Understanding alpha-gal red meat allergy

了解α-半乳糖红肉过敏

• 批准号: 9790908
• 负责人: Scott Palmer Commins
• 金额: $ 46.23万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790908
• 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; Bite; 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; 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; beef; cohort; cytokine; design; epidemiologic data; feeding; food challenge; galactosyl-(1-3)galactose; immunogenic; insight; intradermal injection; lard; mimetics; mouse model; novel; response; sensitizing antigen

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.

项目总结 过敏反应是一种严重的过敏反应，进展迅速，甚至致命。在以下情况下 触发过敏原尚不清楚，确定过敏反应的病因学对长期风险至关重要 管理层。我们最近的工作发现了一种新的针对哺乳动物低聚糖的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有关： 一)首次静脉注射西妥昔单抗期间出现即刻起效过敏反应，以及二)延迟起效 过敏反应在摄取哺乳动物食品(如牛肉和猪肉)后3-6小时发生。首要目标是 这一建议是，明确α-Gal免疫应答的原因和机制，以及 确定导致延迟食物反应的抗原，将有助于深入了解这些因素 管理过敏反应和控制过敏反应的药物。我们的新型α-GAL过敏小鼠模型将允许 美国将测试扁虱叮咬诱导嗜碱性粒细胞依赖的α-Gal特异性免疫反应这一中心假设 由于非传统的T细胞抗原呈递，导致对红肉的迟发过敏反应。这个 研究这些反应的意义不仅来自于理解 新奇的威胁生命的食物过敏形式，也是因为有可能定义一种全新的 与一种重要食品物质有关的反应机理。我们的研究计划侧重于 阐明免疫细胞在小鼠模型中的作用，确定扁虱叮咬在启动IgE和 了解在食用牛肉、猪肉或羊肉3-6小时后血液中出现的抗原。 我们目前的工作表明，在一组患者中存在糖类α-半乳糖的IgE 世卫组织报告称，食用哺乳动物肉类后出现延迟过敏反应和过敏反应。我们相信Ig E到α- GAL代表了一种导致食物过敏的新原因。本提案中概述的具体目标旨在 确定扁虱叮咬在启动α-Gal免疫球蛋白应答中的作用(特定目标1)，并探讨其机制 用于产生IgE(特定目标2)，并阐明延迟反应的机制(特定目标3)。总的来说， 这些研究的独特之处在于提供了对最近发现的影响 美国东南部的3,500名患者，并识别过敏反应中存在的分子 并建立外寄生扁虱叮咬引发免疫球蛋白E反应的模型。