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

炎症性肠病（IBD）影响了超过5万名美国退伍军人。30%没有回应 最初和额外的50%最终甚至对我们最有效的治疗（抗TNF剂）失去反应。 因此，存在对新型治疗剂的未满足的需求。事实上，一种与S1 P特异性相互作用的口服药物 受体-1（S1 P1）（即RPC 1063/ozanimod）在IBD试验中显示出显著的前景，而另一种是 已经FDA批准用于多发性硬化症（即FTY 720）。然而，一个关键的需要仍然是了解 这些药物调节慢性炎症性疾病的机制尚未得到充分研究。 我们的长期目标是了解如何操纵S1 P通路用于IBD的治疗目的。 我们的直接目标是了解树突状细胞为基础的新的S1 P1选择性的作用机制。 在临床前和临床研究中已证实有效的激动剂。 基于S1 P1在前调节性树突状细胞（DC）上的表达，我们假设S1 P1选择性 激动剂调节DC功能和/或它们的迁移，其中它们调节T细胞分化。这 这一假设源于我们的初步数据，表明慢性炎症改变了S1 P的合成 在IBD小鼠模型和人IBD中，S1 P1-选择性和降解（促进DC保留） 激动剂降解S1 P1，促进DC动员至肠系膜淋巴结并改善 在临床相关的IBD小鼠模型中的炎症。 我们的创新方法利用了1. IBD的慢性小鼠模型，概括了许多 人类疾病的特征，2。具有明显下游作用的新药; 3.切削刃 显微镜和质量细胞计数技术，使我们能够直接可视化这些药物对 活的动物和直接在人的肠道上。我们的跨机构研究汇集了我们广泛的 SDVAMC与斯克里普斯研究所在淋巴细胞运输/IBD模型方面的专业知识：S1 P 药理学，拉霍亚过敏和免疫学研究所的新型成像技术， 临床试验样本（Receptos）。 我们的基本原理是，了解这些新型抗炎药的作用机制将导致 优化药物设计，并最大限度地减少与非选择性S1 P受体的多效性效应相关的风险 激动剂（例如FTY 720）对细胞过程的作用。拟议的研究是重要的，因为这条途径是 在小鼠和人类中进化保守。因此，我们的结果可能直接转化为人类IBD， 使我们能够阐明S1 P1选择性试剂的作用机制。此外，我们可能会发现新的 治疗干预的目标，以降低的成本， 生产和管理，与目前的抗体为基础的生物策略。

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.