Graves' hyperthyroidism, a very common autoimmune disorder affecting primarily women, is caused by TSH receptor (TSHR) autoantibodies that mimic the action of TSH. Very recently, the first animal model has been developed with the hallmarks of Graves' hyperthyroidism. We now propose to use this """"""""Chiba"""""""" model to investigate several critical issues in Graves' disease, including exploration of approaches for immune intervention. 1. Addressing critical issues in Graves' disease:- The Chiba mouse model will be used to study the role of thyroid peroxidase (TPO) antibodies (common in Graves' disease), TSHR intramolecular cleavage, gender and iodide ingestion on development and course of hyperthyroidism 2. TSHR Antibody characterization:- TSHR antibodies arising in the Chiba mouse model will be characterized by approaches used for human TSHR autoantibodies, including:- (i) functional assays for TSH binding inhibition (TBI), thyroid stimulating immunoglobulin (TSI) and antibodies that block the biological action of TSH (TSBAb), (ii) epitopes and (iii) flow cytometry with intact cells to examine binding of non-functional TSHR antibodies. 3. TPO antibody characterization:- We will determine whether TPO antibodies in the Chiba model resemble human autoantibodies in terms of their:- (i) affinities, (ii) preferential recognition of native TPO and, (iii) preferential interaction with epitopes in the immunodominant region recognized by human TPO autoantibodies. 4. T Cell responses to TSHR antigen:- With the Chiba model of Graves' disease, we will:- (i) study the role of T cells in providing help in the generation of functional TSHR antibodies, (ii) determine the cytokines secreted by TSHR-specific T cells and, (iii) determine if the proliferative response of TSHR-specific T cell clones will vary depending on the antigen presenting cell (macrophages, B cells or syngeneic TSHR-expressing fibroblasts) 5. Intervention in the immune response in the Chiba model:- The Chiba model now makes feasible studies on the immunotherapy of hyperthyroidism in these animals, a long road that may ultimately provide the basis for immune intervention in human disease. We propose to examine the effect of second signal blockade (anti-CD40L) as a means to:- (i) Prevent the induction of disease and reverse the course of established disease and, (ii) Target a specific antigen (TSHR), rather than employing blanket suppression of the immune response.
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