Trivedi Prerak M, Graham Kate L, Scott Nicholas A, Jenkins Misty R, Majaw Suktilang, Sutherland Robyn M, Fynch Stacey, Lew Andrew M, Burns Christopher J, Krishnamurthy Balasubramanian, Brodnicki Thomas C, Mannering Stuart I, Kay Thomas W, Thomas Helen E
St. Vincent's Institute, Fitzroy, Victoria, Australia.
The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
Diabetes. 2017 Jun;66(6):1650-1660. doi: 10.2337/db16-1250. Epub 2017 Mar 14.
Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics used to treat other diseases to treat type 1 diabetes, especially when there is evidence for overlapping mechanisms. Janus kinase (JAK) 1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and signal transducer and activator of transcription (STAT) 1 pathway in human type 1 diabetes and in mouse models, especially in β-cells. We tested the hypothesis that using these drugs to block the JAK-STAT pathway would prevent autoimmune diabetes. The JAK1/JAK2 inhibitor AZD1480 blocked the effect of cytokines on mouse and human β-cells by inhibiting MHC class I upregulation. This prevented the direct interaction between CD8 T cells and β-cells, and reduced immune cell infiltration into islets. NOD mice treated with AZD1480 were protected from autoimmune diabetes, and diabetes was reversed in newly diagnosed NOD mice. This provides mechanistic groundwork for repurposing clinically approved JAK1/JAK2 inhibitors for type 1 diabetes.
免疫疗法的最新进展尚未改变自身免疫性1型糖尿病的常规治疗方法。有机会将用于治疗其他疾病的疗法重新用于治疗1型糖尿病，尤其是当有证据表明存在重叠机制时。 Janus激酶（JAK）1/JAK2抑制剂正在开发中或用于包括类风湿性关节炎在内的适应症的临床使用中。有充分证据表明，JAK1/JAK2和信号转导及转录激活因子（STAT）1途径在人类1型糖尿病和小鼠模型中被激活，尤其是在β细胞中。我们测试了使用这些药物阻断JAK-STAT途径可预防自身免疫性糖尿病的假设。JAK1/JAK2抑制剂AZD1480通过抑制MHC I类上调来阻断细胞因子对小鼠和人类β细胞的作用。这阻止了CD8 T细胞与β细胞之间的直接相互作用，并减少了免疫细胞向胰岛的浸润。用AZD1480治疗的非肥胖糖尿病（NOD）小鼠免受自身免疫性糖尿病的影响，并且新诊断的NOD小鼠的糖尿病得到逆转。这为将临床批准的JAK1/JAK2抑制剂重新用于治疗1型糖尿病提供了机制基础。
