Dendritic Cell Regulation by Sphingosine-1-phosphate in Inflammatory Bowel Disease

炎症性肠病(IBD)影响着5万多名美国退伍军人。30%的人没有回应 最初，甚至对我们最有效的治疗方法(抗肿瘤坏死因子药物)也有50%的人最终失去反应。 因此，对新疗法的需求尚未得到满足。事实上，一种与S1P特异相互作用的口服药物 受体-1(S1P1)(即RPC1063/ozAnimod)在IBD试验中显示出巨大的前景，而另一种是 已获FDA批准用于多发性硬化症(即FTY720)。然而，一个关键的需要仍然是理解 未充分研究这些药物调节慢性炎症性疾病的机制/S 我们的长期目标是了解如何操纵S1P通路用于IBD的治疗目的。 我们的近期目标是了解基于树突状细胞的新的S1P1-选择性作用机制 在临床前和临床研究中证明有效的激动剂。 基于S1P1在亲调控树突状细胞(DC)上的表达，我们假设S1P1选择性 激动剂调节DC功能和/或它们的迁移，在那里它们调节T细胞分化。这 假设源于我们的初步数据，表明慢性炎症改变了S1P的合成 在IBD小鼠模型和人IBD模型中的降解(促进DC保留)以及S1P1选择性 激动剂降解S1P1，促进DC向肠系膜淋巴结动员并改善 临床相关的IBD小鼠模型中的炎症。 我们的创新方法利用了1.慢性炎症性肠病小鼠模型 人类疾病的特点，2.下游作用明显的新药和3.尖端药物 显微镜和质量细胞仪技术，使我们能够直接可视化这些药物对 活生生的动物，直接在人的肠道上。我们的跨机构研究将我们广泛的 SDVAMC与斯克里普斯研究所在淋巴细胞流量/IBD模型方面的专业知识：S1P 药理学，拉霍亚过敏和免疫学研究所的新成像技术，以及获得 临床试验样本(Receptos)。 我们的理论基础是，了解这些新型抗炎药的作用机制将导致 优化药物设计，将与非选择性S1P受体多效性相关的风险降至最低 细胞过程中的激动剂(如FTY720)。拟议的研究具有重要意义，因为这条途径 在进化上在老鼠和人类身上保守。因此，我们的结果可能直接转化为人类IBD， 使我们能够阐明S1P1-选择剂的作用机制。此外，我们可能会发现新的 治疗干预的目标是用口服药物进行药理学调整，以降低成本 生产和给药，与目前基于抗体的生物策略相比较。

The inflammatory bowel diseases (IBD) affect over 50 thousand US veterans. Thirty percent do not respond initially and an additional 50% eventually lose response to even our most effective therapies (anti-TNF agents). Thus, there is an unmet need for novel therapeutics. Indeed, an oral drug that interacts specifically with S1P receptor-1 (S1P1) (i.e. RPC1063/ozanimod) has shown significant promise in IBD trials, while another is already FDA-approved for multiple sclerosis (i.e. FTY720). However, a critical need remains to understand the understudied mechanism/s through which these drugs modulate chronic inflammatory diseases. Our long-term goal is to understand how to manipulate the S1P pathway for therapeutic purposes in IBD. Our immediate objective is to understand dendritic cell-based mechanisms of action of novel S1P1-selective agonists with proven efficacy in preclinical and clinical studies. Based on the expression of S1P1 on pro-regulatory dendritic cells (DC), we hypothesize that S1P1-selective agonists modulate DC function, and/or their migration, where they modulate T cell differentiation. This hypothesis stems from our preliminary data that demonstrates that chronic inflammation alters S1P synthesis and degradation (promoting DC retention) in IBD mouse models and human IBD and that S1P1-selective agonism degrades S1P1, promoting mobilization of DC to mesenteric lymph node and ameliorating inflammation in clinically-relevant IBD mouse models. Our innovative approach takes advantage of 1. chronic mouse models of IBD that recapitulate many of the characteristics of the human disease, 2. new drugs with distinct downstream actions and 3. cutting edge microscopy and mass cytometry techniques that allow us to directly visualize the effects of these drugs on a living animal and directly on the human intestine. Our inter-institutional studies bring together our extensive expertise in lymphocyte traffic/IBD models at SDVAMC with that of The Scripps Research Institute: S1P pharmacology, novel imaging techniques at the La Jolla Institute of Allergy and Immunology and access to clinical trial samples (Receptos). Our rationale is that understanding the mechanism of action of these novel anti-inflammatories will lead to optimized drug design and minimize the risks related to the pleiotropic effects of non-selective S1P receptor agonists (e.g. FTY720) on cellular processes. The proposed research is significant as this pathway is evolutionarily conserved in mice and humans. Therefore, our results might directly translate to human IBD, enabling us to elucidate the mechanism of action of S1P1-selective agents. Furthermore, we may uncover new targets for therapeutic intervention to be modulated pharmacologically with oral drugs, at reduced cost of production and administration, compared with current antibody-based biologic strategies.