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Communication between skin and gastrointestinal tract in food allergy

食物过敏中皮肤和胃肠道之间的沟通

基本信息

批准号：
9233916
负责人：
Maria CECILIA BERIN
金额：
$ 21.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233916
关键词：
Address Adjuvant Affect Allergens Allergic Allergy to peanuts Anaphylaxis Antigens Atopic Dermatitis Automobile Driving Blood Bone Marrow Cells Child Clinical Communication Consumption Data Development Diarrhea Diet Disease Eczema Epithelial Excoriation Exposure to Food Food Hypersensitivity Foxes Gastrointestinal tract structure Generations Genes Health Home environment House Dust Household Human Hypersensitivity IgE Immune Immune system Immunoglobulin Class Switching Impairment Inflammation Inflammatory Ingestion Injury Innate Immune Response Interleukin-13 Interleukin-4 Intestines Lamina Propria Life Link Lymphoid Cell Mediating Mesentery Methods Modeling Mucous Membrane Multipotent Stem Cells Mus Mutation Oral Patients Population Predisposition Prevention strategy Process Proteins Proto-Oncogene Protein c-kit Reaction Recording of previous events Regulatory T-Lymphocyte Reporter Reporting Risk Risk Factors Role Route Severities Signal Transduction Site Skin Skin injury Small Intestines Stem cells Stratum corneum Structure of aggregated lymphoid follicle of small intestine Symptoms T-Lymphocyte TSLP gene Testing Tissues Urticaria base cytokine design eosinophil experience filaggrin food allergen food antigen gastrointestinal gastrointestinal symptom granulocyte improved lymph nodes mast cell mouse model novel oral tolerance prevent progenitor public health relevance response skin barrier

项目摘要

DESCRIPTION (provided by applicant): IgE-mediated food allergy affects approximately 5-8% of the US population, and there is no approved treatment. The current management strategy consists of allergen avoidance, but accidental ingestions are a common experience for patients. Severity of reactions is not predictable, and can range from mild hives to life- threatening systemic anaphylaxis. Sensitization commonly occurs in the first year of life, and the most predictive risk factor for food allergy is eczema. A developing paradigm is that exposure to foods via household dust promotes epicutaneous sensitization to foods in children with eczema, while dietary avoidance prevents the normal development of oral tolerance. Based on preliminary data, we hypothesize that inflammatory signals from the skin may also contribute to sensitization to foods encountered by the oral route. Using a model of tape-stripping that mimics the excoriations of atopic dermatitis, we observed that a single episode of mild skin damage leads to a significant change in the innate immune milieu of the small intestine. There is an induction of Th2 cytokine expression by resident innate and progenitor cells of the gastrointestinal tract, as well as an influx of innate cells into the inductive sites of the mucosa immune system. Furthermore, tape stripping in the absence of epicutaneous allergen exposure supports the generation of allergic symptoms when mice are repeatedly fed with the antigen. Based on our preliminary data, we hypothesize that signals generated from a compromised skin barrier act systemically to release progenitors from the bone marrow that home to the gastrointestinal tissues, and in addition drive an innate Th2 response from resident cells of the gastrointestinal tissues. This biased innate immune milieu thereby promotes IgE class switch in the mucosal tissues and impairs the development of oral tolerance. We will test this hypothesis in two specific aims. In the first aim, we will determine the mechanism by which damage to the skin leads to an altered immune milieu in the gastrointestinal tissues. We will examine the impact of mild tape stripping-induced injury on innate and progenitor cells in bone marrow, blood, skin, and gastrointestinal tract tissues, and study their cytokine expression using reporter mice. We will determine the role of skin cytokines in driving this innate immune response in the gastrointestinal tract. In the next aim we will determine the functional consequence of this altered immune milieu on the development of tolerance or sensitization to food antigens using mouse models of food allergy. Furthermore, we will examine the impact of the altered immune milieu on generation of Tfh cells and Tregs as well as class switch to IgE. Successful completion of our aims will provide us with a mechanistic understanding of the role of the skin in development of food allergy, and will help us to design appropriate strategies for the prevention of food allergy in early life.

描述（由申请人提供）：IgE 介导的食物过敏影响了大约 5-8% 的美国人口，并且没有批准的治疗方法。目前的管理策略包括避免过敏原，但意外摄入是患者的常见经历。反应的严重程度无法预测，范围可以从轻微的荨麻疹到危及生命的全身过敏反应。过敏通常发生在生命的第一年，食物过敏最具预测性的危险因素是湿疹。一个正在发展的范例是，通过家庭灰尘接触食物会促进患有湿疹的儿童对食物的表皮过敏，而避免饮食会阻碍口腔耐受性的正常发展。根据初步数据，我们假设来自皮肤的炎症信号也可能导致对口服途径遇到的食物过敏。使用模拟特应性皮炎的抓痕的胶带剥离模型，我们观察到单次轻度皮肤损伤会导致小肠先天免疫环境发生显着变化。胃肠道的先天细胞和祖细胞诱导 Th2 细胞因子表达，以及先天细胞涌入粘膜免疫系统的诱导位点。此外，在没有表皮过敏原暴露的情况下，胶带剥离支持当小鼠反复喂食抗原时过敏症状的产生。根据我们的初步数据，我们假设受损的皮肤屏障产生的信号会系统性地从归巢于胃肠道组织的骨髓中释放祖细胞，此外还驱动胃肠道组织驻留细胞的先天性 Th2 反应。这种偏向的先天免疫环境从而促进粘膜组织中 IgE 类别的转换并损害口服耐受的发展。我们将在两个特定目标中检验这一假设。第一个目标是确定皮肤损伤导致胃肠组织免疫环境改变的机制。我们将检查轻度胶带剥离引起的损伤对骨髓、血液、皮肤和胃肠道组织中先天细胞和祖细胞的影响，并使用报告基因研究它们的细胞因子表达老鼠。我们将确定皮肤细胞因子在驱动胃肠道先天免疫反应中的作用。在下一个目标中，我们将使用食物过敏的小鼠模型来确定这种改变的免疫环境对食物抗原耐受性或敏感性发展的功能性影响。此外，我们将研究改变的免疫环境对 Tfh 细胞和 Tregs 的生成以及 IgE 类别转换的影响。成功实现我们的目标将使我们对皮肤在食物过敏发展中的作用有一个机制上的了解，并将帮助我们设计适当的策略来预防生命早期的食物过敏。