Identification of Sorafenib as a Treatment for Type 1 Diabetes

Th1 cell activation is considered a key mediator of the pathogenesis of type 1 diabetes. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of type 1 diabetes. However, given the critical function of Th1 in the immune system, the potential side eff...

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Bibliographic Details
Published in:Frontiers in immunology 2022-02, Vol.13, p.740805-740805
Main Authors: Zeng, Qin, Song, Jianfeng, Wang, Dandan, Sun, Xiaoxiao, Xiao, Yalun, Zhang, Haowei, Xiao, Yang, Zhou, Zhiguang, Deng, Tuo
Format: Article
Language:English
Subjects:
Animals
Diabetes Mellitus, Type 1 - drug therapy
IL-12
Immunology
Interleukin-12
Mice
Mice, Inbred NOD
NOD mice
sorafenib
Sorafenib - pharmacology
Sorafenib - therapeutic use
Th1
Th1 Cells
type 1 diabetes
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Summary:Th1 cell activation is considered a key mediator of the pathogenesis of type 1 diabetes. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of type 1 diabetes. However, given the critical function of Th1 in the immune system, the potential side effects hinder the application of anti-Th1 therapy in the treatment of type 1 diabetes. To identify safe anti-Th1 treatment(s), we screened the FDA-approved tyrosine kinase inhibitor (TKI) drug library using an IL-12-induced Th1 differentiation cell model. We found that among the TKIs with little effect on T cell viability, sorafenib is the top contender for the inhibition of Th1 differentiation. Treatment of NOD mice with sorafenib significantly impeded the development of type 1 diabetes and ameliorated insulitis, which coincided with a specifically decreased accumulation of Th1 cell population in the pancreas but not in peripheral immune organs. Mechanistically, sorafenib indirectly inhibited janus kinase 2 (JAK2) activity and blocked IL-12-induced phosphorylations of JAK2 and signal transducer and activator of transcription 4 (STAT4). Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapy for type 1 diabetes in humans.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2022.740805