1. Small molecule mediated inhibition of RORγ-dependent gene expression and autoimmune disease pathology in vivo.
- Author
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Banerjee, Daliya, Zhao, Linlin, Wu, Lan, Palanichamy, Arumugam, Ergun, Ayla, Peng, Liaomin, Quigley, Catherine, Hamann, Stefan, Dunstan, Robert, Cullen, Patrick, Allaire, Norm, Guertin, Kevin, Wang, Tao, Chao, Jianhua, Loh, Christine, and Fontenot, Jason D.
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RETINOIC acid receptors , *GENE expression , *AUTOIMMUNE disease treatment , *LYMPHOCYTES , *LABORATORY mice - Abstract
Retinoic acid receptor-related orphan nuclear receptor γ (RORγ) orchestrates a pro-inflammatory gene expression programme in multiple lymphocyte lineages including T helper type 17 (Th17) cells, γδ T cells, innate lymphoid cells and lymphoid tissue inducer cells. There is compelling evidence that RORγ-expressing cells are relevant targets for therapeutic intervention in the treatment of autoimmune and inflammatory diseases. Unlike Th17 cells, where RORγ expression is induced under specific pro-inflammatory conditions, γδ T cells and other innate-like immune cells express RORγ in the steady state. Small molecule mediated disruption of RORγ function in cells with pre-existing RORγ transcriptional complexes represents a significant and challenging pharmacological hurdle. We present data demonstrating that a novel, selective and potent small molecule RORγ inhibitor can block the RORγ-dependent gene expression programme in both Th17 cells and RORγ-expressing γδ T cells as well as a disease-relevant subset of human RORγ-expressing memory T cells. Importantly, systemic administration of this inhibitor in vivo limits pathology in an innate lymphocyte-driven mouse model of psoriasis. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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