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Small molecule mediated inhibition of ROR γ ‐dependent gene expression and autoimmune disease pathology in vivo
Author(s) -
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,
Fontenot Jason D.
Publication year - 2016
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12570
Subject(s) - rar related orphan receptor gamma , innate lymphoid cell , orphan receptor , biology , retinoic acid , innate immune system , microbiology and biotechnology , immune system , immunology , cancer research , transcription factor , gene , genetics , foxp3
Summary Retinoic acid receptor‐related orphan nuclear receptor γ ( ROR γ ) 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 ROR γ ‐expressing cells are relevant targets for therapeutic intervention in the treatment of autoimmune and inflammatory diseases. Unlike Th17 cells, where ROR γ expression is induced under specific pro‐inflammatory conditions, γδ T cells and other innate‐like immune cells express ROR γ in the steady state. Small molecule mediated disruption of ROR γ function in cells with pre‐existing ROR γ transcriptional complexes represents a significant and challenging pharmacological hurdle. We present data demonstrating that a novel, selective and potent small molecule ROR γ inhibitor can block the ROR γ ‐dependent gene expression programme in both Th17 cells and ROR γ ‐expressing γδ T cells as well as a disease‐relevant subset of human ROR γ ‐expressing memory T cells. Importantly, systemic administration of this inhibitor in vivo limits pathology in an innate lymphocyte‐driven mouse model of psoriasis.