The investigator proposes to continue her characterization of the T-cells responsible for the initiation of IDDM in the NOD mouse. In previous studies, the investigator has obtained several CD4+ T-cell clones from diabetic NOD mice. Two of these clones, denoted BDC-2.5 and BDC-6.9, respond to beta granule membrane antigens and vary with respect to their capacity to induce disease on transfer into NOD-scid mice. BDC-6.9 T-cells could cause disease alone, while BDC-2.5 required the co-transfer of CD8+ cells from NOD diabetic spleens to cause disease. The current application focuses on the use of these TCR to develop transgenic mice as tools for the characterization of IDD pathogenesis. The investigator has three specific aims: 1) To produce TCR transgenic mice bearing these receptors on the NOD background.
This aim also proposes to characterize the basic phenotypes of these strains with respect to TCR expression and disease incidence. 2) To investigate the TCR transgenic mouse as a model of immunoregulation of autoimmune disease. These studies would approach questions of how autoreactivity is regulated, by characterizing the cellular interactions and regulatory properties of the diabetogenic T-cells in the TCR-Tg mice. These experiments would address the role of CD8 cells by transfer studies into NOD-scid mice with the TCR-Tg T-cells and would assess Th1/Th2 balances in the TCR-Tg mice. Finally, the investigator will study the features and requirements of protocols to attempt to induce antigen-specific tolerance to beta-granule proteins in an adoptive transfer model. 3) To investigate the effects of other genetic contributions to disease in the TCR-Tg mouse. These studies will characterize the effect of MHC genes (E of d and A-asp transgenics) and selected non-MHC genomic intervals, on the diabetes susceptibility of TCR-Tg mice.
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