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

1-磷酸鞘氨醇对炎症性肠病的树突状细胞调节

• 批准号: 9562862
• 负责人: Jesus Rivera-Nieves
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9562862
• 关键词: Address; Affect; Agonist; Animals; Anti-Inflammatory Agents; Antibodies; Attenuated; Binding; Biological; Biopsy; Blood; Blood Vessels; Cell physiology; Cells; Cellular biology; Chronic; Clinic; Clinical Research; Clinical Trials; Colitis; Cytometry; Data; Dendritic Cells; Disease; Disease model; Dose; Drug Design; FDA approved; FOXP3 gene; Family; G-Protein-Coupled Receptors; Goals; Health; Human; Human Characteristics; Hypersensitivity; Ileitis; Immune; Immune response; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Inflammatory disease of the intestine; Institutes; Intestines; Lamina Propria; Lead; Literature; Lymphocyte; Mediating; Mesentery; Microscopy; Molecular; Multiple Sclerosis; Mus; Nature; One-Step dentin bonding system; Oral; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Pre-Clinical Model; Production; Regulation; Regulatory T-Lymphocyte; Research; Research Institute; Risk; Role; Sampling; Signal Transduction; Skin; Sphingolipids; Sphingosine-1-Phosphate Receptor; T cell differentiation; T cell response; T-Lymphocyte; TNF gene; Techniques; Therapeutic; Therapeutic Intervention; Time; Translating; Treatment Efficacy; Ulcerative Colitis; Veterans; adalimumab; adaptive immune response; base; cell motility; clinical efficacy; clinically relevant; cost; effective therapy; human disease; innovation; inter-institutional; lymph nodes; migration; mouse model; multiple sclerosis treatment; neglect; new therapeutic target; novel; novel imaging technique; novel strategies; novel therapeutics; pill; pleiotropism; preclinical study; receptor; response; risk minimization; side effect; sphingosine 1-phosphate; stem; trafficking; translational approach

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.

炎症性肠病 (IBD) 影响着超过 5 万名美国退伍军人。百分之三十没有回应 最初，另外 50% 的患者最终对我们最有效的疗法（抗 TNF 药物）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 特异性相互作用的口服药物 受体-1 (S1P1)（即 RPC1063/ozanimod）在 IBD 试验中显示出显着的前景，而另一种是 已获得 FDA 批准用于治疗多发性硬化症（即 FTY720）。然而，仍然迫切需要了解 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 S1P 通路来治疗 IBD。 我们的直接目标是了解新型 S1P1 选择性的基于树突状细胞的作用机制 在临床前和临床研究中已证明有效的激动剂。 基于 S1P1 在促调节树突状细胞 (DC) 上的表达，我们假设 S1P1 选择性 激动剂调节 DC 功能和/或其迁移，从而调节 T 细胞分化。这 该假设源于我们的初步数据，该数据表明慢性炎症会改变 S1P 合成 IBD 小鼠模型和人类 IBD 中的降解（促进 DC 保留）以及 S1P1 选择性 激动作用会降解 S1P1，促进 DC 动员至肠系膜淋巴结并改善 临床相关 IBD 小鼠模型中的炎症。 我们的创新方法利用了 1. 慢性 IBD 小鼠模型，该模型概括了许多 人类疾病的特点，2.具有独特下游作用的新药，3.前沿 显微镜和质谱流式技术使我们能够直接观察这些药物对细胞的影响 活体动物并直接作用于人类肠道。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：S1P 药理学、拉霍亚过敏和免疫学研究所的新颖成像技术以及获取 临床试验样本（Receptos）。 我们的理由是，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降低与非选择性 S1P 受体多效性效应相关的风险 细胞过程的激动剂（例如 FTY720）。拟议的研究意义重大，因为该途径是 在小鼠和人类中进化上保守。因此，我们的结果可能会直接转化为人类 IBD， 使我们能够阐明 S1P1 选择性药物的作用机制。此外，我们还可能发现新的 治疗干预的目标是通过口服药物进行药理学调节，以降低成本 与当前基于抗体的生物策略相比，生产和管理。