The objective of this proposal is to delineate the mechanisms involved in regulating the induction and resolution of experimental autoimmune thyroiditis (EAT) in mice. Using a model in which EAT is induced by in vitro activated T cells from mouse thyroglobulin (MTg)-sensitized donors, two distinct histopathologic forms of EAT can be induced by activation of the cells under different conditions. Cells activated with MTg alone induce lymphocytic (L) EAT of modest severity; the thyroid infiltrate consists primarily of mononuclear cells and lesions persist for several months. A more severe form of EAT, characterized by a granulomatous inflammatory response in the thyroid, is induced by cells activated with MTg together with anti-IL2R, anti-IL-2 or anti-IFN-gamma mAb. Granulomatous (G EAT is more acute, with complete resolution of lesions within 50-60 days; CD8+ T cells are required for resolution of G-EAT. Results during the previous project period suggest that the subset of CD4+ T cells that induces G-EAT is preferentially activated under conditions which do not allow optimal activation of, or lymphokine production by, IL-2 and IFN-gamma-producing CD4+ (Th1) or CD8+ T cells. Effector cells for G-EAT are probable analogous to the Th2 subset of CD4+ T cells. Activation of cells under conditions which allow activation of CD8+and Th1 cells inhibits the activity of EAT effector cells such that they induce L-EAT; Th1 cells may also be able to induce L-EAT. The major goal of this proposal is to further define the roles of various cell types, cytokines and adhesion molecules in regulating the type of thyroid histopathologic lesion that is produced. The potential contributions of cells recruited into the thyroid by the CD4+ effector cells as well as changes occurring during progression and regression of the lesions will be considered in the design of these studies. There are 3 major specific aims: 1) analysis of the role of cytokines produced by CD4+ and non-CD4+ T cells in regulating the development and effector function of cells that induce and regulate L- and G-EAT, 2) define the mechanisms by which CD8+ T cells regulate the induction and resolution of G-EAT and 3) analyze the specificity, homing and activation requirements of the effector cells for L- and G-EAT.
These aims will be achieved by the use of mice in which genes for CD8+ T cells and for particular cytokines have been deleted, by PCR analysis of T cell receptor and cytokine mRNA isolated from thyroid-infiltrating cells and by analysis of the ability of certain Tg- derived peptides to induce L-and G-EAT. These studies will extend our knowledge of the pathophysiology of autoimmune disease through the analysis of cells and factors which regulate these histologically distinct autoimmune inflammatory responses in the thyroid. This murine EAT model offers a unique opportunity to compare pathophysiologic mechanisms underlying development of distinct types of inflammatory responses induced in a single target organ by the same autoantigen (MTg). The ability to induce a granulomatous autoimmune response in this EAT model offers an excellent opportunity to elucidate the specific cytokine and cellular mechanisms which influence the nature of autoimmune inflammatory responses and may be highly relevant for understanding human diseases exhibiting granulomatous inflammation. These studies will provide information which may lead to more specific forms of therapy for autoimmune diseases exhibiting distinct types of pathology and provide insight into recovery mechanisms.
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