The NOD (non-obese diabetic) mouse develops Type I diabetes mellitus secondary to autoimmune beta cell destruction. Our initial breeding studies indicate that these animals have more than one diabetogenic gene, and that a recessive gene necessary for development of diabetes is contained within the NOD major histocompatibility region. To date in crosses of NOD mice to C3H (H-2K) mice no F1 animals have developed diabetes (0/81) and all F2 or backcross animals (9/9) which have become diabetic are homozygous for the NOD H-2 haplotype. Initial characterization of the NOD H-2 region suggests that it is a natural """"""""recombinant"""""""" (Kd, IA-alphad, IA-betad, IE-alpha non-d non-b, C4 non-d non-b, Db). Currently the actual gene(s) within the MHC contributing to diabetes susceptibility is unknown. We propose to localize and identify the MHC diabetogenic gene of the NOD mouse and to study immunologic effector mechanisms in these animals. In particular we propose to, 1) confirm with further breeding studies the recessive nature of the NOD diabetogenic MHC gene and transfer """"""""all"""""""" the NOD's diabetogenic genes onto a C3H background. 2) Determine whether defined H-2 haplotyes (H-2b C57/bl, H-2d Balb/c) or H-2 recombinants (three strains of H-2g) have an analogous diabetogenic gene. 3) Analyze in detail the H-2 region of the NOD using a) monoclonal antibodies to class I and class II antigens, b) T cell clones of known H-2 restriction, and c) a series of DNA probes for IA-alpha, IA-beta, IE-beta, complement and class I genes. 4) Both monoclonal anti-islet autoantibodies and T cell autoreactive cell lines will be produced to define islet target antigens of the NOD mouse and the relationship of these effector mechanisms to the MHC recessive gene. Finally if the NOD's MHC diabetogenic gene is isolated and characterized, we will attmept to prevent or produce anti-islet autoimmunity and diabetes by introducing through gene transfer (transgenic mice) a relevant H-2 non-diabetogenic gene or the NOD """"""""diabetogenic"""""""" gene and evaluate its influence in breeding studies.
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