Integrated Genomic and Functional Studies of Tolerance Therapy for Peanut Allerg

花生过敏耐受疗法的综合基因组和功能研究

• 批准号: 8605841
• 负责人: Stephen Joseph Galli
• 金额: $ 172.24万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605841
• 关键词: Accident and Emergency department; Address; Adult; Adverse reactions; Allergens; Allergic; Allergy to peanuts; Anaphylaxis; Basophils; Biological Assay; Blood; Blood Tests; Cessation of life; Child; Childhood; Clinical; Clinical Research; Consumption; DNA Sequence; Data; Data Analyses; Development; Diagnosis; Disease; Double-Blind Method; Eating; Event; Food; Food Hypersensitivity; Goals; Hospitals; Human; Immune; Immune response; Immune system; Immunologic Monitoring; Individual; Ingestion; Laboratories; Link; Maintenance; Measures; Methods; Metric; Monitor; Nature; Nuts; Outcome; Patients; Peanuts - dietary; Phase; Phase II Clinical Trials; Phenotype; Placebo Control; Placebos; Population; Protocols documentation; Public Health; Randomized; Regimen; Research; Research Project Grants; Safety; Sampling; Serological; Surveys; Testing; Trees; Work; analytical method; desensitization; food allergen; food challenge; functional genomics; improved; innovation; multidisciplinary; novel strategies; oral immunotherapy; research clinical testing; response; screening; success

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. RELEVANCE: Peanut allergy (PA) is an increasingly common disorder which can cause serious illness and death in children and adults. We will use Innovative approaches for DNA sequencing, immune monitoring, and data analysis to investigate factors responsible for PA and to improve our ability to manipulate the immune system to cure subjects of PA. We will also try to develop rapid blood tests that can be used to tailor treatment for each individual patient with PA in order to improve the safety and efficacy of such treatment. Project 1: Induction of non-tolerance vs. tolerance in children and adults with peanut allergy Project Leader (PL): Nadeau, Kari DESCRIPTION (as provided by applicant): Peanut allergy (PA) is a severe form of food allergy for which improved treatments are needed. However, few studies have been conducted to optimize the safety of oral immunotherapy (OIT) for PA, to tailor OIT protocols according to the needs of individual PA patients, or to identify the immunological mechanism(s) underlying any long-lasting effects of oral immunotherapy (OIT) in such subjects. Specifically, it is not yet clear what factors will determine, in individual subjects, whether OIT induces tolerance (in which no set daily use of that food allergen is needed to allow for its safe consumption). To address these challenges, the Stanford Alliance for Food Allergy Research (SAFAR) plans to link the findings of the Phase 2 clinical study proposed here in Project 1 with the results of each of the other three projects of the U19 proposal focused on mechanistic studies (Projects 2, 3 & 4), as well as with the results of the immune metrics assays carried out by Scientific Core B. Each of these projects and Core B will use patient samples from Project 1 collected at screening and longitudinally throughout the clinical study to integrate all data. We propose three main goals of our research for Project 1: Specific Aim 1: Test whether treatment of PA patients with OIT allows tolerance to be achieved (i.e., allows the subject to stop maintenance ingestion of peanut [during an "avoidance period"] for three months or more but then still undergo a successful double-blind placebo-controlled food challenge [DBPCFC] with peanut). Specific Aim 2: Determine whether treatment with our OIT protocol is safe in children and adults with peanut allergy (PA). Specific Aim 3: Evaluate to what degree current laboratory and clinical testing methods are associated with safety and tolerance outcomes (as identified in Specific Aims 1 and 2) in subjects with PA. By pursuing these aims, we will both: 1) provide the clinical samples, and the clinical outcome data, that will permit the innovative immune monitoring and mechanistic studies proposed in this U19 application to be accomplished, and 2) determine whether performing such immune monitoring has the potential to permit Individualization and optimization of safe and efficacious OIT protocols for individual PA patients. RELEVANCE: Food allergy is an important disease of children and adults that is in need of improved therapy. We propose a study to test whether adult and pediatric patients with one of the most dangerous food allergies, peanut allergy, can become tolerant to peanuts after an oral immunotherapy regimen so that they may be able to eat peanut safely.

