Graves' disease: xenotransplantation model (athymic nude mice)

Abstract

The immunological mechanisms leading to Graves' disease are not yet fully understood. The athymic nude mouse has immunological properties which allow in vivo studies concerning autoimmune thyroid diseases with special regard to the interaction of TSH, TSH receptor antibodies, cytokines, antithyroid drugs, TSH receptor antagonists and human lymphocytes. In our own studies thyroid tissues of patients with Graves' disease, toxic adenomas and non-toxic nodular goiter were xenotransplanted to athymic nude mice. Histology, morphology and function of the transplants were examined 2 days to 2 weeks after injection of bovine TSH, interferon-gamma, Graves' sera with or without addition of a TSH-receptor antagonist and lymphocytes of patients with Graves' disease. Thyroid transplants can be stimulated by TSH, interferon-gamma, Graves' sera and immunoglobulin G. Additional treatment with asialoagalacto-hCG inhibits stimulation of the immunoglobulin. Furthermore, preliminary results show, that engrafted peripheral and especially intrathyroidal lymphocytes from patients with Graves' disease specifically migrate into human thyroid transplants ("homing") and are able to induce functional and histological changes in these tissues. In summary, the xenotransplantation model is well suited for studies concerning pathogenesis, diagnosis and therapy of autoimmune thyroid diseases.

Lymphocyte Homing in Xenotransplanted Human Thyroid Tissue Can Be Inhibited by LFA-1 and ICAM-1 Antibodies

“…In the nude mouse model engrafted lymphocytes, especially of intrathyroidal origin, migrate into human thyroid transplants and induce histological and functional changes (10,11,27). This suggests that the ITL fraction consists mainly of cells with a "thyroid specific memory," as non-thyroid tissue does not result in lymphocyte infiltration (28).…”

“…While binding of the homing receptor CD44 on activated T lymphocytes to endothelial hyaluronan mediates a primary adhesive interaction, the mechanism for subsequent firm adhesion has not been elucidated in detail. Our group and others have shown that especially intrathyroidal lymphocytes (ITL) attach to thyrocytes in GD (9)(10)(11), supporting the hypothesis that lymphocytes with "thyroid-specific homing receptors" migrate from the circulation to the thyroid in GD (12). As gamma delta T cells isolated from thyroid tissue specifically recognize a ligand expressed by thyroid epithelial cells (13), the infiltration of the thyroid gland by lymphocytes is considered the result of expression of adhesion receptors on leukocytes and endothelial cells.…”