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出现过敏反应的最常见原因，据估计，美国急诊科每年约有3万起由食物引起的过敏事件；可悲的是，其中约200起事件被证明是致命的。这些死亡中的大部分是花生或坚果造成的，美国最近的一项调查发现，1.4%的人口对花生或坚果过敏。先前使用传统和快速变应原方案对花生过敏(PA)患者进行的免疫脱敏试验显示了部分应答率，但不幸的是，导致了高发生率的不良反应，包括过敏反应。最近，由A.Wesley Burks博士和他的同事进行的里程碑式的研究表明，通过口服免疫疗法(OIT)方案成功地使花生过敏儿童对花生脱敏。 斯坦福食品过敏研究联盟(SAFAR)是一个多学科的组织，其目标是：1)开发和利用最先进的分析方法，包括人类免疫监测的进展，以提高对引起食物过敏的免疫反应的了解，并为治疗这种疾病的有希望的新方法奠定基础；2)促进诊断、监测和治疗食物过敏对象的改进方法的开发和测试。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OIT的大型安慰剂对照、随机、2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、健康对照组和没有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。这些数据将被用来确定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这种疗法的反应的性质和持久性。此外，我们寻求定义免疫监测参数，包括从临床实验室使用非常少量的血液即可快速执行的嗜碱性粒细胞表型和功能分析得出的结果，这些参数可用于预测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/或为每个个体受试者量身定制OIT方案。我们希望，这项工作将有助于实现为这一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.