The investigator has previously focused on the development of new animal models of autoimmune thyroid disease to understand the immunopathology of thyroid antigen self-recognition. Using both intact and the severe combined immunodeficient (scid) mouse, the investigators have characterized the immune response to the receptor for thyroid stimulating hormone (TSHR), a major autoimmune target in the human thyroid gland. For example, patients with Graves' disease have TSHR autoantibodies which act as TSH agonists and induce thyroid hyperfunction. However, the investigators immunization of mice with recombinant human TSHR induced TSHR autoantibodies lacking in TSH agonist activity. They hypothesize that such an immune response was secondary to minor, but immunologically critical, differences in structure and folding of the human immunizing antigen compared to the mouse TSHR. In this competing renewal, they will develop two new animal models for Graves' disease and evaluate their B-cell and T-cell reactivities. The two specific aims are: 1) to prepare recombinant glycosylated mouse TSHR antigen in an insect cell system. Purified receptor will then be used to immunize intact mice, and they will evaluate their immunological and thyroid functional responses in this homologous system; 2) to develop transgenic mice expressing thyroidal human TSHR antigen and to carry out genetic crosses to produce hTSHR mice homozygous for the scid mutation. These scid-hTSHR mice will be injected with intrathyroidal lymphocytes and engrafted with thyroid tissue from patients with Graves' disease. Hence, the human TSHR-Abs will be able to interact with the transgenic human TSHR and induce thyroid overactivity. The construction of both an intact mouse model for Graves' disease as well as the reproduction of the human disease in scid mice will allow a series of intervention procedures to be pursued as potential therapeutic approaches to a common human disease.
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