Experimental autoimmune thyroiditis (EAT) in mice serves as a prototype for the study of chronic lymphocytic thyroiditis (Hashimoto's disease), as well as other organ-specific autoimmune disorders. The overall goal of this project is to use murine EAT to probe the recognitory and pathogenic mechanisms leading to thyroid dysfunction. As in the human, the autoimmune response is under genetic control. A major thyroid antigen is thyroglobulin (Tg) which can be used to induce EAT in genetically susceptible strains, linked to the major histocompatibility complex (MHC). The recognitory mechanism is under MHC I-A subregion control, but pathogenic mechanisms are influenced by other modifying genes such as the D end of the MHC. We have observed that shared determinants between human and mouse Tg can activate the T lymphocytes of immunized mice to produce thyroid inflammation in vivo and generate cytotoxic T cells in vitro.
Our aims are to: 1) propagate T cell subsets recognizing mouse Tg-specific or shared epitopes by cloning, as well as by fusion to form T cell hybridomas; 2) characterize the T cell lines and their progenies further as to I-subregion restriction and epitope specificity; 3) determine the functional capacities of the T cell lines (and clones) to cause disease in vivo and develop cytotoxicity in vitro, and the effect of D-end genes; 4) examine the kinetics of T cell subsets infiltrating the thyroid and their in situ distribution in immunized animals; and 5) analyze and compare the kinetics of thyroid infiltration of in vitro activated cell lines with those of intact animals.
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