Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand

Laura A. Solt, Naresh Kumar, Philippe Nuhant, Yongjun Wang, Janelle L. Lauer, Jin Liu, Monica A. Istrate, Theodore M. Kamenecka, William R. Roush, Dušica Vidović, Stephan C. Schürer, Jihong Xu, Gail Wagoner, Paul D. Drew, Patrick R. Griffin and Thomas P. Burris ()
Additional contact information
Laura A. Solt: The Scripps Research Institute
Naresh Kumar: The Scripps Research Institute
Philippe Nuhant: The Scripps Research Institute
Yongjun Wang: The Scripps Research Institute
Janelle L. Lauer: The Scripps Research Institute
Jin Liu: The Scripps Research Institute
Monica A. Istrate: The Scripps Research Institute
Theodore M. Kamenecka: The Translational Research Institute, The Scripps Research Institute
William R. Roush: The Scripps Research Institute
Dušica Vidović: The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute
Stephan C. Schürer: The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute
Jihong Xu: University of Arkansas for Medical Sciences
Gail Wagoner: University of Arkansas for Medical Sciences
Paul D. Drew: University of Arkansas for Medical Sciences
Patrick R. Griffin: The Scripps Research Institute
Thomas P. Burris: The Scripps Research Institute

Nature, 2011, vol. 472, issue 7344, 491-494

Abstract: A new class of immunomodulator The nuclear receptors RORα and RORγt (retinoic acid receptor-related orphan receptors α and γt) are essential for the development of TH17 cells, the T-helper cells that produce interleukin-17. Two groups report the identification of RORγt inhibitors, compounds that could have potential in the treatment of autoimmune diseases. Huh et al. used a chemical screen in an insect-cell-based reporter system to identify the cardiac glycoside digoxin and various derivatives as inhibitors of the transcriptional activity of RORγt. Through this mechanism, these compounds block the differentiation of TH17 cells in mice, and inhibit interleukin-17 production in vitro in human T cells. Solt et al. describe a synthetic ligand, named SR1001, that functions as an inverse agonist for RORα and RORγt, and show that it blocks TH17 development in vitro and inhibits experimental encephalomyelitis in mice.

Date: 2011
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DOI: 10.1038/nature10075

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