Dendritic Cell Manipulation: A Novel Therapeutic for Inflammatory Bowel Disease

树突状细胞操作：炎症性肠病的新疗法

• 批准号: 8142980
• 负责人: Jesus Rivera-Nieves
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142980
• 关键词: Accounting; Activities of Daily Living; Address; Admission activity; Adoptive Transfer; Affect; Age; American; Anti-Inflammatory Agents; Anti-Tumor Necrosis Factor Therapy; Anti-inflammatory; Antigen Presentation; Attenuated; Biological Models; Biological Response Modifier Therapy; CCR9 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Crohn' s disease; Data; Dendritic Cells; Development; Disease; Distal part of ileum; Down-Regulation; Enzymes; Epithelial Cells; Equilibrium; Evaluation; Failure; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Home environment; Homeostasis; Homing; Hospitals; Human Resources; IL2RA gene; ITGAM gene; Ileitis; Immune; Immunity; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Integrins; Intention; Interleukin-17; Intestines; Knowledge; Lamina Propria; Life; Ligands; Manuscripts; Measures; Mediating; Messenger RNA; Military Personnel; Modeling; Molecular; Mus; Nature; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Play; Process; Regulation; Regulatory T-Lymphocyte; Role; Services; Severities; Small Intestines; Source; Staging; Stromal Cells; Supplementation; T-Cell Proliferation; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissues; Transforming Growth Factor beta; Tretinoin; Tropism; Tyrosine; Ulcerative Colitis; Up-Regulation; Veterans; Vitamin A; Work; arm; attenuation; base; clinically relevant; cytokine; experience; in vivo; lymph nodes; mouse model; novel; novel therapeutics; response; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): The inflammatory bowel diseases (i.e. ulcerative colitis (UC) and Crohn's disease (CD)) are associated with accumulation of dendritic cells (DC) into the inflamed intestine and draining lymph nodes. These chronic inflammatory conditions may in part be due to failure by DC to induce T cell tolerance in a retinoic acid-dependent manner. To explore whether this is the case we will utilize spontaneous models of chronic murine ileitis to longitudinally examine the role of DC in inducing, perpetuating and regulating Intestinal inflammation. Furthermore, these studies will also examine the sources of retinoic acid (RA) in the terminal ileum of TNF-overproducing (i.e. TNF ARE) and SAMP1/YitFc mice, which spontaneously develop Crohn's-like ileitis and the effect of RA and growth factors that promote expansion of tolerogenic DC on chronic Inflammation. Our preliminary data demonstrates that pro-regulatory CD103POS DC subset and their RA synthetic machinery is decreased in TNF ARE ileal lamina propria at 20-weeks-of-age resulting in a decrease in regulatory CD4+/CD25+/FoxP3+ regulatory T cells, despite upregulation of the RA synthetic machinery of intestinal epithelial cells (IEC). Supplementation with all-trans retinoic acid and administration of fms-like tyrosine ligand (FLT3L) significantly attenuated Ileitis, suggesting that IEC-derived RA was insufficient to sustain intestinal RA concentrations. However, the mechanism of RA- and FLT3L-mediated attenuation of ileitis remains unclear. As a result, the proposed studies will 1) elucidate the mechanisms of regulatory T cell deficiency in models of ileitis 2) examine the mechanism of action of all-trans RA as a therapeutic agent in chronic ileitis. 3) Explore the mechanisms of action of growth factors such as FLT3L and GMCSF behind the attenuation of chronic ileitis. Given the therapeutic effect of RA supplementation and FLT3L administration in clinically relevant models of ileitis, these studies may provide feasibility for the evaluation of dendritic cell-based manipulation as a novel therapeutic strategy in CD. PUBLIC HEALTH RELEVANCE: Inflammatory Bowel Disease (IBD) accounted for 13,468 admissions to VA hospitals from 1986 to 1989. Crohn's disease in particular affects predominantly young Americans (peak incidence age = 24 years), thus it disproportionately affects U.S. military service personnel. Although anti-TNF therapies are effective in up to 70% of patients, this leaves one third of patients with limited therapeutic options. Therefore, alternative biological therapies must be evaluated in IBD. Modulation of proinflammatory responses by tilting the balance towards regulation is an attractive strategy. We show that increasing anti-inflammatory cells and their products attenuates inflammation in mouse models of Crohn's-like IBD with high translational value. These studies aim at understanding how these compounds work, with an ultimate goal to find new drugs to treat the numerous veterans that suffer from IBD.

描述（由申请人提供）： 炎症性肠病（即溃疡性结肠炎（UC）和克罗恩病（CD））与树突状细胞（DC）积聚到发炎肠道和引流淋巴结有关。这些慢性炎症状况可能部分是由于 DC 未能以视黄酸依赖性方式诱导 T 细胞耐受。为了探讨情况是否如此，我们将利用慢性小鼠回肠炎的自发模型来纵向研究 DC 在诱导、维持和调节肠道炎症中的作用。此外，这些研究还将检查 TNF 过量产生（即 TNF ARE）和 SAMP1/YitFc 小鼠末端回肠中视黄酸 (RA) 的来源，这些小鼠会自发发展克罗恩病样回肠炎，以及 RA 和生长因子对产生克罗恩病样回肠炎的影响。促进慢性炎症耐受性 DC 的扩张。我们的初步数据表明，20周龄时，TNF ARE回肠固有层中的促调节CD103POS DC子集及其RA合成机制减少，导致调节性CD4+/CD25+/FoxP3+调节性T细胞减少，尽管肠上皮细胞 (IEC) 的 RA 合成机制。补充全反式视黄酸和施用 fms 样酪氨酸配体 (FLT3L) 显着减轻回肠炎，表明 IEC 衍生的 RA 不足以维持肠道 RA 浓度。然而，RA 和 FLT3L 介导的回肠炎减弱机制仍不清楚。因此，拟议的研究将 1) 阐明回肠炎模型中调节性 T 细胞缺陷的机制 2) 检查全反式 RA 作为慢性回肠炎治疗剂的作用机制。 3）探讨FLT3L、GMCSF等生长因子减轻慢性回肠炎背后的作用机制。鉴于 RA 补充剂和 FLT3L 给药在临床相关回肠炎模型中的治疗效果，这些研究可能为评估基于树突状细胞的操作作为 CD 的新型治疗策略提供可行性。 公共卫生相关性： 1986 年至 1989 年间，退伍军人管理局医院因炎症性肠病 (IBD) 入院的人数为 13,468 人。克罗恩病主要影响美国年轻人（发病高峰年龄 = 24 岁），因此它对美国军人的影响尤为严重。尽管抗 TNF 疗法对高达 70% 的患者有效，但这使得三分之一的患者的治疗选择有限。因此，必须对 IBD 的替代生物疗法进行评估。通过向调节倾斜平衡来调节促炎症反应是一种有吸引力的策略。我们发现，增加抗炎细胞及其产物可以减轻克罗恩病样 IBD 小鼠模型中的炎症，并具有高转化价值。这些研究旨在了解这些化合物如何发挥作用，最终目标是找到新药来治疗众多患有 IBD 的退伍军人。