Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice

Abstract

Introduction: The ‘Th17’ population, a subset of CD4+ T-cells that secrete IL-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti-IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study.

Results: While treatment with either anti-IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (p<0.001). Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti-IL-17 during mature diabetes, as it promoted a period of remission from new onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity following syngeneic islet transplantation, while anti-IL-17 was of no benefit. GAD65-specific ELISPOT and CD4+ adoptive transfer studies showed that IL-25 treatment resulted in a T-cell mediated dominant protective effect against autoimmunity.

Conclusions: These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-directed may be of benefit in this disease.