Tu42 - JAK Inhibitor Ruxolitinib Prevents Autoimmune Diabetes in Non-Obese Diabetes Mice through Inhibition of the JAK-STAT Pathway in Multiple Cell Types

In Type 1 diabetes, pancreatic islet β cells are destroyed by diabetogenic CD8 T cells. Interferons (IFNs) play pathogenic roles in diabetogenic CD8 T cell activation. Ruxolitinib, a Janus Kinase (JAK) 1/2 inhibitor, inhibits receptor signaling of IFNs. The aim of the study was to investigate effects of ruxolitinib on diabetogenic immune responses and diabetes development in non-obese diabetic (NOD) mice.

Female NOD mice were treated with ruxolitinib or vehicle for 10 days prior to disease onset, and mice were monitored for diabetes development. Further, the mechanism of ruxolitinib action was explored.

Insulitis scores were decreased in ruxolitinib-treated NOD pancreas. Ruxolitinib prevented proliferation of adoptively transferred diabetogenic 8.3 CD8 T cells. Bone marrow dendritic cell (BMDC) maturation was affected by ruxolitinib, with evidence of impaired DC function. The proportion of IFNγ⁺CD4⁺, IFNγ⁺CD8⁺ and NKG2D⁺CD8⁺ T cells were decreased in NOD pancreas after ruxolitinib treatment. In vivo killing of islet peptide–pulsed splenocytes was reduced in ruxolitinib-treated NOD PLNs. After ruxolitinib treatment, diabetes development was inhibited in NOD mice and NOD SCID mice that were adoptively transferred with diabetic splenocytes. Further, ruxolitinib inhibited induction of pSTAT1 in BM and peritoneal macrophages as well as lymphocytes stimulated by IFNα, and the upregulation of pSTAT1 in response to IFNα was lower in ruxolitinib-treated PLN cells than in control mice. Our data demonstrate that ruxolitinib inhibits diabetogenic immune responses and diabetes development through inhibiting the JAK-STAT pathway in multiple cell types. Thus, early targeted therapy may be used to delay or prevent disease onset.