Dendritic Cell Manipulation: A Novel Therapeutic for Inflammatory Bowel Disease

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）在发炎的肠和引流淋巴结中的积累有关。这些慢性炎症性疾病可能部分是由于DC未能以视黄酸依赖性方式诱导T细胞耐受。为了探索是否是这种情况，我们将利用慢性小鼠回肠炎的自发模型来纵向检查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过度产生（即TNF ARE）和SAMP 1/YitFc小鼠末端回肠中的视黄酸（RA）来源，这些小鼠自发发展克罗恩样回肠炎，以及RA和生长因子促进致耐受性DC扩增对慢性炎症的影响。我们的初步数据表明，促调节CD 103 POS DC亚群和它们的RA合成机制在20周龄时在TNF ARE回肠固有层中减少，导致调节性CD 4 +/CD 25 +/FoxP 3+调节性T细胞减少，尽管肠上皮细胞（IEC）的RA合成机制上调。补充全反式维甲酸和管理的fms样酪氨酸配体（FLT 3L）显着衰减回肠炎，表明IEC衍生的RA是不足以维持肠道RA浓度。然而，RA和FLT 3L介导的回肠炎减轻的机制仍不清楚。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)探讨生长因子FLT 3L和GM-CSF在慢性回肠炎消退中的作用机制。考虑到RA补充和FLT 3L给药在临床相关回肠炎模型中的治疗作用，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。

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.