Understanding alpha-gal red meat allergy

了解α-半乳糖红肉过敏

基本信息

批准号：
10468062
负责人：
Scott Palmer Commins
金额：
$ 64.85万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2024-03-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468062
关键词：
Adjuvant Adult Affect Allergens Allergic Allergic Reaction Amblyomma Anaphylaxis Antibodies Antibody Response Antigen Presentation Antigen-Presenting Cells Antigens Appearance Automobile Driving Awareness B-Lymphocytes Basophils Binding Blood Blood Circulation CD1 Antigens Carbohydrates Cells Cetuximab Complex Cytotoxic T-Lymphocytes Data Development Dietary Fats Eating Epitopes Etiology Exposure to Fatty acid glycerol esters Food Food Hypersensitivity Formulation Galactose Glycolipids Glycosphingolipids Goals Helper-Inducer T-Lymphocyte Hour Human Hypersensitivity IgE Immune Immune response Individual Ingestion Injections Interleukin-4 Intestines Intravenous Intravenous infusion procedures Label Learning Life Lipids Measures Meat Mediating Medical Modeling Monoclonal Antibodies Mus Oligosaccharides Patients Persons Phenotype Positioning Attribute Production Proteins Radioimmunoassay Reaction Reporting Research Risk Management Role Salivary Glands Shock Source Symptoms T-Cell Activation T-Lymphocyte Testing Th2 Cells Thyroglobulin Ticks Tracer Work absorption allergic response alpha-gal syndrome beef cohort cytokine design epidemiologic data food challenge galactosyl-(1-3)galactose immunogenic insight intradermal injection lard mimetics mouse model novel response sensitizing antigen tick bite tick feeding

项目摘要

PROJECT SUMMARY Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (α-gal), that has been associated with two distinct forms of anaphylaxis: i) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and ii) delayed onset anaphylaxis 3-6 hours after ingestion of mammalian food products (e.g., beef and pork). The overarching goal for this proposal is that defining both the cause and the mechanism of α-gal IgE response, as well as identifying the antigen responsible for the delayed food reactions, will provide insight into the factors that govern allergic responses and control anaphylaxis. Our novel α-gal-allergic mouse model will allow us to test the central hypothesis that tick bites induce a basophil-dependent, α-gal specific immune response that, due to unconventional T cell antigen presentation, results in delayed allergic reactions to red meat. The significance of investigating these reactions comes not only from the obvious importance of understanding a novel life-threatening form of food allergy, but also because of the possibility of defining a totally new mechanism for reactions related to an important food substance. Our plan of research focuses on the elucidating the role of immune cells in the murine model, defining the role of tick bites in initiating the IgE and understanding the antigen that appears in the bloodstream 3-6 hours after eating beef, pork or lamb. Our current work has shown that IgE to the carbohydrate alpha-gal is present in a cohort of patients who report delayed anaphylaxis and allergic reactions after eating mammalian meat. We believe that IgE to α- gal represents a novel cause of food allergy. The specific aims outlined in this proposal are designed to establish the role of tick bites in initiating the α-gal IgE response (Specific Aim 1), investigate the mechanism for IgE production (Specific Aim 2) and elucidate the mechanism for delayed reactions (Specific Aim 3). Overall, these studies are uniquely positioned to provide insight into a recently recognized allergic response that affects >3,500 patients in the southeastern U.S. as well as identify the molecules present during an allergic reaction and establish a model for ecto-parasitic tick bites initiating an IgE response.

项目概要过敏反应是一种严重的过敏反应，在某些情况下可能会迅速进展并致命。触发过敏原尚不清楚，确定过敏反应的病因对于长期风险至关重要我们最近的工作发现了一种针对哺乳动物寡糖的新型 IgE 抗体反应。表位半乳糖-α-1,3-半乳糖 (α-gal)，与两种不同形式的过敏反应相关： i) 首次静脉注射西妥昔单抗期间立即发生过敏反应，以及 ii) 延迟发生摄入哺乳动物食品（例如牛肉和猪肉）后 3-6 小时发生过敏反应总体目标。该提案的目的是定义 α-gal IgE 反应的原因和机制，以及识别导致食物反应延迟的抗原，将有助于深入了解这些因素我们的新型 α-gal 过敏小鼠模型将允许控制过敏反应和控制过敏反应。我们来检验蜱虫叮咬会诱导嗜碱性粒细胞依赖性、α-半乳糖特异性免疫反应的中心假设由于非常规的 T 细胞抗原呈递，导致对红肉的迟发性过敏反应。研究这些反应的重要性不仅来自于理解一种新颖的危及生命的食物过敏形式，而且还因为有可能定义一种全新的食物过敏我们的研究计划集中于与重要食品物质相关的反应机制。阐明免疫细胞在小鼠模型中的作用，定义蜱虫叮咬在启动 IgE 和了解食用牛肉、猪肉或羊肉后 3-6 小时血液中出现的抗原。我们目前的工作表明，一组患者中存在针对碳水化合物 α-gal 的 IgE 报告称，食用哺乳动物肉后出现迟发性过敏反应和过敏反应。我们认为，IgE 会转变成 α-。 gal 代表了食物过敏的一种新原因。本提案中概述的具体目标旨在：确定蜱虫叮咬在启动 α-gal IgE 反应中的作用（具体目标 1），研究其机制 IgE 产生（具体目标 2）并阐明延迟反应的机制（具体目标 3）。这些研究具有独特的定位，可以深入了解最近发现的影响健康的过敏反应。美国东南部超过 3,500 名患者并识别了过敏反应期间存在的分子并建立启动 IgE 反应的体外寄生蜱叮咬模型。