The TSH receptor is the primary antigen of the uniquely human, autoimmune, hyperthyroid disease named after Robert Graves (Graves Disease). An animal model resembling Graves disease has been recently developed using an immunization procedure with syngeneic fibroblasts which were engineered to constitutively express MHC class II antigen and transfected with a full length cDNA for the human TSH receptor. Such mice develop high serum levels of T4, T3 and thyroid stimulating and blocking antibodies along with markedly enlarged thyroid glands. This proposal uses this new model to derive panels of monoclonal TSH receptor antibodies with simulating, blocking or neutral activity. In particular, the aims of the proposal (1) To derive stimulating and blocking monoclonal antibodies to the TSH receptor from mice with induced hyperthyroid Graves disease, (2) to characterize the linear and non-linear antigenic epitopes for the derived TSH receptor antibodies, (3) to examine the fine spcificity of TSH receptor monoclonal receptor antibodies with regard to their growth stimulating/inhibiting potential and their activation/inactivation of differentiated thyroid cell function and (4) to utilize selected monoclonal antibodies as TSH receptor probes. In particular we will determine the conformational changes induced by TSH receptor antibody binding and the role that TSH receptor cleavage plays in such changes. These data will provide the first characterization of murine TSH receptor antibodies with thyroid stimulating ability and allow the investigation of their antigen binding characteristics. Identification of their target epitopes will lead to new etiologic insights and treatment strategies for human Graves disease.
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