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: 8795668
• 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: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795668
• 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; differential expression; experience; in vivo; intestinal homeostasis; 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.

描述（由申请人提供）： 炎症性肠道疾病（即溃疡性结肠炎（UC）和克罗恩病（CD））与树突状细胞（DC）的积累到发炎的肠和排水淋巴结有关。这些慢性炎症条件可能部分是由于DC未能以视黄酸依赖性方式诱导T细胞耐受性。为了探索是否是这种情况，我们将利用慢性鼠回肠炎的自发模型纵向研究DC在诱导，永久性和调节肠道炎症中的作用。此外，这些研究还将检查tnf超产生末端的视网膜酸（RA）的来源（即TNF）和SAMP1/YITFC小鼠，这些小鼠自发地发展了Crohn's样卵巢炎，以及促进耐受性DC对慢性DC促进的RA和生长因子的影响。 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).补充全反式视黄酸和FMS样酪氨酸配体（FLT3L）的给药可显着减弱回肠炎，这表明IEC衍生的RA不足以维持肠道RA浓度。然而，RA-和FLT3L介导的回肠炎的衰减的机制尚不清楚。结果，拟议的研究将1）阐明回肠炎模型中调节性T细胞缺乏症的机制2）检查全反型RA作为慢性回肠炎的治疗剂的作用机理。 3）探索生长因子的作用机理，例如FLT3L和GMCSF，背后是慢性回肠炎的衰减。鉴于RA补充和FLT3L给药在临床相关的肠胃炎模型中的治疗作用，这些研究可能为评估基于树突细胞的操作评估作为CD中的一种新型治疗策略提供了可行性。