Fingolimod improves the outcome of experimental Graves' disease and associated orbitopathy by modulating the autoimmune response to the thyroid stimulating hormone receptor.
Fingolimod improves the outcome of experimental Graves' disease and associated orbitopathy by modulating the autoimmune response to the thyroid stimulating hormone receptor.
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DOI：
10.1089/thy.2018.0754
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发表时间：
2019-09
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通讯作者：
Svenja Plöhn;Matthias Hose;A. Schlüter;L. Michel;S. Diaz-Cano;U. Hendgen-Cotta;J. Banga;N. Bechrakis;W. Hansen;A. Eckstein;U. Berchner‐Pfannschmidt
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作者：
Svenja Plöhn;Matthias Hose;A. Schlüter;L. Michel;S. Diaz-Cano;U. Hendgen-Cotta;J. Banga;N. Bechrakis;W. Hansen;A. Eckstein;U. Berchner‐Pfannschmidt
格雷夫斯病和格雷夫斯眼眶病与刺激促甲状腺激素受体（TSHR）自身抗体和自身反应性T细胞有关。最近的体外研究表明，鞘氨醇-1-磷酸（S1 P）信号参与眼眶病。在本研究中，我们探索了S1 P受体拮抗剂芬戈莫德在Graves病小鼠模型中的免疫调节潜力。芬戈莫德在疾病发作期间预防性口服给药或在疾病发作后治疗性口服给药。在疾病发作期间给予芬戈莫德完全阻止了促TSH受体自身抗体的形成。疾病发作后的干预很少减少促甲状腺激素释放激素刺激性自身抗体和封闭性自身抗体诱导的一些动物。因此，以血清甲状腺素水平升高、甲状腺形态增生伴T细胞浸润、体重增加、体温升高和心动过速为特征的自身免疫性甲状腺功能亢进症在预防性治疗中未表现出来，在治疗性治疗动物中表现出较轻的表现。重要的是，眼眶组织检查显示，通过减少T细胞浸润、脂肪生成和透明质酸沉积，眼眶病表现显著改善。自身免疫性甲状腺功能亢进症和眼眶病伴有外周和脾脏T细胞比例的变化，CD 3+，CD 4+，CD 8 + T细胞升高。脾脏中活化T细胞CD 4 + CD 25+升高，而调节性T细胞CD 4 + Foxp 3+细胞保持不变。芬戈莫德降低升高的T细胞水平并增加CD 4 + CD 25 + Foxp 3+调节性T细胞群。总疾病结果的分析显示，在疾病发作期间的治疗保护动物免受自身免疫性甲状腺功能亢进症和眼眶病。值得注意的是，疾病发作后的治疗干预抑制了一半动物的疾病，另一半动物的疾病仍处于轻度阶段。这项研究的结果支持一项临床试验，以调查免疫和临床效益的早期治疗与S1 P为基础的药物在格雷夫斯病。
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.