The BB rat develops an autoimmune insulin dependent diabetes mellitus (IDDM) that closely resembles human IDDM. However, little is know about the predisposing abnormalities that lead to diabetes, or about the initiating factors that result in the autoimmune destruction of insulin-producing beta cells. The present proposal is designed to test the hypothesis that T cell abnormalities that lead to IDDM in BB rats result from defects in the development of prothymocytes and/or their differentiation in the thymus. Our working model to test this hypothesis is that two T cell developmental defects have occurred in diabetes-prones BB (DP) rats: 1) The generation of autoreactive diabetes effectors T cells; 2) the inability to generate RT6+ regulatory T cells. We believe that the relative balance of diabetes effector and regulatory T cells is an important factor in ultimately determining susceptibility or resistance to IDDM.
Specific Aim 1 will identify and characterize the predisposing factors important in the susceptibility of DP rats to IDDM. We will determine the role of intrinsic versus cells or lack or regulatory RT6+ T cells. The stage of T cell development (prethymic, intrathymic, postthymic) and the cellular and/or environmental mechanism(s) that result in T cell developmental defects will be determined.
Specific Aim 2 will investigate the initiating factors important in the pathogenesis of IDDM. A lymphocyte transfusion model of protection of DP rats will used to study the role(s) of regulatory (RT6+) T cells in preventing diabetes. A novel model IDDM, the RT6-depleted diabetes resistant BB (DR) rat that """"""""spontaneously"""""""" develops diabetes, will be used to investigate the autoimmune effector mechanisms that mediate destruction of beta cells. We will compare the effector and regulatory mechanism(s) that induce or prevent diabetes in DP and RT6-depleted DR rate to determine whether they are the same or different. Our ultimate goal is to understand both the predisposing and initiating factors important in the pathogenesis of IDDM in BB rats. These experiments should allow us to test our hypothesis, and to formulate possible therapeutic modalities for the treatment of human IDDM.
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