Integrated Genomic and Functional Studies of Tolerance Therapy for Peanut Allerg

食物过敏已成为一个世界性的公共卫生问题，对花生的过敏尤其成问题。在美国，摄入有害的食物过敏原是医院急诊室中出现的过敏反应的最常见的单一原因，据估计，每年在美国急诊室中出现约30，000起食物引起的过敏事件;不幸的是，这些事件中约有200起证明是致命的。花生或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%的人口对花生或坚果过敏。在花生过敏（PA）患者中使用传统和快速过敏原方案进行免疫脱敏的先前试验显示了部分反应率，但不幸的是，导致了高比例的不良反应，包括过敏反应。最近，A. Wesley Burks及其同事通过口服免疫治疗（OIT）方案成功地使花生过敏儿童对花生脱敏。 斯坦福大学食物过敏研究联盟（SAFAR，发音为“更安全”）是一个多学科小组，其目标是：1）开发和利用最先进的分析方法，包括人类免疫监测的进展，以提高对引起食物过敏的免疫反应的理解，并成为治疗这种疾病的有希望的新方法的基础，和2）有助于开发和测试诊断、监测和治疗食物过敏受试者的改进方法。在本U19申请中，我们建议在PA儿童和成人中进行一项大型安慰剂对照、随机、2期OIT临床试验，并测量来自接受试验的PA患者以及适当对照受试者（即安慰剂治疗的PA受试者、健康对照和未接受PA的特应性对照组）的纵向样本中的广泛细胞、血清学和临床结果。这些数据将用于确定关键免疫系统参数在OIT期间如何改变，以及哪些参数最能预测患者对该疗法的反应的性质和持久性。此外，我们试图定义免疫监测参数，包括来自嗜碱性粒细胞表型和功能分析的结果，这些结果可以在临床实验室中使用非常少量的血液快速进行，可以用于预测PA受试者对花生的临床反应性，以提高OIT方案的安全性和有效性，和/或为每个个体受试者定制OIT方案。我们希望这项工作将有助于实现为这种严重疾病设计安全有效的治疗方法的目标。

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 ofthe 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.