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Endocrinology Vol. 140, No. 3 1392-1398
Copyright © 1999 by The Endocrine Society

ARTICLES

Regulation and Transfer of a Murine Model of Thyrotropin Receptor Antibody Mediated Graves’ Disease1

M. Kita, L. Ahmad, R. C. Marians, H. Vlase, P. Unger, P. N. Graves and T. F. Davies

Division of Endocrinology and Metabolism (M.K., L.A., R.C.M., H.V., P.N.G., T.F.D.), Departments of Medicine and Pathology (P.U.), Mount Sinai School of Medicine, New York, New York 10128

Address all correspondence and requests for reprints to: Dr. T. F. Davies, Mount Sinai Medical Center, Box 1055, 1 Gustave L. Levy Place, New York, New York 10128. E-mail: tdavies{at}smtplink.mssm.edu

In order to replicate a recently described murine model of Graves’ disease, we immunized AKR/N (H-2k) mice ip, every 2 weeks, with either a clone of fibroblasts expressing both the human TSH receptor (hTSHR) and murine major histocompatibility complex (MHC) class II molecules or with fibroblasts expressing the MHC class II molecules alone. Mice were bled, and their thyroid hormone levels measured, at 6, 12, and up to 18 weeks after the first immunization. Between 11–12 weeks after immunization, a significant number of mice began to die spontaneously and were found to have developed large goiters. Thirty to 40% of mice immunized with hTSHR transfected fibroblasts showed markedly increased serum T3 and T4 hormone levels by 12 weeks compared with controls, with the highest thyroid hormone levels being T3: 420 ng/dl (normal < 70) and T4: 16.5 µg/dl (normal < 5). The murine serum demonstrated the presence of antibodies to the TSHR, as evidenced by inhibition of labeled TSH binding to the hTSHR, and these sera had in vitro thyroid stimulating activity. Many of the hyperthyroid mouse exhibited weight loss and hyperactivity and, on examination, their thyroids had the histological features of thyroid hyperactivity including thyroid enlargement, thyroid cell hypertrophy, and colloid droplet formation - all consistent with Graves’ disease. In contrast, a small number of mice (< 5%) developed hypothyroidism with low serum T4 levels and markedly increased TSH concentrations and evidence of thyroid hypoplasia. Both hyperthyroidism and hypothyroidism were successfully transferred to naive mice using ip cells of immunized mice. Surprisingly, hypothyroidism occurred in many recipient mice even after transfer from hyperthyroid donors.

These results confirmed that immunization with naturally expressed hTSHR in mammalian cells was able to induce functional TSHR autoantibodies that either stimulated or blocked the mouse thyroid gland and induced hyperthyroidism or thyroid failure. Furthermore, both blocking and stimulating antibodies coexisted in the same mice as evidenced so clearly by the transfer of hypothyroidism from hyperthyroid mice. The addition of a Th2 adjuvant (pertussis toxin) caused approximately 50% of the animals to become hyperthyroid beginning early at 9 weeks, whereas a Th1 adjuvant (CFA) delayed the disease onset such that only 10% were hyperthyroid by 12 weeks. As with human autoimmune thyroid disease, the T cell control of this murine model may be critical and requires more extensive investigation.




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