Fingolimod Improves the Outcome of Experimental Graves' Disease and Associated Orbitopathy by Modulating the Autoimmune Response to the Thyroid-Stimulating Hormone Receptor
| Autor: | Lars Michel, Nikolaos E. Bechrakis, Salvador J. Diaz-Cano, Svenja Plöhn, Matthias Hose, Utta Berchner-Pfannschmidt, Ulrike B. Hendgen-Cotta, Anke Schlüter, J. P. Banga, Wiebke Hansen, Anja Eckstein |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
Regulatory T cell Endocrinology Diabetes and Metabolism Graves' disease T cell medicine.medical_treatment Medizin 030209 endocrinology & metabolism CD8-Positive T-Lymphocytes T-Lymphocytes Regulatory Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Internal medicine medicine Animals IL-2 receptor Autoantibodies Mice Inbred BALB C Fingolimod Hydrochloride business.industry FOXP3 Receptors Thyrotropin Immunotherapy medicine.disease Fingolimod Graves Disease Graves Ophthalmopathy medicine.anatomical_structure 030220 oncology & carcinogenesis Female business CD8 medicine.drug |
| Popis: | Graves' disease (GD) and Graves' orbitopathy are associated with stimulating thyrotropin receptor (TSHR) autoantibodies and autoreactive T cells. Recent in vitro studies suggested that sphingosine-1-phosphate (S1P) signaling is involved in the pathogenesis of orbitopathy. In this study, we explored the immune modulatory potential of S1P receptor antagonist fingolimod in a murine model for GD. 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 preventively and showed milder manifestation in therapeutically treated animals. Importantly, examination of orbital tissue showed significant amelioration of orbitopathy manifestations through 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+, and CD8+ T cells. Activated T cells CD4+CD25+ were elevated whereas regulatory T cells CD4+Foxp3+ cells remained unchanged in spleens. Fingolimod decreased elevated T cell levels and increased CD4+CD25+Foxp3+ regulatory T cell 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 GD. |
| Databáze: | OpenAIRE |
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