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: 8462368
• 负责人: Stephen Joseph Galli
• 金额: $ 163.48万
• 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/8462368
• 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（由申请人提供）：食物过敏已成为世界范围的公共卫生问题，其中对花生过敏尤其成问题。在美国，摄入有害的食物过敏原是医院急诊科发生过敏反应的最常见原因，据估计，美国急诊科每年会发生约 30,000 起由食物引起的过敏事件；遗憾的是，其中约 200 起事件被证明是致命的。其中大部分死亡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。先前对花生过敏（PA）患者使用传统和灯心过敏原方案进行免疫脱敏试验显示出部分反应率，但不幸的是，导致了包括过敏反应在内的高不良反应发生率。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，通过口服免疫疗法 (OIT) 方案成功地使花生过敏儿童对花生脱敏。斯坦福食物过敏研究联盟（SAFAR，读作“更安全”）是一个多学科团体，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步，以提高对引起食物过敏的免疫反应的理解，并为治疗这种疾病的有希望的新方法奠定基础；2）为改进诊断方法的开发和测试做出贡献， 监测和治疗食物过敏的受试者。在此 U19 申请中，我们建议对患有 PA 的儿童和成人进行一项大型安慰剂对照、随机、2 期 OIT 临床试验，并测量接受试验的 PA 患者以及适当对照受试者（即安慰剂治疗的 PA 受试者组、健康对照和无 PA 的特应性对照）的纵向样本的广泛细胞、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，以及哪些最能预测患者对该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极少量的血液快速进行，可用于预测临床反应性 PA 受试者中的花生，以提高 OIT 方案的安全性和有效性，和/或定制 每个受试者的 OIT 协议。我们希望此类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。 相关性：花生过敏 (PA) 是一种日益常见的疾病，可导致儿童和成人严重疾病和死亡。我们将使用 DNA 测序、免疫监测和数据分析的创新方法来研究 PA 的影响因素，并提高我们操纵免疫系统来治愈 PA 受试者的能力。我们还将尝试开发快速血液检测，用于为每位 PA 患者制定治疗方案，以提高治疗的安全性和有效性。 项目 1：对花生过敏的儿童和成人诱导不耐受与耐受 项目负责人 (PL)：Nadeau, Kari 描述（由申请人提供）：花生过敏（PA）是一种严重的食物过敏，需要改进的治疗方法。然而，很少有研究来优化口服免疫疗法 (OIT) 治疗 PA 的安全性，根据个别 PA 患者的需求定制 OIT 方案，或确定口服免疫疗法 (OIT) 对此类受试者产生长期影响的免疫机制。具体来说，目前尚不清楚哪些因素将决定个体受试者中 OIT 是否会引起耐受性（其中不规定每日使用该食物过敏原） 需要考虑到其安全消费）。为了应对这些挑战，斯坦福食物过敏研究联盟 (SAFAR) 计划将项目 1 中提出的 2 期临床研究的结果与 U19 提案中侧重于机制研究的其他三个项目（项目 2、3 和 4）的结果以及科学核心 B 进行的免疫指标分析的结果联系起来。这些项目和核心 B 中的每一个都将使用项目 1 在筛选和筛选时收集的患者样本。 在整个临床研究中纵向整合所有数据。我们为项目 1 提出了三个主要研究目标： 具体目标 1：测试 PA 患者的 OIT 治疗是否能够实现耐受性（即，允许受试者[在“避免期”]停止维持摄入花生三个月或更长时间，但随后仍然成功地接受花生双盲安慰剂对照食物挑战 [DBPCFC]）。具体目标 2：确定我们的 OIT 方案治疗对于患有花生过敏 (PA) 的儿童和成人是否安全。具体目标 3：评估当前实验室和临床测试方法与 PA 受试者的安全性和耐受性结果（如具体目标 1 和 2 中确定的）相关的程度。通过追求这些目标，我们将：1）提供临床样本和临床结果数据，这将 允许完成本 U19 申请中提出的创新免疫监测和机制研究，以及 2) 确定执行此类免疫监测是否有可能为个体 PA 患者个体化和优化安全有效的 OIT 方案。 相关性：食物过敏是儿童和成人的一种重要疾病，需要改进的治疗。我们提出了一项研究，以测试患有最危险的食物过敏之一——花生过敏的成人和儿童患者在接受口服免疫治疗方案后是否能够对花生产生耐受性，以便他们能够安全地食用花生。