Identification of Sorafenib as a Treatment for Type 1 Diabetes.
Identification of Sorafenib as a Treatment for Type 1 Diabetes.
复制标题
索拉非尼治疗 1 型糖尿病的鉴定
DOI：
10.3389/fimmu.2022.740805
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发表时间：
2022
影响因子：
7.3
通讯作者：
Deng T
中科院分区：
文献类型：
--
作者：
Zeng Q;Song J;Wang D;Sun X;Xiao Y;Zhang H;Xiao Y;Zhou Z;Deng T
Th 1细胞活化被认为是1型糖尿病发病机制的关键介质。靶向IL-12诱导的Th 1细胞分化似乎是阻断1型糖尿病发展的有效途径。然而，鉴于Th 1在免疫系统中的关键功能，潜在的副作用阻碍了抗Th 1治疗在1型糖尿病治疗中的应用。为了鉴定安全的抗Th 1治疗，我们使用IL-12诱导的Th 1分化细胞模型筛选FDA批准的酪氨酸激酶抑制剂（TKI）药物库。我们发现，在对T细胞活力几乎没有影响的TKI中，索拉非尼是抑制Th 1分化的最佳竞争者。用索拉非尼治疗NOD小鼠显著阻碍了1型糖尿病的发展并改善了胰岛炎，这与胰腺中Th 1细胞群的特异性减少而不是外周免疫器官中的Th 1细胞群的积累相一致。从机制上讲，索拉非尼间接抑制janus激酶2（JAK 2）活性，并阻断IL-12诱导的JAK 2和信号转导和转录激活因子4（STAT 4）的磷酸化。由于索拉非尼被归类为FDA批准的药物，因此它可以作为额外实验的初步先导点，可能是人类1型糖尿病的有希望的治疗方法。
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.