Optimizing Tolerance Induction in Peanut Allergy: The DEVIL Study

描述（由申请人提供）：这份K23奖申请描述了杜克大学医学中心儿科过敏和免疫学部门的讲师Brian Vickery博士的职业发展计划。该奖项将为维克里博士提供必要的支持和培训，使其成为一名独立的儿童过敏性疾病的医师调查员。具体而言，该奖项将使Vickery博士能够实现以下目标：(1)掌握设计和执行临床试验所需的技能；（二）熟练掌握适用于纵向研究分析的高级生物统计学技能；(3)发展机械性免疫监测分析的专门知识；(4)实现独立的研究事业，开展高影响的以患者为导向的研究，重点研究基于免疫耐受的过敏性疾病治疗方法。为了实现这些目标，维克里博士组建了一个指导咨询委员会，由食物过敏和免疫耐受方面的国际专家韦斯利·伯克斯博士领导。Burks博士将领导其他具有丰富指导经验的知名研究人员团队，他们的科学兴趣包括基础和转化免疫学，儿科药理学和临床试验。维克里博士将在生物统计学、研究设计、药理学和先进的实验室方法方面提供高级教学课程，以补充这种密集的职业发展指导。花生过敏是一种严重且可能致命的免疫问题，影响了美国和其他发达国家约1%的儿童。如果没有有效的疾病改善治疗，患者会遭受严重的身体和心理疾病，包括生活质量的严重下降，这是由于危及生命的过敏反应始终存在的风险。根据最近的研究，强调了生命早期过敏反应的潜在可塑性，以及在这一关键时期口服暴露的作用。我们设计了一项单中心随机临床试验，对40名9 - 36个月新诊断为花生过敏的儿童进行低剂量和高剂量花生口服免疫疗法（OIT）的早期干预。该项目的目标是：通过在治疗期间短暂地改变反应性和降低过敏反应的风险（即脱敏），生产一种新的治疗方法，使花生过敏受试者迅速受益（目标一）；评估这种治疗随着时间的推移永久改变花生特异性免疫反应的能力，从而允许停止治疗（即耐受）（Aim I）；并了解其作用机制（目标二）。在提供临床研究指导培训经验的同时，这一创新试验直接关注了几个关键的知识空白，这些空白必须得到解决，以便开发出第一个临床可用的食物过敏治疗方法，并改变护理标准。这项工作的结果有可能改变花生过敏的治疗方式，通过开发一种安全、廉价、可行和有效的疾病改善疗法，可以立即提供给婴幼儿。该项目将研究花生口服免疫治疗对幼儿的早期干预，产生人类免疫耐受的重要新科学知识，并检查治疗对健康相关生活质量的影响。

DESCRIPTION (provided by applicant): This K23 award application describes a career development plan for Dr. Brian Vickery, an Instructor in the Division of Pediatric Allergy and Immunology at Duke University Medical Center. This award will provide Dr. Vickery with the necessary support and training to develop into an independent physician-investigator specializing in allergic disorders of childhood. Specifically, the award will enable Dr. Vickery to accomplish the following goals: (1) to master skills necessary to design and execute clinical trials; (2) to become proficient in advanced biostatistical skills suitable for analysis of longituinal studies; (3) to develop expertise in mechanistic immune monitoring assays; and (4) to achieve an independent research career conducting high-impact patient- oriented research focusing on immune tolerance-based therapies for allergic disorders. To accomplish these goals, Dr. Vickery has assembled a mentorship advisory committee led by Dr. Wesley Burks, an international expert in food allergy and immunological tolerance. Dr. Burks will lead a team of other renowned investigators with extensive mentorship experience, whose scientific interests collectively include basic and translational immunology, pediatric pharmacology, and clinical trials. Dr. Vickery will complement this intensive career development guidance with advanced didactic coursework in biostatistics, research design, pharmacology, and advanced laboratory methods. Peanut allergy is a severe and potentially fatal immunologic problem affecting approximately 1% of children in the U.S. and other developed nations. Without an effective disease-modifying therapy, patients suffer significant physical and psychological morbidity, including the profound reduction in quality of life that results from an ever-present risk of life-threatening anaphylaxis Based on recent studies highlighting the potential plasticity of allergic responses early in life, and the role of oral exposure during this critical period, we have designed a single-center randomized clinical trial to test early intervention with low-dose and high-dose peanut oral immunotherapy (OIT) in 40 newly diagnosed peanut-allergic children aged 9 - 36 months. The goals of this project are: to produce a new treatment that would rapidly benefit peanut-allergic subjects, by transiently altering reactivity and lowering the risk of anaphylaxis while on treatmen (i.e., desensitization) (Aim I); to assess the ability of this treatment to permanently alter the peanut-specific immune response over time, allowing discontinuation of therapy (i.e., tolerance) (Aim I); and to understand its mechanism of action (Aim II). While providing a mentored training experience in clinical research, this innovative trial focuses directly on several critical knowlede gaps that must be addressed in order to develop the first clinically available food allergy treatment and change the standard of care. The outcome of this work has the potential to change the way peanut allergy is treated, by developing a safe, inexpensive, feasible, and effective disease-modifying therapy that could be made immediately available to infants and toddlers. This project will study early intervention with peanut oral immunotherapy in young children, generate important new scientific knowledge of immunologic tolerance in humans, and examine the impact of treatment on health-related quality of life.