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Repurposed JAK1/JAK2 inhibitor reverses established autoimmune insulitis in non-obese diabetic mice


Trivedi, PM; Graham, KL; Scott, NA; Jenkins, MR; Majaw, S; Sutherland, RM; Fynch, S; Lew, AM; Burns, CJ; Krishnamurthy, B; Brodnicki, TC; Mannering, SI; Kay, TW; Thomas, HE
2017-03-14
Diabetes
Journal Article in press
Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics from other diseases to type 1 diabetes, especially when there is evidence for overlapping mechanisms. JAK1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and STAT1 pathway in human type 1 diabetes and in mouse models, especially in beta 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 beta cells by inhibiting MHC class I upregulation. This prevented the direct interaction between CD8+ T cells and beta 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.
ADA
Immunology; Chemical Biology
10.2337/db16-1250
28292965
Refer to copyright notice on published article.

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Creation Date 2017-04-12 10:42:27 Last Modified 2017-04-12 12:07:55