effort to define immunotherapeutic targets in high risk individuals, our major focus is to delineate how and when 'Idd ' genes regulate the cellular and molecular effectors of IDDM pathogenesis. Unlike IDDM, which is the convergence of multiple, genetically-regulated pathways, our hypothesis is that the obligate steps that drive early islet inflammation may be more directly related to the action of individual 'Idd' genes. My thesis demonstrates the utility of this approach. I present novel data showing that NOD-derived alleles at 'Idd4, 5, 9, 11' and ' 13' regulate the contingent macrophage and T cell-dependent pathways that drive islet infiltration (insulitis). We found that the T cells first recruited to islets lesions of young NOD mice exerted a profound impact on downstream disease severity. Genetic analysis revealed that the T cell recruitment to islets drove progression of insulitis and was regulated by NOD-derived alleles at 'Idd5' and 'Idd13'. The absence of either of these genetic determinants led to the uncoupling of T cell from APC infiltration of islet lesions, mild insulitis and IDDM resistance. Strikingly, we also found that islet-reactive T cell pathogenesis is macrophage-dependent, as NOD macrophages; induced IDDM in genetically-resistant NOR recipient mice. A comparative analysis of NOD and NOR macrophage function linked dysregulated nitric oxide synthase ('Nos2') gene expression to inheritance of the NOD-derived 'Idd4' locus. A critical role for NOD-derived alleles at both 'Idd4' and 'Idd9'/'11 ' was also observed in the susceptibility to the macrophage- and T cell-dependent steps that mediated a chemically-accelerated model of NOD IDDM. Thus, my research shows that a subset of essential 'Idd' loci control the T cell- and macrophage-dependent pathways that drive IDDM pathogenesis. Our analyses have overcome a fundamental limitation in diabetes research.Ph.D