LIGHT/TNFSF14 in allergic esophagitis remodeling

摘要 胃肠道粘膜的慢性炎症可导致组织纤维化和其他特征 限制胃肠道正常功能的重塑。这一点在以下患者中尤为明显 嗜酸性食管炎(EoE)是一种由口服和航空抗原介导的变态反应性疾病，发病率不断上升 和发病率。EoE的特点是食道纤维化和僵硬，以及平滑肌运动障碍， 导致食物阻塞和狭窄、呕吐、食欲不振、无法茁壮成长和吞咽困难。当前 EOE治疗包括抗原消除饮食和局部皮质类固醇，可以限制炎症，但 这些措施可能无法长期控制疾病或逆转食道重塑和 功能障碍。尽管几种炎症介质被认为是导致心脏炎症的因素。 食道，特别是IL-5、IL-13和TGFb，对于扩大我们对蛋白质的理解是非常重要的 这推动了EoE的纤维化和重塑，以便为治疗干预定义新的潜在靶点。 我们先前已经发现肿瘤坏死因子超家族的成员，即LIGHT (TNFSF14)与其受体hvem(TNFRSF14)和LTbR(TNFRSF3)相互作用，促进组织 在严重哮喘和特应性皮炎模型中，由变应原驱动的肺和皮肤重塑。基座 根据新的初步数据，LIGH、HVEM和LTbR在活动期的食道组织中过度表达 Hvem和LTbR在食道上皮细胞和成纤维细胞中表达，其在EoE患者中的表达 表达与EoE特有的炎症介质相关；重组光就足够了 诱导小鼠食道EoE样重塑特征；光缺乏小鼠受到保护 从过敏原诱导的EoE样病，我们建议检验光和它的 受体是过敏性食道纤维化和重塑的关键介质和驱动因素。在这个多PI中 应用，我们结合了Michael Croft(LJI和UCSD)的专业知识，他发现了组织重塑 LIGH和SEMA ACVES(UCSD)的活动，他们展示了 儿科EoE受试者的食道重塑，与我们的合作研究员Richard Kurten(ACRI)，一位 过敏性疾病中的人体体外模型系统。我们将利用原代人类食道EoE和正常 细胞、组织和活检，以及过敏性食管炎的小鼠模型，以剖析 轻在EoE发病机制中的作用。这些研究将有助于揭开食道组织重塑的机制， 并具有快速临床翻译的潜力，因为光阻断抗体可用于 治疗用途。

ABSTRACT Chronic inflammation of the gastrointestinal mucosa can lead to fibrosis and other features of tissue remodeling that limit normal functioning of the gastrointestinal tract. This is particularly apparent in patients with Eosinophilic Esophagitis (EoE), an oral- and aero-antigen mediated allergic disease of increasing prevalence and incidence. EoE is characterized by esophageal fibrosis and rigidity, and smooth muscle dysmotility, resulting in food impactions and strictures, vomiting, poor appetite, failure to thrive, and dysphagia. Current EoE treatments include antigen elimination diets and topical corticosteroids that can limit inflammation, but these measures may not control disease long term or reverse the course of esophageal remodeling and dysfunction. Although several inflammatory mediators are thought to contribute to inflammation in the esophagus, specifically IL-5, IL-13, and TGFb, it is of great importance to extend our understanding of proteins that drive fibrosis and remodeling in EoE, in order to define new potential targets for therapeutic intervention. We have previously found that members of the tumor necrosis factor (TNF) superfamily, namely LIGHT (TNFSF14) interacting with its two receptors HVEM (TNFRSF14) and LTbR (TNFRSF3), promote tissue remodeling in the lungs and skin driven by allergens in models of severe asthma and atopic dermatitis. Based on novel preliminary data that LIGHT, HVEM, and LTbR are over-expressed in esophageal tissue from active EoE patients; that HVEM and LTbR are expressed in esophageal epithelial cells and fibroblasts and their expression correlates with inflammatory mediators characteristic of EoE; that recombinant LIGHT is sufficient to induce EoE-like remodeling features in the mouse esophagus; and that LIGHT-deficient mice are protected from EoE-like disease induced by allergen, we propose to test the central hypothesis that LIGHT and its receptors are pivotal mediators and drivers of allergic esophagus fibrosis and remodeling. In this multi-PI application, we combine the expertise of Michael Croft (LJI and UCSD) who discovered the tissue remodeling activities of LIGHT and Seema Aceves (UCSD) who demonstrated the presence and potential mechanisms of esophageal remodeling in pediatric EoE subjects, with our co-investigator Richard Kurten (ACRI), an expert in human ex vivo model systems in allergic diseases. We will utilize primary human esophageal EoE and normal cells, tissues, and biopsies, as well as murine models of allergic esophagitis, in order to dissect the roles of LIGHT in EoE pathogenesis. These studies will help unravel the mechanisms of esophageal tissue remodeling, and have the potential for rapid clinical translation since LIGHT blocking antibodies are available for therapeutic use.