Introduction

Retinoic Acid Related Orphan Nuclear Receptor gamma T (RORγT) is a lineage specifying transcription factor for IL-17 expressing cells, which may contribute to the pathogenesis of Inflammatory Bowel Disease (IBD). VPR-254 is a selective in vitro inhibitor of RORγT.

Aims

The main goals of our study were twofold: (1) To determine if ex vivo treatment with VPR-254 reduced relevant cytokine (IL-17 and IL-21) secretion from colonic strips of mice with colitis; (2) To determine if treatment of mice with VPR-254 attenuated parameters of colitis, using three murine IBD models.

Methods

VPR-254 was evaluated ex vivo in a colonic strip assay, using tissue from mice with Dextran sulfate sodium (DSS)-induced colitis. In vivo, VPR-254 was evaluated for efficacy in DSS, Trintirobenzenesulfonic acid (TNBS) and Anti-CD40 antibody-induced murine models of colitis.

Results

VPR-254 reduced the production of key pro-inflammatory cytokines (e.g., IL-17) in ex vivo and in vivo models of colitis. This small molecule inhibitor of RORγT also improved various morphometric and histological parameters associated with three diverse murine models of IBD.

Conclusion

Our results support the concept that an inhibitor of ROR-gamma T may have potential utility for the treatment of IBD.

中文翻译：

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VPR-254：ROR-γT抑制剂，具有治疗炎性肠病的潜在效用。

介绍

维甲酸相关的孤儿核受体Gamma T（RORγT）是一个谱系，指定了表达IL-17的细胞的转录因子，这可能有助于炎症性肠病（IBD）的发病。VPR-254是一种选择性的RORγT体外抑制剂。

目的

我们研究的主要目的是双重的：（1）确定VPR-254的离体治疗是否能减少结肠炎小鼠结肠条的相关细胞因子（IL-17和IL-21）的分泌；（2）使用三种鼠IBD模型来确定用VPR-254治疗的小鼠是否减弱了结肠炎的参数。

方法

VPR-254在结肠剥离试验中进行了离体评估，使用了得自硫酸葡聚糖钠（DSS）诱导的结肠炎的小鼠组织。在体内，评估了VPR-254在DSS，三苯甲基苯磺酸（TNBS）和抗CD40抗体诱导的小鼠结肠炎小鼠模型中的功效。

结果

VPR-254在结肠炎的离体和体内模型中减少了关键促炎细胞因子（例如IL-17）的产生。这种RORγT的小分子抑制剂还改善了与三种IBD鼠模型相关的各种形态学和组织学参数。

结论

我们的结果支持了ROR-γT抑制剂可能具有治疗IBD的潜在效用的概念。