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

Authors :
Zhang M
Chong KK
Chen ZY
Guo H
Liu YF
Kang YY
Li YJ
Shi TT
Lai KK
He MQ
Ye K
Kahaly GJ
Shi BY
Wang Y
Source :
JCI insight [JCI Insight] 2023 Feb 08; Vol. 8 (3). Date of Electronic Publication: 2023 Feb 08.
Publication Year :
2023

Abstract

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.

Details

Language :
English
ISSN :
2379-3708
Volume :
8
Issue :
3
Database :
MEDLINE
Journal :
JCI insight
Publication Type :
Academic Journal
Accession number :
36580373
Full Text :
https://doi.org/10.1172/jci.insight.160377