ROR Inverse Agonist Suppresses Insulitis and Prevents Hyperglycemia in a Mouse Model of Type 1 Diabetes

Hyperglycemia associated with type 1 diabetes is a consequence of immune-mediated destruction of insulin producing pancreatic beta-cells. Although it is apparent that both CD8(+) T cells and T(H)1 cells are key contributors to type 1 diabetes, the function of T(H)17 cells in disease onset and progression remains unclear. The nuclear receptors retinoic acid receptor-related orphan receptors-alpha and gamma t (ROR alpha and ROR gamma t) play critical roles in the development of T(H)17 cells and ROR-specific synthetic ligands have proven efficacy in several mouse models of autoimmunity. To investigate the roles and therapeutic potential for targeting the RORs in type 1 diabetes, we administered SR1001, a selective ROR alpha/gamma inverse agonist, to nonobese diabetic mice. SR1001 significantly reduced diabetes incidence and insulitis in the treated mice. Furthermore, SR1001 reduced proinflammatory cytokine expression, particularly T(H)17-mediated cytokines, reduced autoantibody production, and increased the frequency of CD4(+)Foxp3(+) T regulatory cells. These data suggest that T(H)17 cells may have a pathological role in the development of type 1 diabetes, and use of ROR-specific synthetic ligands targeting this cell type may prove utility as a novel treatment for type 1 diabetes.