The overall objective of this application is to define mechanisms by which MHC class I loci contribute to diabetogenesis in NOD mice. Despite the fact that pancreatic Beta cells from NOD mice express high levels of MHC class 1, and that CD8+ T cells are required to initiate disease, little attention has been focused on the mechanisms by which the class I alleles of the H-2g7 haplotype interact with the genes within the unusual class 11 region to effect diabetogenesis.
The first aim to be addressed is whether MHC class I expression is required to mediate the selection and targeting of Beta cell autoreactive T cells in NOD mice. These questions will be evaluated through a series of experiments utilizing a stock of NOD mice made class I deficient by the presence of a disrupted Beta2-microglobulin (Beta2m) gene. In previously published work the applicant has demonstrated that antigen presenting cells (APC) expressing a diabetes resistant MHC can block the development of diabetogenic T cells from NOD bone marrow.
The second aim of this proposal is to determine if the ability of a diabetes resistant MHC haplotype to block the development of diabetogenic T cells is retained in the absence of class I expression. Stocks of MHC class I deficient NOD mice expressing class II alleles from diabetes resistant MHC haplotypes will be generated to achieve this aim.
The third aim focuses on the applicant's finding that the ability of NOD APC to mediate clonal deletion of autoreactive CD8+ T cells may be impaired since MHC class I expression is aberrantly down- regulated in a tissue specific fashion in IFNgamma treated macrophages from NOD mice, but not in macrophages from diabetes resistant H-2g7 identical NOR mice. Segregation analysis of (NOD x NOR)F2 progeny will delineate which of the four chromosomal regions distinguishing NOD from NOR mice contribute to defective trans-regulation of MHC class I expression, and determine if this defect contributes to diabetogenesis. These studies may aid in the identification of new genetic and immunophenotypic markers for susceptibility to autoimmune insulin dependent diabetes in humans.
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