Immunologic basis of phenotypic heterogeneity in peanut allergy

花生过敏表型异质性的免疫学基础

• 批准号: 10415893
• 负责人: Maria CECILIA BERIN
• 金额: $ 13.58万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-06 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415893
• 关键词: Allergens; Allergic; Allergy to eggs; Allergy to peanuts; Antibodies; Basophils; Binding; Bioinformatics; Biological; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cells; Clinical; Communities; Data; Detection; Development; Diet; Diet therapy; Dietary Intervention; Disease; Dose; Effector Cell; Enrollment; Epinephrine; Epitopes; Exposure to; Flow Cytometry; Food Hypersensitivity; Goals; Grant; Heterogeneity; Hypersensitivity; IgE; IgG4; Immune; Immune response; Immunoglobulins; Immunologics; In Vitro; Individual; Lead; Link; Measures; Mediating; Milk; Milk Hypersensitivity; Minority; Molecular; Oral; Organ; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Prognosis; Publishing; Randomized; Reaction; Resolution; Role; Sampling; Severities; Signal Transduction; Stains; Symptoms; T cell response; T-Lymphocyte; TNFSF5 gene; Testing; Th2 Cells; Time; Variant; Whole Blood; base; cell type; clinical heterogeneity; clinical phenotype; clinical predictors; cohort; cytokine; dietary; disease heterogeneity; disease prognosis; effective intervention; egg; food challenge; high dimensionality; improved; in vivo; novel; oral immunotherapy; peripheral blood; personalized approach; personalized management; personalized medicine; predicting response; randomized trial; response; success; therapeutic target; tool; treatment strategy

Project 2-Summary There is heterogeneity in many aspects of peanut allergy (PA), including the dose of peanut that triggers symptoms (the threshold), the severity of symptoms that are induced, and the type of symptoms (target organ(s)) that are triggered. A significant minority (up to 20%) will outgrow their PA, while the majority retains clinical reactivity. We propose that this natural heterogeneity in the clinical phenotype of PA is a valuable opportunity to understand immune mechanisms contributing to disease. We hypothesize that distinct immune responses at the level of IgE, IgG4, CD4+ T cells, and basophils underlie important clinical heterogeneity, and furthermore we hypothesize that these distinct immune profiles form a basis for prognosis of PA. Through the Clinical Core, we will have access to 200-250 subjects undergoing oral food challenge for PA who have a low or high threshold of reactivity to peanut, or who are not allergic. We will also have access to 98 high-threshold subjects randomized to receive sub-threshold peanut in the diet (or continue avoidance), and who will have a diverse set of clinical outcomes over the 2.5 years that they are studied. We will perform high dimensional immune profiling on these subjects to identify pathways linking immune and clinical responses to peanut. We have found that bioinformatics analysis of IgE binding to epitopes in milk allergens can predict not only clinical phenotype of milk allergy, but accurately predict treatment success after milk oral immunotherapy. We will apply this approach to test if epitope binding can predict clinical reactivity to peanut, and predict response to dietary intervention. We have also identified that the magnitude and differentiation of the peanut-specific Th2 response is highly heterogeneous in PA subjects. We will determine the clinical implications of Th2 heterogeneity within this diverse cohort, using a combination of CD154-based detection and phenotypic analysis of peanut-responsive T cells by flow cytometry, and multiplex cytokine assays. We have developed CyTOF-based approaches to study the response of cells in whole blood to peanut, and have published as well as preliminary data demonstrating that we can identify signaling and activation in basophils and other cell types not only in vitro but also in vivo. We hypothesize that broad profiling of the activation of cells in whole blood by CyTOF will identify novel communities of responding cells that discriminate between key clinical phenotypes of PA. The successful completion of our project will build a clinical-immune network of PA that overlays a detailed clinical phenotype over a high dimensional network of peanut-specific antibodies, T cells, and effector cell responses. We anticipate that this clinical-immune network will not only reveal mechanisms, but will be an essential tool for guiding personalized management and treatment strategies for PA.

项目2-摘要 花生过敏(PA)的许多方面都有异质性，包括引发花生过敏的花生剂量 症状(阈值)、诱发的症状的严重性和症状的类型(目标 器官(S))被触发。少数人(高达20%)将超过他们的个人助理，而大多数人将保留 临床反应性。我们认为PA临床表型的这种自然异质性是一种有价值的 有机会了解导致疾病的免疫机制。我们假设不同的免疫力 在IgE、IgG4、CD4+T细胞和嗜碱性粒细胞水平上的反应是重要的临床异质性的基础。 此外，我们假设这些不同的免疫特征构成了PA预后的基础。通过 临床核心，我们将有200-250名受试者接受口服食物挑战的PA谁有低 或对花生反应门槛高，或对花生不过敏。我们还将获得98高门槛 受试者被随机接受饮食中低于阈值的花生(或继续回避)，谁将有 在他们被研究的2.5年中，不同的临床结果集。我们将表演高次元 对这些受试者进行免疫图谱分析，以确定将免疫和临床反应联系起来的途径。我们 研究发现，牛奶变应原中IgE结合表位的生物信息学分析不仅可以预测临床 牛奶过敏的表型，但准确地预测牛奶口服免疫治疗后的治疗成功。我们会 应用这种方法来测试表位结合是否可以预测花生的临床反应性，并预测对花生的反应 饮食干预。我们还鉴定了花生特异的Th2的大小和分化 PA受试者的反应具有高度的异质性。我们将确定Th2的临床意义 使用基于CD154的检测和表型相结合的方法，在这个不同的队列中实现异质性 花生反应性T细胞的流式细胞术分析和多重细胞因子分析。我们已经开发出 以细胞为基础的方法研究全血细胞对花生的反应，并已发表 作为初步数据，我们可以在嗜碱性粒细胞和其他类型的细胞中识别信号和激活 不仅在体外，而且在体内也是如此。我们假设全血中细胞激活的概貌是通过 CyTOF将识别新的反应细胞群落，以区分关键的临床表型 爸。我们项目的成功完成将建立PA的临床免疫网络，覆盖详细的 花生特异性抗体、T细胞和效应细胞高维网络的临床表型 回应。我们预计，这个临床免疫网络不仅将揭示机制，而且将是一种 指导PA的个性化管理和治疗策略的基本工具。