Rapamycin improves Graves' orbitopathy by suppressing CD4+ cytotoxic T lymphocytes

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 of CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mTOR complex 1 (mTORC1) i...

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Published in:JCI insight 2023-02, Vol.8 (3)
Main Authors: Zhang, Meng, Chong, Kelvin Kl, Chen, Zi-Yi, Guo, Hui, Liu, Yu-Feng, Kang, Yong-Yong, Li, Yang-Jun, Shi, Ting-Ting, Lai, Kenneth Kh, He, Ming-Qian, Ye, Kai, Kahaly, George J, Shi, Bing-Yin, Wang, Yue
Format: Article
Language:English
Subjects:
Animals
Autoimmunity
CD4-Positive T-Lymphocytes - metabolism
Endocrinology
Fibrosis
Graves Ophthalmopathy - metabolism
Inflammation
Mice
Sirolimus
T-Lymphocytes, Cytotoxic - metabolism
TOR Serine-Threonine Kinases
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Summary: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 of CD4+ 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+ CTLs and the reduction of orbital inflammation, adipogenesis, and fibrosis. CD4+ 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+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.160377