{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:17:30Z","timestamp":1790727450099,"version":"4.1.0"},"reference-count":50,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Key R&D Program of China","award":["2018YFC1311500"],"award-info":[{"award-number":["2018YFC1311500"]}]},{"DOI":"10.13039\/501100007128","name":"Natural Science Foundation of Shaanxi Province","doi-asserted-by":"crossref","award":["2018JM70990"],"award-info":[{"award-number":["2018JM70990"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["224646"],"award-info":[{"award-number":["224646"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Clinical research award of the first affiliated hospital of Xi\u2019an Jiaotong university","award":["XJTU1AF-CRF-2019-020"],"award-info":[{"award-number":["XJTU1AF-CRF-2019-020"]}]},{"DOI":"10.13039\/501100001809","name":"National Science Foundation of China","doi-asserted-by":"crossref","award":["82170805,81970679,32125009,32070663,82270827,82201238"],"award-info":[{"award-number":["82170805,81970679,32125009,32070663,82270827,82201238"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"<jats:p>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves\u2019 orbitopathy (GO). However, little is known about therapeutic targeting of CD4\n                    <jats:sup>+<\/jats:sup>\n                    CTLs. Herein, we studied the effect of rapamycin, an approved mTOR complex 1 (mTORC1) inhibitor, in a GO mouse model, in vitro, and in patients with refractory GO. In the adenovirus-induced model, rapamycin significantly decreased the incidence of GO. This was accompanied by the reduction of both CD4\n                    <jats:sup>+<\/jats:sup>\n                    CTLs and the reduction of orbital inflammation, adipogenesis, and fibrosis. CD4\n                    <jats:sup>+<\/jats:sup>\n                    CTLs from patients with active GO showed upregulation of the mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and the clinical activity score in steroid-refractory patients with GO. Single-cell RNA-Seq revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4\n                    <jats:sup>+<\/jats:sup>\n                    CTLs. In conclusion, rapamycin is a promising treatment for CD4\n                    <jats:sup>+<\/jats:sup>\n                    CTL-mediated inflammation and fibrosis in GO.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.160377","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T12:00:26Z","timestamp":1672315226000},"source":"Crossref","is-referenced-by-count":41,"title":["Rapamycin improves Graves\u2019 orbitopathy by suppressing CD4+ cytotoxic T lymphocytes"],"prefix":"10.1172","volume":"8","author":[{"given":"Meng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2587-1323","authenticated-orcid":true,"given":"Kelvin K.L.","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and 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