Humanized HLA transgenic NOD mice to identify pancreatic beta cell autoantigens of potential clinical relevance to type 1 diabetes.

The mechanistic basis by which the H2(g7) major histocompatibility complex (MHC) provides the primary risk factor for the development of T cell-mediated autoimmune type 1 diabetes (T1D) in non-obese diabetic (NOD) mice involves contributions not only from the unusual A(g7) class II molecule, but also from the more common K(d) and/or D(b) class I variants it encodes. Similarly, transgenic studies in NOD mice have confirmed the possibility first suggested in association studies that in the proper genetic context the common human HLA-A2.1 class I variant can mediate diabetogenic CD8 T cell responses. T1D continues to develop in a further refined NOD stock that expresses human HLA-A2.1, but no murine class I molecules (designated NOD.beta2m-.HHD). Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an important antigenic target of diabetogenic CD8 cells in standard NOD mice. Three IGRP-derived peptides have also been identified that are presented by human HLA-A2.1 molecules to diabetogenic CD8 T cells in NOD.beta2m-.HHD mice. At least one of these IGRP peptides (265-273) can also be the target of autoreactive CD8 T cells in HLA-A2.1-expressing human T1D patients. Studies are currently under way to determine whether HLA-A2.1-restricted IGRP peptides can be used in a tolerance-inducing protocol that inhibits T1D development in NOD. beta2m-.HHD mice. If so, this knowledge could ultimately lead to the development of a similar T1D prevention protocol in humans

Mapping of the diabetes polygene Idd3 on mouse Chromosome 3 using novel congenic strains

Development of novel congenic mouse strains has allowed us to better define the location of the diabetogenic locus, Idd3, on Chromosome (Chr) 3. Congenic strains were identified by use of published and newly developed microsatellite markers, their genomes fingerprinted by a rapid, fluorescence-based approach, and their susceptibility to type 1 diabetes evaluated. The maximum interval containing Idd3 is now approximately 4 cM