title: ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes.
abstract: Hyperglycemia associated with type 1 diabetes is a consequence of immune-mediated destruction of insulin producing pancreatic β-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-α and γt (RORα and RORγt) 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 RORα/γ 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.
authors.affiliation: Department of Molecular Therapeutics (L.A.S., S.B., S.C., T.M.K.), The Scripps Research Institute, Jupiter, Florida 33458; and Department of Pharmacological and Physiological Science (T.B.P.), Saint Louis University School of Medicine, St Louis, Missouri 63104.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.forename: Subhashis
authors.initials: S
authors.lastname: Banerjee
authors.forename: Sean
authors.initials: S
authors.lastname: Campbell
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D000818:Animals; D001323:Autoantibodies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006943:Hyperglycemia / Q000517:prevention & control*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007328:Insulin; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539739:Rora protein, mouse; C558809:SR1001; D013449:Sulfonamides; D013844:Thiazoles