LIGHT/TNFSF14 in allergic esophagitis remodeling

摘要 胃肠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。这在患有以下疾病的患者中尤其明显 嗜酸性粒细胞性食管炎 (EoE)，一种口腔和空气抗原介导的过敏性疾病，患病率不断增加 和发生率。 EoE 的特点是食管纤维化和僵硬，以及平滑肌运动障碍， 导致食物嵌塞和狭窄、呕吐、食欲不振、发育迟缓和吞咽困难。当前 EoE 治疗包括消除抗原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管重塑的过程， 功能障碍。尽管多种炎症介质被认为会导致炎症 食管，特别是 IL-5、IL-13 和 TGFb，对于扩展我们对蛋白质的理解非常重要 驱动 EoE 纤维化和重塑，以确定治疗干预的新潜在目标。 我们之前发现肿瘤坏死因子（TNF）超家族的成员，即LIGHT (TNFSF14) 与其两个受体 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，过敏原驱动的肺部和皮肤重塑。基于 根据新的初步数据，LIGHT、HVEM 和 LTbR 在活动性食管组织中过度表达 EoE患者； HVEM和LTbR在食管上皮细胞和成纤维细胞中表达及其 表达与 EoE 的炎症介质特征相关；重组光就足够了 在小鼠食道中诱导 EoE 样重塑特征；光线不足的小鼠受到保护 从过敏原诱发的 EoE 样疾病中，我们建议检验光及其 受体是过敏性食管纤维化和重塑的关键介质和驱动因素。在这个多PI 我们结合了发现组织重塑的 Michael Croft（LJI 和 UCSD）的专业知识 LIGHT 和 Seema Aceves (UCSD) 的活动证明了 儿科 EoE 受试者的食管重塑，与我们的联合研究员 Richard Kurten (ACRI) 合作，他是以下领域的专家 过敏性疾病的人体离体模型系统。我们将利用原代人类食管 EoE 和正常 细胞、组织和活组织检查，以及过敏性食管炎的小鼠模型，以剖析 EoE 发病机制中的光。这些研究将有助于揭示食管组织重塑的机制， 并且具有快速临床转化的潜力，因为 LIGHT 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.