描述（如申请人提供）：食物过敏已成为全球公共卫生问题，对花生的过敏尤其有问题。在美国，摄入冒犯食物过敏原是医院急诊室中过敏反应的最常见原因，据估计，每年在美国急诊室中看到约30,000例食物引起的过敏反应；可悲的是，其中约200个事件证明是致命的。花生或树坚果会导致大多数这些死亡，最近在美国进行的一项调查发现，1.4％的人口对花生或树坚果过敏。先前在花生过敏患者中使用传统和RUSH过敏原方案对免疫脱敏的试验（PA）显示出部分反应率，但不幸的是，包括过敏反应的不良反应率很高。最近，A。WesleyBurks及其同事的具有里程碑意义的研究表明，通过口服免疫疗法（OIT）方案使花生过敏儿童脱敏到花生方面的成功。斯坦福食品过敏研究联盟（Safar，明显的“更安全”）是一个多学科的群体，其目标是：1）开发和利用最新的分析方法，包括人体免疫监测的进步，以提高人们对免疫反应的理解，从而对食物过敏产生的免疫反应，并促进这种方法来探讨这种方法，以促进这种疾病的发展，并促进了该疾病的发展，并促进了2），并促进了2），并促进了2），并促进了2），并促进了2），并促进了2次促进的方法，并促进了2），并促进了2次促进的方法，并促进了2次促进的方法。监测并用食物过敏治疗受试者。在此U19应用中，我们建议在患有PA的儿童和成年人中对OIT进行大型安慰剂对照，随机，2阶段的临床试验，并测量来自正在进行该试验的PA患者的纵向患者中的纵向，纵向样本中的各种细胞，血清学和临床发现，以及来自适当的对照对象（以及不受适当对照的PA受试者的控制），以及由PA的控制，以及由PAPA的控制。这些 数据将用于确定OIT期间关键免疫系统参数如何改变，并且最能预测患者对该疗法的反应的性质和耐用性。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得出的发现，可以在临床实验室中使用非常少量的血液进行迅速进行，这些血液可用于预测临床反应性 在PA受试者中花生，以提高OIT方案的安全性和功效，和/或量身定制 对每个主题的OIT协议。我们希望这样的工作将有助于实现对这种严重疾病进行安全有效治疗治疗的目标。 相关性：花生过敏（PA）是一种日益常见的疾病，可能导致儿童和成人严重疾病和死亡。我们将使用创新方法来进行DNA测序，免疫监测和数据分析来研究负责PA的因素，并提高我们操纵免疫系统以治愈PA受试者的能力。我们还将尝试开发快速的血液检查，可用于为每个患有PA的患者调整治疗，以提高这种治疗的安全性和功效。 项目1：患有花生过敏的儿童和成人的不耐受性与公差 项目负责人（PL）：纳多，卡里 描述（申请人提供）：花生过敏（PA）是一种严重的食物过敏，需要改善治疗方法。但是，很少有研究以优化PA的口服免疫疗法（OIT）的安全性，根据单个PA患者的需求来量身定制OIT方案，或者确定在此类受试者中口服免疫疗法（OIT）持久影响的免疫机制。具体而言，尚不清楚在单个受试者中，OIT是否会诱发公差（在这种情况下，没有日常使用该食物过敏原是什么因素 需要允许其安全的消费）。为了应对这些挑战，斯坦福食品过敏研究联盟（SAFAR）计划将项目1的2阶段临床研究结果与U19建议的其他三个项目的结果联系起来，该提议的其他三个项目的侧重于机械研究（项目2、3＆4）（项目2、3＆4），以及从科学的核心项目和核心核心范围内进行的B.在整个临床研究中纵向整合所有数据。我们提出了针对项目1的研究的三个主要目标：特定目标1：测试对OIT患者的治疗是否可以实现宽容（即，允许受试者停止对花生的维持[在“避免期间”或更长时间[在“避免时期”中），但随后仍然经历了成功的双打安慰剂控制食品挑战[DBPCFC]。具体目标2：确定我们的OIT方案的治疗是否在患有花生过敏（PA）的儿童和成人中是安全的。特定目的3：评估当前实验室和临床测试方法与患有PA受试者的安全性和耐受性结果（如特定目标1和2中所示）有关。通过追求这些目标，我们将俩：1）提供临床样本和临床结果数据，将 允许在本应用U19应用中提出的创新免疫监测和机理研究，2）确定执行这种免疫监测是否有可能允许个体化和优化对个别PA患者的安全有效的OIT方案。 相关性：食物过敏是需要改善治疗的儿童和成人的重要疾病。我们提出了一项研究，以测试成人和儿科患者患有最危险的食物过敏之一，花生过敏，在口服免疫疗法治疗方案后可以耐受花生的耐受性，以便他们可以安全地吃花生。