VISUALIZING INSULITIS--IDDM PATHOGENESIS AND THERAPY

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DESCRIPTION: (Adapted from the Investigator's abstract): Insulin-dependent diabetes mellitus (IDDM) is a severely debilitating autoimmune disease caused by selective destruction of the islet beta cells by an autoimmune process that involves lymphocyte infiltration. The non-obese diabetic (NOD) mouse spontaneously develops IDDM and shows many of the characteristics of human IDDM. It has been demonstrated that the effector phase of the disease is mediated by T cells, and, in adoptive transfer studies, requires both CD4+ and CD8+ T cells for maximal disease transfer. To study beta cell loss and the molecular and cellular events that precede insulitis, noninvasive assays using bioluminescent reporters will be developed that assess the spatial and temporal features of lymphocyte trafficking and beta cell loss. We will employ an imaging strategy that allows an analysis of the trafficking of adoptively transferred cells to learn more about pathophysiology of IDDM and to localize the site of immunotherapy mediated by the adoptively transferred cells. Using these imaging strategies we can assess the timing of initial antigen encounter in vivo, and localize the sites of this interaction and determine if dendritic cells get pulsed with autoantigen locally or in regional nodes. The study in real time of pancreatic beta cell mass will allow an in depth analysis of the temporal events surrounding islet beta cell destruction. The studies outlined in this project intend to explore the feasibility of adoptive transfer of CD4+ T cells, transduced to express "regulatory" proteins as a form of adoptive T cell mediated immunotherapy of autoimmune disease. If these studies demonstrate adoptive T cell mediated gene therapy, by delivering the "regulatory" proteins to sites of autoimmune inflammation, it offers an attractive possibility for human gene therapy of autoimmune diseases including IDDM. The excitement of these studies relates to the specific targeting of gene therapy to the inflammatory lesion, the direct observation of this phenomenon, and the ready adaptability of this form of therapy to human disease. Positive results raise the possibility of transferring this technology from the NOD mouse model to human disease.