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)聚集在炎症肠段和引流淋巴结有关。这些慢性炎症状态的部分原因可能是DC未能以维甲酸依赖的方式诱导T细胞耐受。为了探索是否是这种情况，我们将利用自发的小鼠回肠炎模型来纵向研究DC在诱导、持续和调节肠道炎症中的作用。此外，这些研究还将检测自发发展成克罗恩样回肠炎的肿瘤坏死因子过度分泌(即肿瘤坏死因子)和SAMP1/YitFc小鼠回肠末端的维甲酸(RA)的来源，以及RA和促进耐受性DC扩大的生长因子在慢性炎症中的作用。我们的初步数据显示，在20周龄的回肠固有层，尽管肠上皮细胞(IEC)的RA合成机制上调，但CD103POS DC亚群及其RA合成机制减少，导致回肠固有层调节性T细胞CD4+/CD25+/FoxP3+减少。补充全反式维甲酸和给予FMS样酪氨酸配体(Flt3L)可显著减轻回肠炎，提示IEC来源的RA不足以维持肠道RA的浓度。然而，RA和Flt3L介导的抑制回肠炎的机制仍不清楚。因此，这些研究将1)阐明回肠炎模型中调节性T细胞缺陷的机制；2)研究全反式维甲酸作为慢性回肠炎治疗剂的作用机制。3)探讨生长因子Flt3L、GMCSF在慢性回肠炎消退中的作用机制。鉴于RA补充和Flt3L应用于临床相关回肠炎模型的疗效，这些研究可能为以树突状细胞为基础的手法作为CD治疗新策略的评估提供可行性。

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.