The objective of this proposal is to define the mechanisms involved in induction and regulation of autoimmunity using a murine model of experimental autoimmune thyroiditis (EAT). The experimental model for these studies involves induction of EAT by in vitro activated CD4+ T cells from mouse thyroglobulin (MTg)-sensitized donors. During the previous project period the cell-cell interactions involved in activation of the CD4+ EAT effector T cells were defined and monoclonal antibodies (mAbs) directed against cells involved in the autoimmune response were shown to prevent or reverse induction of EAT in this model. A major focus of the renewal application derives from the unexpected observation that MTg-sensitized spleen cells induced markedly increased EAT and anti-MTg autoantibody responses following culture of cells with MTgand mAbs directed against the interleukin-2 receptor (anti-IL-2R). In most cases recipients of cells cultured with MTg and anti-IL-2R mAbs had almost complete thyroid destruction and evidence of unique histopathologic lesions. A major goal of this application therefore is to delineate the mechanisms by which anti-IL-2R mAbs increase the activity of EAT effector cells and to determine how IL-2 and other lymphokines produced by distinct subsets of CD4+ T cells regulate both the activation and effector stages of EAT. A second major goal is to compare the effectiveness of several mAbs and lymphokines in preventing or reversing both classical EAT and the very severe EAT lesions induced in recipients of cells cultured with anti-IL-2R mAbs and to determine the role of lymphokines in EAT pathogenesis. These studies will address basic questions concerning regulatory interactions between subsets of CD4+ T cells and the lymphokines they produce and will examine mechanisms by which CD4+ EAT effector cells or their products induce damage to the thyroid. These studies will be important for increasing our understanding of the mechanisms by which self-reactive T cells become activated and who they damage target organs in autoimmune disease. Although these studies will be carried out using an experimentally induced autoimmune disease in animals, information gained from them could be applicable to understanding how self-reactive cells are activated and induce organ damage in human autoimmune diseases. Defining the potential and effectiveness of various lymphokines and mAbs for therapy of a disease having manifestations with widely varying severity and distinct histopathology should provide useful information for devising more rational approaches for treating autoimmune diseases in man.
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