289-OR: JAK Inhibitors Block Interferon and Common Gamma Chain Cytokine Signaling to Reverse Diabetes in NOD Mice

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, play an important role in facilitating the destruction of insulin-secreting β cells by CD8⁺ T cells in type 1 diabetes. We previously showed that inhibiting JAK1/JAK2 reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own did not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain family cytokines, including IL-2, IL-21, IL-7 and IL-15, may also affect progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We compared JAK1-selective inhibitors with our previous data with JAK1/JAK2 inhibition. JAK1-selective inhibitors reduced IL-21, IL-2 and IL-7 signaling in T cells (p<0.05) and IFN-γ signaling in β cells, but did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, JAK1-selective inhibitors reduced CD8⁺ T cell proliferation (Ki-67) in islets, reduced immune cell infiltration into islets and prevented MHC class I upregulation on β cells as measured by flow cytometry. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with JAK1-selective inhibitors.

Our results indicate that JAK inhibitors block common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFNγ receptor deficiency alone. Our studies pave the way for use of this class of drug in clinical trials for type 1 diabetes.