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Fingolimod improves the outcome of experimental Graves' disease and associated orbitopathy by modulating the autoimmune response to the thyroid stimulating hormone receptor.

Graves' disease and Graves´ orbitopathy are associated with stimulating thyrotropin receptor (TSHR) autoantibodies and autoreactive T cells. Recent in vitro studies suggested sphingosine-1-phosphate (S1P) signaling is involved in orbitopathy. In the current study we explored the immune modulatory potential of S1P receptor antagonist fingolimod in a murine model for Graves' disease. Fingolimod was orally administered preventively during disease onset or therapeutically after disease onset. Administration of fingolimod during disease onset completely prevented the formation of TSHR-stimulating autoantibodies. Intervention after disease onset rarely reduced TSHR-stimulating autoantibodies and blocking autoantibodies were induced in some animals. Consequently, autoimmune hyperthyroidism characterized by elevated serum thyroxin levels, hyperplastic thyroid morphology accompanied by T-cell infiltration, weight gain, enhanced body temperature and tachycardia did not manifest in preventively and showed milder manifestation in therapeutically treated animals. Importantly, examination of orbital tissue showed significant amelioration of orbitopathy manifestations by reduction of T-cell infiltration, adipogenesis and hyaluronan deposition. Autoimmune hyperthyroidism and orbitopathy were accompanied by changes in peripheral and splenic T-cell proportions with high CD3+, CD4+, CD8+ T cells. Activated T cells CD4+CD25+ were elevated while regulatory T cells CD4+Foxp3+ cells remained unchanged in spleens. Fingolimod decreased elevated T-cell levels and increased CD4+CD25+Foxp3+ regulatory T-cells populations. Analysis of total disease outcome revealed that treatment during disease onset protected animals against autoimmune hyperthyroidism and orbitopathy. Of note, therapeutic intervention after disease onset suppressed disease in half of the animals and in the other half disease remained at mild stages. The results of this study support a clinical trial to investigate the immunologic and clinical benefits of early treatment with S1P-based drugs in Graves' disease.