Repurposed JAK1/JAK2 inhibitor reverses established autoimmune insulitis in NOD mice

P.M. Trivedi, K.L. Graham, N.A. Scott, M.R. Jenkins, S. Majaw, R.M. Sutherland, S. Fynch, A.M. Lew, C.J. Burns, B. Krishnamurthy, T.C. Brodnicki, S.I. Mannering, T.W. Kay, H.E. Thomas

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)1650-1660
Number of pages11
JournalDiabetes
Volume66
Issue number6
DOIs
Publication statusPublished - 22 Mar 2017

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