Immunologic basis of phenotypic heterogeneity in peanut allergy

花生过敏表型异质性的免疫学基础

基本信息

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
项目类别：
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

项目摘要

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-总结花生过敏（PA）的许多方面都存在异质性，包括引发花生过敏的剂量症状（阈值）、诱发症状的严重程度以及症状类型（目标被触发的器官。相当一部分人（最多 20%）将不再需要他们的 PA，而大多数人仍保留临床反应性。我们认为 PA 临床表型的这种自然异质性是有价值的有机会了解导致疾病的免疫机制。我们假设独特的免疫 IgE、IgG4、CD4+ T 细胞和嗜碱性粒细胞水平的反应是重要的临床异质性的基础，并且此外，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，我们将接触 200-250 名接受口服食物挑战的 PA 受试者，这些受试者的 PA 水平较低或对花生的反应阈值高，或不过敏的人。我们还将获得98级高门槛受试者随机接受饮食中低于阈值的花生（或继续避免），并且谁将有研究的 2.5 年中出现了不同的临床结果。我们将进行高维对这些受试者进行免疫分析，以确定将花生的免疫和临床反应联系起来的途径。我们发现 IgE 与牛奶过敏原表位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率。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，并预测对花生的反应饮食干预。我们还发现花生特异性 Th2 的程度和分化 PA 受试者的反应具有高度异质性。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来确定这个多样化队列中的异质性通过流式细胞术和多重细胞因子测定分析花生反应性 T 细胞。我们开发了基于 CyTOF 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，证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，而且在体内。我们假设全血中细胞活化的广泛分析 CyTOF 将识别新的反应细胞群落，区分关键临床表型宾夕法尼亚州。我们项目的成功完成将建立一个 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上的临床表型回应。我们预计这个临床免疫网络不仅会揭示机制，而且将成为一个指导 PA 个性化管理和治疗策略的重要工具。