Understanding alpha-gal red meat allergy

了解α-半乳糖红肉过敏

• 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
• 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

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.

项目摘要 过敏反应是一种严重的过敏反应，可以迅速发展和致命。在哪里 触发过敏原是未知的，确定过敏反应的病因至关重要 管理。我们最近的工作确定了对哺乳动物寡糖的新型IgE抗体反应 表位，半乳酮-Alpha-1,3-甲乳转酮（α-GAL），与两种不同形式的过敏反应相关： i）在第一次接触静脉内西妥昔单抗和ii）延迟发作时立即发作过敏反应 摄入哺乳动物食品（例如牛肉和猪肉）后3-6小时过敏。总体目标 对于这个建议，可以定义α-gal igE响应的原因和机制，以及 确定负责延迟食物反应的抗原，将洞悉这些因素 控制过敏反应并控制过敏反应。我们的新型α-Gal-过敏小鼠模型将允许 我们测试滴答叮咬的中心假设会影响嗜碱性粒细胞的α-GAL特异性免疫反应 由于非常规T细胞抗原表现，这会导致对红肉的过敏反应延迟。这 研究这些反应的重要性不仅来自理解一个明显的重要性 新颖的食物过敏形式威胁生命的形式，也是因为有可能定义一个全新的 与重要食品有关的反应机制。我们的研究计划着重于 阐明免疫细胞在鼠模型中的作用，定义滴答物在启动IgE和 了解吃牛肉，猪肉或羊肉后3-6小时出现在血液中的抗原。 我们目前的工作表明，在一系列患者中提出了碳水化合物α-gal的IgE 报告说，吃哺乳动物肉后延迟过敏反应和过敏反应。我们认为IgE至α- GAL代表了食物过敏的新原因。本提案中概述的具体目的旨在 确定滴答叮咬在启动α-gal IgE响应中的作用（特定目标1），研究机制 用于IgE的产生（特定目标2）并阐明了延迟反应的机制（特定目标3）。全面的， 这些研究是独特的，可以洞悉影响最近公认的过敏反应 >美国东南部的3500名患者，并确定在过敏反应期间存在的分子 并建立一个用于寄生虫壁虱位的模型启动IgE响应。