Immunologic Effects of Human Peripheral and Intrathyroidal Lymphocytes on Xenotransplanted Human Thyroid Tissue in Athymic Nude Mice

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Abstract
T cells are intimately involved in the etiology and pathogenesis of human autoimmune thyroid disease. In order to further elucidate the immunologic mechanisms leading to Graves' disease (GD), we investigated the effects of human lymphocytes derived from patients with autoimmune and nonautoimmune thyroid diseases on human thyroid tissue xenotransplanted into nude mice. Eight weeks after transplantation of thyroid tissue from 26 patients with nonautoimmune thyroid disease (nontoxic nodular goiter [NTG]) into nude mice, peripheral (PBL) and intrathyroidal lymphocytes (ITL) from 14 patients with NTG and 12 patients with GD were engrafted into the animals. ITL and PBL subsets were analyzed by flow cytometer before engraftment. Two days after lymphocyte engraftment, the thyroid transplants were examined histologically (HE) as well as immunohistologically by staining with monoclonal antibodies directed against CD3 (T-cell activation and signal transduction), immunoglobulin G (IgG), HLA class II and CD31 (human endothelium). After injection of GD lymphocytes, thyroid transplants contained significantly more CD3, HLA class II, and CD4 expressing cells. Engrafted PBL and especially ITL from patients with GD specifically migrated into human thyroid transplants but not into the mouse thyroids, induced expression of class II products and led to IgG production by plasma cells. Persistence of human endothelium has been proven by positive CD31 staining. In conclusion, our data demonstrate that an organ-specific immune response is induced only by GD lymphocytes that migrate specifically into the thyroid transplants. Persistence of human endothelial cells in the transplants suggests that homing in this in vivo model reflects the situation in GD patients.

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