The adaptive immune response to food antigens in the gut

肠道内对食物抗原的适应性免疫反应

• 批准号: 10455274
• 负责人: Stephanie Caroline Eisenbarth
• 金额: $ 44.8万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455274
• 关键词: Affect; Allergens; Allergic; Allergic Reaction; Allergy to peanuts; Anaphylaxis; Anatomy; Animals; Antibodies; Antibody Response; Attenuated; B-Cell Antigen Receptor; B-Lymphocytes; B-cell receptor repertoire sequencing; Bioinformatics; Biological Assay; Biological Markers; Cells; Child; Clinical; Clone Cells; Collaborations; Conflict (Psychology); Data; Development; Diagnostic; Ecology; Egg White; Epitopes; Experimental Models; FDA approved; Food; Food Hypersensitivity; Food production; Generations; Goals; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Hypersensitivity; IgA2; IgE; Immune; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunologics; Inflammatory; Ingestion; Interleukin-13; Intervention; Knock-out; Knockout Mice; Lead; Life; Location; Mediator of activation protein; Methods; Microbe; Modeling; Mucous Membrane; Mus; Natural History; Pathogenicity; Pathway interactions; Patients; Penetration; Peyer' s Patches; Positioning Attribute; Production; Reaction; Research; Risk; Role; Sampling; Stimulus; Structure of germinal center of lymph node; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Therapeutic; Toxin; United States; absorption; adaptive immune response; allergic response; antimicrobial; combat; experimental study; food allergen; food antigen; gut bacteria; gut microbiota; lymphoid structures; mesenteric lymph node; microbiome; mouse model; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; oral immunotherapy; oral tolerance; pathogenic microbe; prevent; response; stool sample

Food allergy affects approximately 8% of US children. The most severe form of food allergy results in anaphylaxis, which can be life-threatening. Currently only one FDA-approved therapy for peanut allergy exists, which is oral immunotherapy (OIT). Other food allergies lack approved treatments. Although a promising intervention, peanut OIT does not work for all children, often only mitigates anaphylaxis risk temporarily and can itself cause life-threating reactions. Therefore most patients must try to avoid food allergens to prevent allergic reactions. New strategies to treat food allergies are needed; however, progress is stymied because we lack a mechanistic understanding of the factors that attenuate allergy to food. Food-antigen specific immunoglobulin E (IgE) is a central mediator of anaphylactic reactions. In contrast, gut IgA to food antigens is presumed to be beneficial as part of a tolerogenic response. However, it is still unknown how IgA to food is induced and how this cellular mechanism is related to induction of food-specific IgE. Our preliminary data demonstrate that despite potentially opposing functions, food-specific IgA and IgE are often co-produced in children with food allergy. Indeed we find in mouse models that many of the immune stimuli that induce IgE are the same ones that induce IgA. Our preliminary data challenge the current, but untested, paradigm that the steady state/tolerogenic response to food antigens involves IgA . Our goal is to identify how food- specific gut IgA is induced, its relationship to food-specific IgE and to define the role of IgA in food allergy. To mechanistically define the role of T cell subsets we created new mouse models to selectively knockout specific T cell subsets along with particular effector functions. These models will also enable us to test the isolated role of food-specific IgA in the gut by eliminating the select T cell subset that drives food-specific IgA without impacting microbe-specific IgA or food-specific IgE. To definitively identify the role of IgA in food allergy, we also developed new mouse models that isolate IgA from IgE production to food. To define the clonal relationship of food-specific IgA and IgE B cells early after peanut immunization we established collaborations with bioinformatics experts in B cell receptor repertoire analyses. Finally, we developed a method to detect peanut- and egg-white-specific IgA in human stool samples and will use these assays to characterize the food- specific gut IgA response in atopic children and separately, children undergoing oral immunotherapy with peanut. Our preliminary studies demonstrate that the generation of food-specific IgA occurs through an entirely novel immunological pathway, distinct mechanistically from microbe-specific-IgA and physically from food- specific IgE and question current models of how IgA might mitigate the allergic response to food. If successful, our experiments will define the fundamental immunologic rules that govern the production of food-reactive IgE and IgA and thereby identify new therapeutic and diagnostic possibilities for those with food allergy. 1

食物过敏影响约8%的美国儿童。最严重的食物过敏会导致 过敏反应，这可能会危及生命。目前只有一种FDA批准的花生过敏疗法存在， 口服免疫疗法（OIT）其他食物过敏缺乏批准的治疗方法。虽然一个有前途的 但是，花生OIT并不适用于所有儿童，通常只能暂时减轻过敏反应的风险， 本身就会引起危及生命的反应。因此大多数患者必须尽量避免食物过敏原，以防过敏 反应.治疗食物过敏的新策略是必要的;然而，进展受阻，因为我们缺乏 对减弱食物过敏的因素的机械理解。 食物抗原特异性免疫球蛋白E（IgE）是过敏反应的中心介质。与此相反， 肠道IgA对食物抗原的应答被认为是有益的，作为耐受性应答的一部分。但是依然 尚不清楚食物中的伊加是如何被诱导的，以及这种细胞机制如何与食物特异性IgE的诱导相关。 我们的初步数据表明，尽管有潜在的相反功能，食物特异性伊加和IgE往往是 食物过敏的儿童体内共同产生。事实上，我们在小鼠模型中发现，许多免疫刺激， 诱导的IgE与诱导的伊加相同。我们的初步数据挑战了目前的，但未经测试的，范式 对食物抗原的稳态/致耐受性应答涉及伊加。我们的目标是找出食物- 特异性肠道伊加的诱导，其与食物特异性IgE的关系，并定义伊加在食物中的作用 过敏 为了从机制上确定T细胞亚群的作用，我们建立了新的小鼠模型， 特异性T细胞亚群沿着特定效应子功能。这些模型还将使我们能够测试 通过消除驱动食物特异性伊加的选择性T细胞亚群， 而不影响微生物特异性伊加或食物特异性IgE。为了明确确定伊加在食物过敏中的作用， 我们还开发了新的小鼠模型，将伊加从IgE产生中分离出来，并转移到食物中。为了定义克隆 花生免疫后早期食物特异性伊加和IgE B细胞的关系 与生物信息学专家在B细胞受体库分析。最后，我们开发了一种方法来检测 花生和蛋清特异性伊加在人类粪便样本，并将使用这些测定来表征食品- 特异性肠道伊加反应在特应性儿童和单独，儿童接受口服免疫治疗与花生。 我们的初步研究表明，食物特异性伊加的产生是通过一个完整的 新的免疫途径，在机制上不同于微生物特异性伊加，在物理上不同于食物， 特异性IgE和问题的伊加如何可能减轻对食物的过敏反应的当前模型。如果成功， 我们的实验将确定控制食物反应性IgE产生的基本免疫规则 和伊加，从而为那些食物过敏的人确定新的治疗和诊断可能性。 1