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

花生过敏症阈值表型的免疫基础及临床意义 花生过敏(PA)很常见，影响到美国2%-5%的学龄儿童。PA的特性各不相同 在个体中广泛存在，一些人对百分之一的花生产生反应，另一些人直到 吃了很多花生。症状可能从轻微的皮疹到致命的过敏反应。没有食品和药物管理局- 经批准的治疗，所有PA患者都严格避免过敏原。关于PA的研究最多 专注于那些对花生最细腻敏感的人。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的人有更高的 反应阈值，并被排除在当前的研究方法之外。我们假设自然界中 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 对这些烘焙形式的食物有耐受性的人不仅会容忍它们被纳入饮食中，而且还会 曝光使分辨率提高了14-16倍。我们假设饮食接触亚临界值 那些反应性阈值水平较高的人的花生水平可能会导致显著的临床改善。 此外，研究PA的天然异质性是阐明其机制的宝贵机会。 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(自助餐厅试验)，以调查一种原型方法，在该方法中，患有 适中的PA(至少耐受100毫克花生)每天摄入低于阈值的量，并随着水平的增加 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。 自助餐厅的研究将提供来自高表型受试者样本的丰富生物库。我们 预计筛查200-250名受试者，包括低阈值、高阈值和致敏但不过敏， 为了招募98名符合自助餐厅试验高门槛标准的受试者。我们将获得 来自随机接受饮食治疗或避免饮食的受试者的纵向样本。我们将全面 高通量表位分析法检测抗体应答，流式细胞仪检测花生特异性T细胞应答 细胞术和全血细胞周期图激活以构建详细的PA临床免疫网络，以及 分析免疫指标与临床参数的关系。我们将确定生物标志物和关键原因 通过对PA的外周血转录本执行基于网络的集成检查来驱动PA 受试者，在食物挑战前和食物挑战后，以及饮食治疗前后进行采样。成功完成 这些目标将导致(1)适用于大多数PA患者的简单、低成本的治疗选择；(2) PA的免疫和分子机制鉴定及饮食治疗的反应；(3)外周 将实际影响PA临床护理的血液生物标记物；(4)个性化方法的潜力 PA的治疗；和(5)极其丰富的临床、免疫和转录数据资源，以及 向研究界公开提供分析工具。

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.