Type 1 diabetes (T1D) is an autoimmune disease that results when insulin-secreting beta cells are destroyed in the pancreas. CD4+ and CD8+ T cells reactive to beta cell antigens escape central and peripheral tolerance mechanisms and infiltrate the islets of Langerhans. The development of therapies that prevent beta cell specific T cells from entering the islets and killing the beta cells is of great interest to the field.
Our laboratory and others have noted that IFN-gamma plays an important role in the development of diabetes. IFN-gamma is known to upregulate MHC class I on beta cells, which is required for their direct destruction by CD8+ cytotoxic T lymphocytes. Further, CD4+ diabetogenic T cells adoptively transferred into mice lacking IFN-gamma receptor do not migrate efficiently into the islets, and show a long delay in disease onset. We sought a way to therapeutically knockdown IFN-gamma signaling in mice in vivo, in the hope of emulating this effect.
Here we use a specific Jak1/2 inhibitor, AZD1480, to inhibit downstream transduction of IFN-gamma. We found that treatment completely inhibited IFN-gamma induced STAT1 phosphorylation and MHC class-I upregulation in mouse and human islets in vitro, and mouse beta cells in vivo. NOD.Rag1-/- mice treated with AZD1480 and adoptively transferred with BDC2.5 beta cell-specific CD4+ T cells showed minimal infiltration and remained diabetes free while treatment continued. We are currently testing whether the inhibitor can reverse disease in diabetic animals. This data will provide a platform for designing clinical trials for blocking Jak1/2 signaling in human T1D.