LIGHT/TNFSF14 in allergic esophagitis remodeling

LIGHT/TNFSF14 在过敏性食管炎重塑中的作用

• 批准号: 10115702
• 负责人: Seema S Aceves
• 金额: $ 56.89万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115702
• 关键词: Affect; Allergens; Allergic; Allergic Disease; Antibodies; Antigens; Asthma; Atopic Dermatitis; Biological Models; Biopsy; Blocking Antibodies; Caring; Cell Proliferation; Cell physiology; Cells; Cellular Structures; Characteristics; Childhood; Chronic; Clinical; Data; Deglutition; Deglutition Disorders; Desire for food; Diet; Disease; Eosinophilic Esophagitis; Epithelial Cells; Esophageal Tissue; Esophagitis; Esophagus; Etiology; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Protein; Failure to Thrive; Fibroblasts; Fibrosis; Food; Functional disorder; Gastrointestinal tract structure; Health Care Costs; Human; Hyperplasia; Hypertrophy; Immune response; Immune system; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Injections; Interleukin-13; Interleukin-5; LIGHT protein; Lead; Lung; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Modeling; Mucous Membrane; Mus; Normal Cell; Oral; Organ; Organ Donor; Pathogenesis; Pathologic; Pathway interactions; Patients; Personal Satisfaction; Phenotype; Play; Pre-Clinical Model; Prevalence; Production; Proteins; Reagent; Recombinants; Research Personnel; Role; Safety; Scleroderma; Severities; Severity of illness; Skin; Skin Tissue; Smooth Muscle; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Structure; Structure of parenchyma of lung; Systemic Scleroderma; T-Lymphocyte; TNF gene; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Tissues; Topical Corticosteroids; Tumor Necrosis Factors; Vomiting; base; clinical translation; food consumption; gastrointestinal; gastrointestinal function; herpesvirus entry mediator; high voltage electron microscopy; in vivo; keratinocyte; member; motility disorder; mouse model; neutralizing antibody; new therapeutic target; novel; overexpression; periostin; phase I trial; receptor; synergism; targeted treatment; therapeutic target

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.

摘要 胃肠道粘膜的慢性炎症可导致纤维化和组织的其他特征 重塑，限制胃肠道的正常功能。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），一种流行率不断增加的口服和空气抗原介导的过敏性疾病 和发病率。EoE的特征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、发育不良和吞咽困难。电流 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管重塑的过程， 功能障碍虽然认为几种炎症介质有助于炎症， 食管，特别是IL-5，IL-13和TGF β，扩展我们对蛋白质的理解非常重要 驱动EoE中的纤维化和重塑，以确定治疗干预的新的潜在靶点。 我们以前发现，肿瘤坏死因子（TNF）超家族成员，即LIGHT， TNFSF 14与其两种受体HVEM（TNFRSF 14）和LTbR（TNFRSF 3）相互作用，促进组织 在严重哮喘和特应性皮炎模型中由过敏原驱动的肺和皮肤重塑。基于 根据新的初步数据，LIGHT、HVEM和LTbR在食管组织中过表达， EoE患者; HVEM和LTbR在食管上皮细胞和成纤维细胞中表达， 表达与EoE特征性炎症介质相关;重组LIGHT足以 在小鼠食管中诱导EoE样重塑特征;并且LIGHT缺陷小鼠受到保护 从过敏原诱导的类EoE疾病，我们建议测试的中心假设，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 应用，我们联合收割机的专业知识迈克尔克罗夫特（LJI和UCSD）谁发现了组织重塑 LIGHT和Seema Aceves（UCSD）的活动，他们证明了 我们的合作研究者Richard库尔滕（阿克里）是一位食管重建方面的专家， 过敏性疾病中的人离体模型系统。我们将利用原代人食管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 LIGHT在EoE发病机制中的作用这些研究将有助于揭示食管组织重塑的机制， 并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。