Integrated Genomic and Functional Studies of Tolerance Therapy for Peanut Allerg

描述（由申请人提供）：食物过敏已成为一个全球性的公共卫生问题，其中花生过敏问题尤为严重。在美国，摄入有害的食物过敏原是医院急诊科发生过敏反应的最常见原因，据估计，美国急诊科每年约有30,000例食物引起的过敏事件；不幸的是，其中大约有200起是致命的。花生或树坚果是导致这些死亡的主要原因，美国最近的一项调查发现，1.4%的人口对花生或树坚果过敏。先前在花生过敏（PA）患者中使用传统和快速过敏原方案的免疫脱敏试验已显示出部分反应率，但不幸的是，已导致高不良反应率，包括过敏反应。最近，A. Wesley Burks博士及其同事进行的具有里程碑意义的研究表明，通过口服免疫治疗（OIT）方案，花生过敏儿童对花生脱敏成功。斯坦福食物过敏研究联盟（SAFAR，发音为“更安全”）是一个多学科组织，其目标是：1)开发和利用最先进的分析方法，包括人类免疫监测方面的进展，以提高对引起食物过敏的免疫反应的理解，并为治疗这种疾病提供有希望的新方法；2)促进改进方法的开发和测试，以诊断、监测和治疗食物过敏的受试者。在这项U19申请中，我们建议在患有PA的儿童和成人中进行一项大规模的安慰剂对照、随机的二期临床试验，并在接受试验的PA患者以及适当的对照受试者（即接受安慰剂治疗的PA受试者、健康对照组和非PA的特应性对照组）的纵向样本中测量广泛的细胞、血清学和临床结果。这些数据将用于确定OIT期间关键免疫系统参数是如何改变的，以及哪些参数最能预测患者对该治疗反应的性质和持久性。此外，我们试图定义免疫监测参数，包括从嗜碱性粒细胞表型和功能分析中得出的结果，这些结果可以在临床实验室中使用非常少量的血液快速执行，可用于预测PA受试者对花生的临床反应性，提高OIT方案的安全性和有效性，和/或根据每个受试者定制OIT方案。我们希望这项工作将有助于实现设计一种安全有效的治疗这种严重疾病的目标。

DESCRIPTION (as provided by applicant): Food allergies have become a world-wide public health problem, and allergy to peanuts is particularly problematic. In the U.S., ingestion of offending food allergens is the single most common cause of anaphylaxis seen in hospital emergency departments, and it is estimated that about 30,000 food-induced anaphylactic events are seen in U.S. emergency departments each year; sadly, about 200 of these events prove fatal. Either peanuts or tree nuts cause the majority of these deaths, and a recent survey in the U.S. found that 1.4% of the population is allergic to peanuts or tree nuts. Prior trials of immune desensitization using traditional and rush allergen protocols in patients with peanut allergy (PA) have shown partial rates of response but, unfortunately, have resulted in high rates of adverse reactions, including anaphylaxis. Recently, landmark studies by Dr. A. Wesley Burks and colleagues have shown success in desensitizing peanut-allergic children to peanut via an oral immunotherapy (OIT) protocol. The Stanford Alliance for Food Allergy Research (SAFAR, pronounced "safer") is a multidisciplinary group whose goals are: 1) to develop and exploit state-of-the-art analytical methods, including advances in human immune monitoring, to improve understanding of the immune responses that give rise to food allergies and that underlie promising new approaches to treat this disorder, and 2) to contribute to the development and testing of improved approaches to diagnose, monitor, and treat subjects with food allergies. In this U19 application, we propose to conduct a large placebo-controlled, randomized, Phase 2 clinical trial of OIT in children and adults with PA and to measure a broad range of cellular, serologic, and clinical findings in longitudinal samples from PA patients undergoing the trial, as well as from appropriate control subjects (namely, groups of placebo-treated PA subjects, healthy controls, and atopic controls without PA). These data will be used to determine how key immune system parameters are altered during OIT, and which are most predictive of the nature and durability of patient responses to this therapy. In addition, we seek to define immune monitoring parameters, including findings derived from analyses of basophil phenotype and function that can be rapidly performed in a clinical laboratory using very small amounts of blood, that could be used to predict the clinical reactivity to peanut in PA subjects, to improve the safety and efficacy of OIT protocols, and/or to tailor the OIT protocol to each individual subject. We hope that such work will help to achieve the goal of devising a safe and effective curative treatment of this severe disorder.