Targeting cytokines involved in T cell proliferation and function in a mouse model of type 1 diabetes

Cytokines functioning through the JAK-STAT pathway amplify immune responses in autoimmune and inflammatory diseases and drive some T cell lymphomas. Therefore, JAK inhibitors have shown efficacy in multiple autoimmune diseases as well as T cell malignancies. My PhD work focused on the role of common gamma chain cytokines in T cell proliferation and their contribution to autoimmune diabetes and T cell lymphomas. In chapter 2, I used the JAK1 selective inhibitor ABT 317 to reverse spontaneous diabetes in NOD mice. I confirmed that the JAK1 inhibitor can block IFNgamma activity to prevent MHC class I upregulation on beta cells and weaken the interaction between T cells and beta cells. More importantly, my research revealed that the JAK1 inhibitor reduced common chain cytokines, IL-21, IL-2, IL-15 and IL-7 signalling in T cells and inhibited both CD4+ and CD8+ T cell proliferation and differentiation. In a recent study by our lab, Jhala et al showed that islet autoantigen-specific T cells from NOD mice lacking IFNgamma receptors (Ifngr1 mutant mice) are present at >10-fold in number compared to wild-type NOD mice, and this expansion is due to increased response of Ifngr1 mutant T cells to common gamma chain cytokines. It emphasises reducing T-cell proliferation as an important way that JAK inhibitors preserve beta cells. In chapter 3, I studied checkpoint inhibitor-induced diabetes by injecting NOD mice with anti-PD-L1 antibodies. Diabetes was induced rapidly after the administration of anti-PD-L1 due to activation of already existing islet-specific T cells that can destroy beta cells. There is currently no effective therapy to prevent checkpoint inhibitor-induced diabetes. I used a JAK1/JAK2 inhibitor to block the effect of cytokines on T cells and beta cells. The JAK1/JAK2 inhibitor prevented anti-PD-L1 induced diabetes. Using JAK inhibitors after checkpoint inhibitors in a tumour model did not reverse or abrogate the anti-tumour effects of checkpoint inhibitors. This