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

花生过敏的免疫基础和临床意义 花生过敏（PA）是常见的，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，其他人直到他们吃了花生才出现症状。 吃了很多花生症状可以从轻微的皮疹到致命的过敏反应。没有FDA- 批准的治疗，所有PA患者都严格避免过敏原。关于PA的大多数研究 专注于那些对花生最敏感的人免疫治疗试验通常排除 阈值剂量超过1/3花生（100毫克）的受试者。然而，大多数患有PA的人 反应阈值，并排除在目前的研究方法。我们假设自然的 PA的异质性是研究的宝贵机会。我们已经证明牛奶或鸡蛋过敏 对烘焙形式的这些食物具有耐受性的个体不仅容忍它们被包含在饮食中，而且 曝光将分辨率提高14-16倍。我们假设饮食中暴露于低于阈值的 在那些具有较高阈值水平的反应性的人中，花生水平可以导致显著的临床改善。 此外，研究PA的天然异质性是阐明PA的机制的宝贵机会。 疾病为了研究PA表型异质性的临床意义和机制，我们将进行一项 随机开放喂养试验（CAFETERIA试验），以研究一种原型方法， 中度PA（耐受至少100 mg花生）每天摄入低于阈值的量，随着水平的增加， 每三个月测试一次。饮食干预的影响将在1年和2年时通过口服食物挑战进行测试。 CAFETERIA研究将为来自高表型受试者的样本提供丰富的生物储存库。我们 预计筛选200-250名受试者，包括低阈值、高阈值和致敏但不过敏， 以招募98名符合CAFETERIA试验高阈值标准的受试者。我们将获得 从随机分配到饮食治疗或避免饮食的受试者的纵向样本。全面 通过高通量表位测定分析抗体应答，通过流式细胞术分析花生特异性T细胞应答， 流式细胞术和通过CyTOF的全血活化以构建PA的详细临床免疫网络，以及 分析免疫指标与临床指标的关系。我们将确定生物标志物和关键的因果关系， 通过对来自PA的外周血转录组进行基于网络的综合检查， 受试者，在食物激发前后以及饮食治疗前后采样。成功完成 这些目标将导致（1）适用于大多数PA患者的简单低成本治疗选择;（2） PA的免疫和分子机制以及对饮食治疗的反应的鉴定;（3）外周 将实际影响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;和（5）临床，免疫和转录数据的非常丰富的资源， 分析工具将向研究界公开提供。

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.