Preclinical characterisation of JAK1/JAK2 inhibitors for treatment of type 1 diabetes

Trivedi PM1, Scott NA1, Jenkins MR2, Brodnicki TC1, Kay TW1 and Thomas HE1

  1. St Vincents Institute, Fitzroy, Victoria, Australia.
  2. Walter and Eliza Hall Institute, Parkville, Victoria, Australia.

There is an opportunity to repurpose therapeutics from other diseases to type 1 diabetes, especially when there is evidence for overlapping mechanisms. We generated directed networks based on the phenotypes of gene knockout non-obese diabetic (NOD) mice, a mouse model of type 1 diabetes. The JAK-STAT pathway was important in T cells and pancreatic beta cells, the target of T cell-mediated destruction. We tested the hypothesis that blocking the response to cytokines that activate the JAK-STAT pathway would prevent autoimmune diabetes and tested the effects of drugs that selectively inhibit JAK1/JAK2. JAK inhibitors successfully blocked IFNγ-induced phosphorylation of STAT1 and IFNγ-induced MHC class-I upregulation in mouse and human islets. Mouse islets were protected from CTL-mediated killing in vitro by JAK inhibitors. Time-lapse microscopy shows the inhibitor prevented the direct interaction between CTLs and beta cells, reducing calcium flux in the CTL and synapse duration. JAK inhibitors blocked the effect of cytokines on beta cells in vivo by inhibiting MHC class I upregulation, and reduced infiltration of immune cells into islets. Furthermore, NOD mice treated with JAK inhibitors were protected from autoimmune diabetes, and diabetes was reversed in newly diagnosed NOD mice. Interestingly, deficiency of receptors for all three interferons (IFNγ, IFNα, IFNλ) did not prevent diabetes in NOD mice, suggesting that JAK inhibitors block cytokine signals other than interferons that are crucial for diabetes development. Future work will study this. Our work provides mechanistic groundwork for re-purposing clinically approved JAK inhibitors for type 1 diabetes, and provides a platform for testing many of the >150 kinase inhibitors under development for other diseases for efficacy in autoimmune diabetes.