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
Immunology Research, Biogen, Cambridge, MA, USA.
Translational Sciences - Genetics & Genomics, Biogen, Cambridge, MA, USA.
Immunology. 2016 Apr;147(4):399-413. doi: 10.1111/imm.12570. Epub 2016 Jan 26.
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.
维甲酸受体相关孤儿核受体γ（RORγ）在多种淋巴细胞谱系中协调促炎基因表达程序，这些谱系包括17型辅助性T细胞（Th17细胞）、γδT细胞、固有淋巴细胞和淋巴组织诱导细胞。有确凿证据表明，表达RORγ的细胞是治疗自身免疫性疾病和炎症性疾病的相关治疗靶点。与Th17细胞不同，Th17细胞中的RORγ表达是在特定促炎条件下诱导产生的，而γδT细胞和其他固有样免疫细胞在稳态下表达RORγ。在预先存在RORγ转录复合物的细胞中，小分子介导的RORγ功能破坏是一个重大且具有挑战性的药理学障碍。我们提供的数据表明，一种新型、选择性且强效的小分子RORγ抑制剂可以阻断Th17细胞和表达RORγ的γδT细胞以及人类表达RORγ的记忆T细胞的疾病相关亚群中依赖RORγ的基因表达程序。重要的是，在体内全身施用这种抑制剂可减轻银屑病固有淋巴细胞驱动小鼠模型中的病理变化。
