113-OR: Identification of Sorafenib for the Treatment of Type 1 Diabetes

Type 1 diabetes (T1D) is an immune-mediated disease characterized by impairment of pancreatic beta cells. To date, a comprehensive cure is not available. Th1 cell activation is considered a key mediator of the pathogenesis of T1D. IL-12-induced STAT4 activation is a paramount signaling pathway to instigate Th1 cell differentiation. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of T1D. 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 T1D. 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 sorafenib, an oral anti-cancer drug, is a top contender for inhibition of Th1 differentiation relative to induced toxicity. Sorafenib inhibited IL-12-induced Th1 cell differentiation in a dose-dependent manner without any change of CD4+ T-cell viability. Treatment of NOD mice with sorafenib significantly impeded the development of T1D and ameliorated insulitis, which coincided with a specifically decreased aggregate of Th1 cell population in pancreas but not in peripheral immune organs. Inflammatory cytokines and Th1 signature transcription factor Tbet mRNA expression in pancreas were decreased in sorafenib-treated NOD mice compared to vehicle-treated NOD mice. Mechanistically, sorafenib directly inhibited JAK2 activity and blocked IL-12-induced phosphorylations of JAK2 and STAT4. In conclusion, sorafenib administration inhibits the development of T1D by suppressing IL-12b/JAK2/STAT4 signaling-mediated Th1 cell differentiation specifically in pancreas in NOD mice. Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapeutic for T1D in humans. Disclosure Q. Zeng: None. J. Song: None. X. Sun: None. D. Wang: None. Y. Xiao: None. Z. Zhou: None. T. Deng: None.