T cells from mouse thyroglobulin (MTg)-sensitized donors activated in vitro with MTg, anti-IL-2R and/or IL-12 induce severe granulomatous experimental autoimmune thyroiditis (G-EAT) in recipient mice. Thyroid lesions reach maximal severity at 19-21 days and completely resolve by 35-50 days if all thyroid follicles are not damaged. Depletion of CD8+ T cells inhibits resolution. If most thyroid follicles are damaged at day 21, there is continuing inflammation, with decreased serum T4, fibrosis and atrophy of the thyroid. The objective is to define the mechanisms involved in resolution and fibrosis of G-EAT and to determine if resolution can be promoted by preventing or reversing fibrosis. MTg- specific CD4+ T cells initiate injury to the thyroid by releasing cytokines. Cytokine-deletion mutant mice will be used to determine how particular inflammatory mediators regulate induction and resolution of G-EAT. CD4+ T cells or cytokines also recruit other cells to the thyroid; these include other inflammatory cells which induce more damage, and CD8+ T cells which become activated and terminate the inflammatory response, possibly by inducing apoptosis of CD4+ T cells. When inflammation is very severe, CD8+ T cells are unable to terminate the inflammation and lesions progress to fibrosis. Excessive production of TGFbeta by inflammatory cells is hypothesized to play a major role in excessive collagen deposition resulting in fibrosis. These studies will test the hypothesis that CD8+ T cells promote resolution of G-EAT, in part, by inducing apoptosis of inflammatory cells and that fibrosis develops when TGFbeta is overproduced. TGFbeta inhibitors and depletion of CD4+ T cells or neutrophils will be used to attempt to promote resolution and prevent or reverse fibrosis. This murine G-EAT model is a well-characterized animal model of autoimmune disease in which the host's immune system promotes healing of lesions. Our studies are aimed at understanding the mechanisms that enable the host to regulate and resolve this autoimmune inflammatory response and understanding how to prevent or reverse more severe destructive inflammatory responses that result in a failure of resolution, and a fibrotic end-stage disease. Granulomatous inflammation and fibrosis occur in many human diseases with presumed autoimmune mechanisms. These studies should provide directions for new clinical investigations that may lead to more rational and specific forms of therapy and provide insight into recovery mechanisms for autoimmune diseases, particularly those associated with granulomatous immunopathology, vasculitis and fibrosis.
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