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-Summary 花生过敏的许多方面都有异质性（PA），包括触发的花生剂量 症状（阈值），诱发症状的严重程度和症状类型（目标 触发的器官。少数族裔（高达20％）将超越其PA，而大多数人保留 临床反应性。我们建议PA的临床表型中的这种自然异质性是有价值的 了解有助于疾病的免疫机制的机会。我们假设这种独特的免疫力 IgE，IgG4，CD4+ T细胞和嗜碱性粒子水平的反应是重要的临床异质性和 此外，我们假设这些独特的免疫特征构成了PA预后的基础。通过 临床核心，我们将可以访问患有低较低的PA的200-250名受试者 或对花生的反应性高阈值，或者不是过敏。我们还将访问98个高阈值 受试者随机接受饮食中的阈值花生（或继续避免），谁将有一个 在研究它们的2。5年中，各种各样的临床结果。我们将执行高维度 对这些受试者进行免疫分析，以确定将免疫和临床反应与花生的反应联系起来的途径。我们 已经发现，对牛奶过敏原中IgE结合的IgE结合的生物信息学分析不仅可以预测临床 牛奶过敏的表型，但可以准确预测牛奶口服免疫疗法后的治疗成功。我们将 应用这种方法来测试表位结合是否可以预测对花生的临床反应性，并预测对 饮食干预。我们还确定了花生特异性TH2的大小和分化 在PA受试者中，反应高度异质。我们将确定TH2的临床意义 这种多样的队列中的异质性，使用基于CD154的检测和表型的组合 通过流式细胞仪和多重细胞因子测定法分析花生反应性T细胞。我们已经发展了 基于Cytof的方法研究全血细胞对花生的反应，并发表了 作为初步数据，表明我们可以识别嗜碱性粒细胞和其他细胞类型中的信号传导和激活 不仅在体外，而且体内。我们假设通过 Cytof将确定响应细胞的新型社区，这些细胞区分关键的临床表型 PA。我们项目的成功完成将建立PA的临床免疫网络，该网络覆盖了详细的 高维特异性抗体，T细胞和效应细胞的高维网络上的临床表型 回答。我们预计该临床免疫网络不仅会揭示机制，而且将是一个 指导PA的个性化管理和治疗策略的重要工具。