{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T06:21:37Z","timestamp":1777875697670,"version":"3.51.4"},"reference-count":65,"publisher":"SAGE Publications","issue":"9","license":[{"start":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T00:00:00Z","timestamp":1567296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:p>\n                    Graves' disease (GD) and Graves' orbitopathy are associated with stimulating thyrotropin receptor (TSHR) autoantibodies and autoreactive T cells. Recent\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    , CD4\n                    <jats:sup>+<\/jats:sup>\n                    , and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Activated T cells CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD25\n                    <jats:sup>+<\/jats:sup>\n                    were elevated whereas regulatory T cells CD4\n                    <jats:sup>+<\/jats:sup>\n                    Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    cells remained unchanged in spleens. Fingolimod decreased elevated T cell levels and increased CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD25\n                    <jats:sup>+<\/jats:sup>\n                    Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1089\/thy.2018.0754","type":"journal-article","created":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T10:17:38Z","timestamp":1561457858000},"page":"1286-1301","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":18,"title":["Fingolimod Improves the Outcome of Experimental Graves' Disease and Associated Orbitopathy by Modulating the Autoimmune Response to the Thyroid-Stimulating Hormone Receptor"],"prefix":"10.1177","volume":"29","author":[{"given":"Svenja","family":"Pl\u00f6hn","sequence":"first","affiliation":[{"name":"Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Hose","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anke","family":"Schl\u00fcter","sequence":"additional","affiliation":[{"name":"Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Michel","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvador","family":"Diaz-Cano","sequence":"additional","affiliation":[{"name":"Department of Histopathology, King's College Hospital, King's College, London, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike B.","family":"Hendgen-Cotta","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasvinder Paul","family":"Banga","sequence":"additional","affiliation":[{"name":"Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolaos E.","family":"Bechrakis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wiebke","family":"Hansen","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Utta","family":"Berchner-Pfannschmidt","sequence":"additional","affiliation":[{"name":"Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2019,9,17]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0905750"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-012-8312-8"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.01.013"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/00004728-197903060-00019"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0043-125065"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2014.0475"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2813"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2010.1634"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.15-17863"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-20684"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-017-1037-3"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.18-25466"},{"key":"e_1_3_4_14_2","first-page":"CD009371","article-title":"Fingolimod for relapsing-remitting multiple sclerosis","volume":"4","author":"La Mantia L","year":"2016","unstructured":"La Mantia L, , Tramacere I, , Firwana B, , Pacchetti I, , Palumbo R, , Filippini G. 2016. 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