Abstract
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.
Highlights
Type 1 diabetes is an immune-mediated disease characterized by the impairment of insulinproducing pancreatic beta cells
T cell-based immunotherapies, such as an anti-CD3 monoclonal antibody, CTLA4Ig fusion protein and low-dose anti-thymocyte globulin, have emerged for the treatment of type 1 diabetes [1]. These immunotherapies have shown some benefits in human clinical trials, but Abbreviations: APCs, antigen-presenting cells; Cy, Cyclophosphamide; I-A2, insulinoma-associated antigen 2; JAK2, janus kinase 2; LADA, latent autoimmune diabetes in adults; MLN, mesenteric lymph node; PBMCs, Peripheral blood mononuclear cells; PDGFR, platelet derived growth factor receptor; Pancreatic lymph nodes (PLNs), pancreatic lymph nodes; PPI, preproinsulin; STAT4, signal transducer and activator of transcription 4; TKI, tyrosine kinase inhibitor; Tregs, regulatory T cells; TYK2, tyrosine kinase 2; VEGFR, vascular endothelial growth factor receptor; ZnT8, zinc transporter 8; Cy, cyclophosphamide; MLN, mesenteric lymph node; PMBC, peripheral blood mononuclear cells
A TKI mainly targeting Raf for the treatment of renal and liver cancers, strongly blocked IL-12induced Th1 cell differentiation by inhibiting the phosphorylations of JAK2 and STAT4
Summary
Type 1 diabetes is an immune-mediated disease characterized by the impairment of insulinproducing pancreatic beta cells. T cell-based immunotherapies, such as an anti-CD3 monoclonal antibody, CTLA4Ig fusion protein and low-dose anti-thymocyte globulin, have emerged for the treatment of type 1 diabetes [1]. These immunotherapies have shown some benefits in human clinical trials, but Abbreviations: APCs, antigen-presenting cells; Cy, Cyclophosphamide; I-A2, insulinoma-associated antigen 2; JAK2, janus kinase 2; LADA, latent autoimmune diabetes in adults; MLN, mesenteric lymph node; PBMCs, Peripheral blood mononuclear cells; PDGFR, platelet derived growth factor receptor; PLNs, pancreatic lymph nodes; PPI, preproinsulin; STAT4, signal transducer and activator of transcription 4; TKI, tyrosine kinase inhibitor; Tregs, regulatory T cells; TYK2, tyrosine kinase 2; VEGFR, vascular endothelial growth factor receptor; ZnT8, zinc transporter 8; Cy, cyclophosphamide; MLN, mesenteric lymph node; PMBC, peripheral blood mononuclear cells. In the face of an increasing type 1 diabetes population, it is urgent to development more effective and safer T cell-based immunotherapies
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