机构：[1]Department of Endocrinology, The First Afiliated Hospital of Xi'an Jiaotong University, Xi'an, China[2]Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China[3]Department of Ophthalmology and Visual Science, The Prince of Wales Hospital, Hong Kong, China[4]Biobank of The First Afiliated Hospital of Xi 'an Jiaotong University, Xi'an, China[5]Genome Institute, The First Afliated Hospital of Xian Jiaotong University, Xi'an, China[6]Center for Mathematical Medical, The First Afilited Hospital of Xi'an Jiaotong University, Xi'an, China[7]Department of Ophthalmology, Tangdu Hospital, Air Force Military Medical University, Xian, China[8]Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China临床科室内分泌科首都医科大学附属北京同仁医院首都医科大学附属同仁医院[9]Department of Ophthalmology, Tung Wah Eastern Hospital, Hong Kong, China[10]MOE Key Laboratory for Inelligent Networks & Network Security, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi an, China[11]School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi' an Jiaotong University, Xian, China[12]School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China[13]Faculty of Science, L eiden University, L eiden, The Netherlands[14]Johannes Gutenberg University Medical Center, Department of Medicine I, Molecular Thyroid Lab, Mainz, Germany
CD4+ cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves' orbitopathy (GO). However, little is known about therapeutic targeting CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mTORC1 inhibitor, in GO mouse model, in vitro and in refractory GO patients. In the adenovirus-induced model, rapamycin significantly decreased the incidence of orbitopathy. This was accompanied by reduction of CD4+ CTLs, and improvement of inflammation, adipogenesis and fibrosis in orbits. CD4+CTLs from active GO patients showed upregulation of mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and clinical activity score in steroid-refractory GO patients. Single-cell RNA sequencing revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.
基金：
This study was supported by the National Key R&D Program of China (grant NO.
2018YFC1311500 (B. Y. S)), National Science Foundation of China (NSFC) (grant NO.
82170805 (B. Y. S), 81970679 (B. Y. S), 32125009 (K. Y), 32070663(K. Y), 82270827(Y.
W), 82201238(M.Z)), Natural Science Foundation of Shaanxi Province (2018JM70990 (Y.
W)), China Postdoctoral Science Foundation (224646(Y. W)) and Clinical research awardof the first afiliated hospital of Xi'an Jiaotong university (XJTU1AF-CRF-2019-020(Y. W)).
第一作者机构：[1]Department of Endocrinology, The First Afiliated Hospital of Xi'an Jiaotong University, Xi'an, China
通讯作者：
通讯机构：[1]Department of Endocrinology, The First Afiliated Hospital of Xi'an Jiaotong University, Xi'an, China[5]Genome Institute, The First Afliated Hospital of Xian Jiaotong University, Xi'an, China[10]MOE Key Laboratory for Inelligent Networks & Network Security, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi an, China[14]Johannes Gutenberg University Medical Center, Department of Medicine I, Molecular Thyroid Lab, Mainz, Germany[*1]The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710000, China[*2]The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710000, China[*3]JGU Medical Center, Langenbeckstr. 1, Building 302 T, level 1,Mainz 55131, Germany
推荐引用方式(GB/T 7714)：
Zhang Meng,Chong Kelvin Kl,Chen Zi-Yi,et al.Rapamycin improves Graves' orbitopathy by suppressing CD4+cytotoxic T lymphocytes[J].JCI INSIGHT.2023,8(3):doi:10.1172/jci.insight.160377.
APA：
Zhang Meng,Chong Kelvin Kl,Chen Zi-Yi,Guo Hui,Liu Yu-Feng...&Wang Yue.(2023).Rapamycin improves Graves' orbitopathy by suppressing CD4+cytotoxic T lymphocytes.JCI INSIGHT,8,(3)
MLA：
Zhang Meng,et al."Rapamycin improves Graves' orbitopathy by suppressing CD4+cytotoxic T lymphocytes".JCI INSIGHT 8..3(2023)
医学