Immune Basis & Clinical implications of Threshold-Based Phenotypes of Peanut Allergy

免疫基础

基本信息

批准号：
10415888
负责人：
Maria CECILIA BERIN
金额：
$ 152.47万
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/10415888
关键词：
Affect Allergens Allergic Allergy to eggs Allergy to peanuts Anaphylaxis Antibodies Antibody Response Bioinformatics Biological Assay Biological Markers Biology Characteristics Child Clinical Clinical Data Communities Computational Biology Data Diet Diet therapy Dietary Intervention Disease Dose Economic Burden Enrollment Epitopes Exanthema Exposure to FDA approved Flow Cytometry Food Food Hypersensitivity Funding Genetic Transcription Genomics Goals Heterogeneity Hypersensitivity IgE Immune Immunologics Immunology Individual Ingestion Investigation Lead Life Machine Learning Measures Medical Milk Milk Hypersensitivity Molecular Network-based Nutritional Oral Patients Persons Phase III Clinical Trials Phenotype Predictive Value Proteins Protocols documentation Quality of life Randomized Reaction Recovery Research Research Personnel Resolution Resources Sampling Schedule School-Age Population Severities Speed Symptoms T cell response T-Lymphocyte Testing Treatment Cost Urticaria Visit Whole Blood allergic response analytical tool base biobank biomarker identification clinical care clinical practice cohort cost data tools desensitization dietary egg feeding food allergen food challenge high dimensionality immunotherapy trials individualized medicine intervention cost learning network neglect oral diagnostics oral immunotherapy outcome prediction peripheral blood personalized approach prototype response screening transcriptome

项目摘要

Summary: Immune Basis and Clinical Implications of Threshold-Based Phenotypes of Peanut Allergy Peanut allergy (PA) is common, affecting 2-5% of school-age children in the US. The characteristics of PA vary widely among individuals, with some reacting to 1/100th of a peanut and others not having symptoms until they have ingested many peanuts. Symptoms can vary from mild rashes to fatal anaphylaxis. There is no FDA- approved treatment, and all patients with PA are managed with strict allergen avoidance. Most research on PA has focused on those with the most exquisite sensitivity to peanut. Immunotherapy trials commonly exclude subjects with a threshold dose over 1/3 of a peanut (100mg). However, most individuals with PA have higher thresholds of reaction and are excluded from current research approaches. We hypothesize that the natural heterogeneity of PA is a valuable opportunity for investigation. We have shown that milk or egg allergic individuals with tolerance to baked forms of these foods not only tolerate their inclusion in the diet, but this exposure increases the rate of resolution 14-16-fold. We hypothesize that dietary exposure to sub-threshold levels of peanut in those with higher threshold levels of reactivity could lead to significant clinical improvement. Furthermore, studying the natural heterogeneity of PA is a valuable opportunity to elucidate mechanisms of disease. To study the clinical implications and mechanism of phenotypic heterogeneity in PA, we will conduct a randomized open feeding trial (CAFETERIA trial) to investigate a prototype approach where children with moderate PA (tolerating at least 100 mg of peanut) ingest a sub-threshold amount daily, with increasing levels tested every 3 months. The impact of dietary intervention will be tested at 1 and 2 years by oral food challenge. The CAFETERIA study will provide a rich biorepository of samples from highly phenotyped subjects. We anticipate screening 200-250 subjects, including low threshold, high threshold, and sensitized but not allergic, in order to enroll 98 subjects that meet the high threshold criteria for the CAFETERIA trial. We will obtain longitudinal samples from subjects randomized to dietary therapy or avoidance. We will comprehensively profile antibody responses by high-throughput epitope assay, peanut-specific T cell responses by flow cytometry, and whole blood activation by CyTOF to construct a detailed clinical-immune network of PA, and analyze the relationship between immune and clinical parameters. We will identify biomarkers and key causal drivers of PA by performing integrated network-based examination of peripheral blood transcriptomes from PA subjects, sampled before and after food challenge, and before and after dietary therapy. Successful completion of these aims will result in (1) a simple low-cost treatment option applicable to the majority of those with PA; (2) an identification of immune and molecular mechanisms of PA and response to dietary therapy; (3) peripheral blood biomarkers that will practically impact clinical care of PA; (4) the potential for personalized approaches to the treatment of PA; and (5) a tremendously rich resource of clinical, immune, and transcriptional data and analytic tools to be made publicly available to the research community.

摘要：基于阈值的花生过敏表型的免疫基础和临床意义花生过敏 (PA) 很常见，影响美国 2-5% 的学龄儿童。 PA的特性各不相同在个体中广泛存在，有些人对 1/100 的花生有反应，而另一些人直到他们吃完之后才出现症状。摄入了很多花生。症状多种多样，从轻微的皮疹到致命的过敏反应。没有FDA—— 批准的治疗方法，并且所有 PA 患者均严格避免过敏原。大多数关于 PA 的研究专注于那些对花生最敏感的人。免疫治疗试验通常排除阈剂量超过花生的 1/3（100 毫克）的受试者。然而，大多数患有 PA 的人都有较高的反应阈值并被排除在当前的研究方法之外。我们假设自然 PA 的异质性是一个宝贵的研究机会。我们已经证明牛奶或鸡蛋过敏对这些食物的烘焙形式有耐受性的人不仅可以耐受将它们纳入饮食中，而且还可以耐受这些食物。曝光使分辨率提高 14-16 倍。我们假设饮食暴露于亚阈值对于具有较高反应阈值水平的人来说，花生水平可能会带来显着的临床改善。此外，研究 PA 的自然异质性是阐明 PA 机制的宝贵机会。疾病。为了研究 PA 表型异质性的临床意义和机制，我们将进行随机开放喂养试验（CAFETERIA 试验）旨在研究一种原型方法，其中中度 PA（耐受至少 100 毫克花生）每天摄入低于阈值的量，并且水平不断增加每 3 个月测试一次。饮食干预的影响将在 1 岁和 2 岁时通过口服食物挑战进行测试。 CAFETERIA 研究将提供一个丰富的生物样本库，其中包含来自高度表型受试者的样本。我们预计筛查200-250名受试者，包括低阈值、高阈值、致敏但不过敏，为了招募 98 名符合 CAFETERIA 试验高阈值标准的受试者。我们将获得来自随机接受饮食治疗或避免饮食治疗的受试者的纵向样本。我们将全面通过高通量表位测定分析抗体反应，通过流式分析花生特异性 T 细胞反应细胞计数和 CyTOF 全血激活，构建详细的 PA 临床免疫网络，以及分析免疫和临床参数之间的关系。我们将确定生物标志物和关键因果关系通过对 PA 外周血转录组进行基于网络的综合检查来确定 PA 的驱动因素受试者在食物挑战之前和之后以及饮食治疗之前和之后进行采样。顺利完成这些目标将导致 (1) 一种适用于大多数 PA 患者的简单低成本治疗方案； (2) 确定 PA 的免疫和分子机制以及对饮食疗法的反应； (3)周边实际影响 PA 临床护理的血液生物标志物； (4) 个性化方法的潜力 PA的治疗； (5) 极其丰富的临床、免疫和转录数据资源向研究界公开提供的分析工具。