| First Author | Solt LA | Year | 2015 |
| Journal | Endocrinology | Volume | 156 |
| Issue | 3 | Pages | 869-81 |
| PubMed ID | 25560829 | Mgi Jnum | J:221923 |
| Mgi Id | MGI:5641836 | Doi | 10.1210/en.2014-1677 |
| Citation | Solt LA, et al. (2015) ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes. Endocrinology 156(3):869-81 |
| abstractText | 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 TH1 cells are key contributors to type 1 diabetes, the function of TH17 cells in disease onset and progression remains unclear. The nuclear receptors retinoic acid receptor-related orphan receptors-alpha and gammat (RORalpha and RORgammat) play critical roles in the development of TH17 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 RORalpha/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 TH17-mediated cytokines, reduced autoantibody production, and increased the frequency of CD4(+)Foxp3(+) T regulatory cells. These data suggest that TH17 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. |
