IL-33 and food allergy

IL-33 和食物过敏

• 批准号: 9509328
• 负责人: Steven F Ziegler
• 金额: $ 56.63万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9509328
• 关键词: Acute; Adult; Affect; Allergens; Allergic; Allergic Disease; Allergic Reaction; Allergic inflammation; Allergic rhinitis; Allergy to peanuts; Anaphylaxis; Animals; Antibody Response; Antigens; Arachis; Asthma; Atopic Dermatitis; Biological Models; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Clinical; Cream; Cutaneous; Data; Developed Countries; Development; Diagnostic; Diarrhea; Epithelial Cells; Event; Exhibits; Exposure to; FGFR1 gene; Food; Food Hypersensitivity; Functional disorder; Gastrointestinal tract structure; Genes; Genetic Polymorphism; Goals; Grant; Human; Human Genetics; Immune; Immune response; Immunologics; Impairment; Inbred BALB C Mice; Inflammation; Inflammatory Response; Intestines; Lead; Leucocytic infiltrate; Life; Longitudinal Studies; Mediating; Mind; Modeling; Molecular; Mus; Mutation; Oils; Oral; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Prevalence; Pruritus; Public Health; Risk; Risk Factors; Role; Route; Sampling; Shapes; Signal Transduction; Site; Skin; Surface; Swelling; Symptoms; TSLP gene; Tail; Testing; Topical application; Variant; Work; airborne allergen; allergic response; antigen challenge; cytokine; early onset; economic impact; epidemiology study; food allergen; food antigen; genetic variant; genome wide association study; mouse model; new therapeutic target; novel; prevent; receptor; response; sensitizing antigen; skin barrier; symptom treatment; therapeutic development; tool

Project Summary The prevalence of food allergies has increased in the past several decades with an estimated 5% of children and 3-4% of adults in industrialized countries affected. Food allergies are defined by an adverse immune response following exposure to a given food and can manifest in symptoms ranging from localized itching, swelling and diarrhea to acute anaphylaxis. Currently, there are few available treatments to either prevent or cure food allergies, and available medications only treat symptoms following onset of the allergic response. Given the public health and economic impact of food allergies, there is an urgent need to identify new targets for the development of therapeutics for treatment, as well as potential diagnostic tools, to treat this debilitating condition. It is well-established that allergic diseases tend to develop in a sequential manner in childhood, a phenomenon referred to as the `atopic march'. This phenomenon commonly manifests as a child with atopic dermatitis going on to subsequently develop asthma, or allergic reactions to aeroallergens. In addition to asthma and allergic rhinitis, epidemiological studies have demonstrated that cutaneous inflammation associated with atopic dermatitis (AD) is a significant risk factor for the development of food allergies. In addition, animal studies using models of epicutaneous sensitization have demonstrated that this route of sensitization can predispose to antigen-induced allergic inflammation at other barrier sites. Taken together, these data indicate that the skin may be a highly relevant site of food allergen sensitization. However, the immunological mechanisms through which antigen sensitization in the skin can predispose to allergic inflammation in the intestine are unclear. It is becoming increasingly clear that cytokines produced by epithelial cells at barrier surfaces play an important role in shaping the responses to food antigens. These cytokines include TSLP, IL-25 and IL-33, which are expressed in coordinated fashion and have the ability to promote type 2 inflammatory responses through the activation of specific innate immune cell populations. Important for the work in this project, several studies have found that TSLP-mediated epicutaneous sensitization can exacerbate allergen-induced airway or GI tract inflammation, supporting a role for TSLP in the atopic march. We have established a model of food allergic responses in mice that allows us to perform epicutaneous sensitization in the presence of low levels of TSLP or IL-33, followed by oral challenge with the same antigen. Interestingly, it appears that IL-33 is critically important during both sensitization and oral challenge. We will use this model, in conjunction with samples from human patients with food allergies, to investigate the role of IL-33 in the loss of tolerance to food-related antigens (Aim 1), and determine whether polymorphisms in the IL-33 and IL-1RL1 correlate with allergic responses to food antigens (Aim 2).

项目概要 在过去的几十年里，食物过敏的患病率有所增加，估计有 5% 工业化国家的儿童和 3-4% 的成年人受到影响。食物过敏的定义是不利的 接触特定食物后的免疫反应，可以表现为局部症状 瘙痒、肿胀、腹泻至急性过敏反应。目前，这两种疾病都没有可用的治疗方法 预防或治疗食物过敏，现有药物只能治疗过敏发作后的症状 回复。鉴于食物过敏对公共卫生和经济的影响，迫切需要确定 开发治疗方法的新目标以及潜在的诊断工具来治疗这种疾病 虚弱的状况。 众所周知，过敏性疾病往往在儿童时期以连续的方式发生， 这种现象被称为“特应性行军”。这种现象通常表现为患有特应性过敏的儿童 皮炎随后发展为哮喘或对空气过敏原的过敏反应。此外 哮喘和过敏性鼻炎等流行病学研究表明，皮肤炎症 与特应性皮炎 (AD) 相关的细菌是发生食物过敏的重要危险因素。在 此外，使用表皮致敏模型的动物研究表明，这种途径 致敏作用可能导致其他屏障位点发生抗原诱导的过敏性炎症。综合起来， 这些数据表明，皮肤可能是食物过敏原致敏高度相关的部位。然而， 皮肤中的抗原致敏可通过免疫学机制诱发过敏 肠道炎症尚不清楚。 越来越清楚的是，屏障表面上皮细胞产生的细胞因子发挥着重要作用。 在形成对食物抗原的反应中发挥重要作用。这些细胞因子包括 TSLP、IL-25 和 IL-33， 以协调方式表达并能够促进 2 型炎症反应 通过激活特定的先天免疫细胞群。对于该项目的工作很重要，有几个 研究发现，TSLP介导的表皮致敏可加剧过敏原诱发的气道或 胃肠道炎症，支持 TSLP 在特应性进展中的作用。我们建立了食品模型 小鼠过敏反应，使我们能够在低水平的存在下进行表皮致敏 TSLP 或 IL-33，然后用相同抗原进行口服攻击。有趣的是，IL-33 似乎对 在致敏和口腔挑战期间都很重要。我们将结合示例使用该模型 来自患有食物过敏的人类患者，研究 IL-33 在食物相关耐受性丧失中的作用 抗原（目标 1），并确定 IL-33 和 IL-1RL1 的多态性是否与过敏相关 对食物抗原的反应（目标 2）。