Autoimmune diabetes in the BB rat, an animal model of human insulin- dependent diabetes mellitus (IDDM), is a T cell-dependent disorder. We hypothesize that the predisposition to IDDM in these animals is the consequence of two intrathymic T cell developmental defects. We hypothesize that the first defect leads to the generation of autoreactive cells in both diabetes-prone (DP) and coisogenic diabetes- resistant (DR) BB rats and that the second defect impairs the generation of RT6+ regulatory T cells only in DP rats. Expression of both defects leads to spontaneous IDDM in the DP animal. Our analysis suggests that the relative balance between effector and regulatory T cell populations during ontogeny is a key factor that modulates the expression of IDDM in BB rats and possibly in other species. Our hypothesis is based on observations made during previous grant periods. 1) DP rat thymocyte maturation appears normal until late stages of CD4+CD8+ development both in vivo and in thymic organ cultures. 2) Thymocytes export to peripheral lymphoid tissues is reduced in DP rats, and recent thymic emigrants (RTEs) fail to differentiate into mature Thy1-RT6+ T cells. 3) An abnormally high percentage of RTEs undergo intrahepatic apoptosis in DP rats. 4) The thymuses of 8 week old, but not 4 week old, DR rats contain large numbers of autoreactive cells that adoptively transfer IDDM to athymic recipients, 5) Cells generated in DR adult thymic organ culture (ATOC) adoptively transfer IDDM to athymic recipients, but only in the absence of RT6+ regulatory T cells. 6) Autoreactive cells generated in DR rat ATOC can be tolerized in vitro. 7) Thymic epithelial defects develop in BB rats, and their appearance coincides temporally with the emergence of autoreactive T cells in both DP and DR rats. We will test our hypothesis in two Specific Aims.
Specific Aim No.1 is to investigate the cellular, biochemical, and molecular basis for the failure of RT6+ regulatory cells to develop in DP rats.
Specific Aim No. 2 is to investigate the cellular basis for the intrathymic defects that permit the development of diabetogenic effector T cells in BB rats. Our ultimate goal is to understand the T cell developmental defects that predispose to the expression of IDDM and autoimmunity. The results of these studies should define the intrathymic developmental defects that lead to diabetes pathogenesis, identify mechanisms by which T cell developmental defects are expressed, and clarify the role of intrathymic developmental defects in the predisposition to IDDM in genetically susceptible individuals.
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