Threshold, Severity, and Immunotherapy of Peanut Allergy

摘要 近几十年来，花生过敏的患病率增加了两倍，在美国一些地区，高达5%的儿童受到影响。 花生过敏通常是终生的，可能是致命的，并影响生活质量。这些因素支持我们的理论基础。 继续研究花生过敏，以更新我们的AADCRC。我们的应用程序解决了几个未满足的问题 花生过敏研究和护理方面的需求。无法预测的花生过敏反应的严重程度是一种负担 对于受影响的个人。目前的检测方法在预测反应严重程度方面的效用有限。扩展我们的 从机理上认识反应严重程度是指导花生更好处理的关键 过敏。尽管口服免疫疗法(Oit)正在临床上用于脱敏，但只有一种产品 为低门槛儿童设计的药物已获批准，对治疗的反应具有很大的变数。初步 我们目前AADCRC(2018-2023年)内的一项随机临床试验的结果支持，有一个共同的 易治疗的高阈值花生过敏表型。所有完成大剂量花生注射的人 在我们的试验中，黄油OIT在OIT后持续无反应，没有任何不良反应 效果。类似于之前西奈山AADCRC对烘焙鸡蛋和烘焙的研究带来的革命性影响 牛奶对鸡蛋和牛奶过敏的治疗和了解，我们目前AADCRC的发现可以 改变全球约50%对花生过敏的高阈值患者的花生过敏治疗方法。这些 研究结果还强调，需要进一步的研究来了解oit和oit背后的机制。 跨阈值频谱的响应。不同的结果激发了对所有人的检查 OIT的阈值，以确定可用于个性化治疗的内型。下一阶段 西奈山AADCRC将是一个双核心、双项目方案，重点关注以下新问题 花生过敏的反应严重程度、阈值和免疫治疗。我们将解决我们的总体假设，即 循环细胞亚群、分子网络和代谢途径的动态变化 花生反应的严重程度和对OIT的反应在机理上是相关的。我们将协同西奈山的切割 通过临床核心(路径)和管理核心的EDGE临床OIT计划，具有两个互补性 研究项目(Rosetta和Impala)，将扩展对反应严重性、阈值和 花生过敏的免疫治疗。我们将在血液样本时间序列分析的创新基础上再接再厉 从接受双盲、安慰剂控制的食物挑战的儿童到研究所有阈值的受试者 以确定OIT前后反应严重程度的体内机制。Rosetta将利用 转录组学和系统生物学，以揭示反应严重性、OIT和内型的潜在机制 对OIT的回应。黑斑羚将通过细胞和途径特异性研究来补充这一努力，以扩大我们的 对过敏反应中先天免疫的认识。我们的综合计划将丰富机械 认识花生过敏，推进个体化用药，找出花生过敏治疗新靶点。

SUMMARY Peanut allergy has tripled in prevalence in recent decades, affecting up to 5% of children in some US regions. Peanut allergy is typically life-long, can be fatal, and impacts quality of life. These factors support our rationale to continue studying peanut allergy for this renewal of our AADCRC. Our application addresses several unmet needs in peanut allergy research and care. The unpredictable severity of peanut allergic reactions is a burden for affected individuals. Current assays have limited utility in predicting reaction severity. Expanding our mechanistic understanding of reaction severity is an essential step for guiding better treatment for peanut allergy. Although oral immunotherapy (OIT) is gaining clinical use for desensitization, only one product designed for low-threshold children is approved, and response to treatment is highly variable. Preliminary results from a randomized clinical trial within our current AADCRC (2018-2023) support that there is a common phenotype of high-threshold peanut allergy that is easy to treat. All who have completed high-dose peanut butter OIT in our trial have demonstrated sustained unresponsiveness following OIT without any adverse effects. Similar to the revolutionizing impact that prior Mount Sinai AADCRC studies of baked egg and baked milk had on the treatment and understanding of egg and milk allergy, our current AADCRC’s findings could alter the approach to peanut allergy worldwide for the ~50% who have high threshold peanut allergy. These findings also emphasize that further research is needed to understand mechanisms underlying OIT and OIT response across the threshold spectrum. The contrasting outcomes motivate examination of individuals of all thresholds undergoing OIT to identify endotypes that can be used to personalize treatment. The next stage of the Mount Sinai AADCRC will be a dual core, dual project program that focuses on new questions about reaction severity, threshold, and immunotherapy of peanut allergy. We will address our overall hypothesis that dynamic changes in circulating cellular subpopulations, molecular networks, and metabolic pathways are mechanistically linked to peanut reaction severity and response to OIT. We will synergize Mount Sinai’s cutting edge clinical OIT program via a clinical core (PATHWAYS) and administrative core with two complementary research projects (ROSETTA and IMPALA) that will extend understandings of reaction severity, threshold, and immunotherapy of peanut allergy. We will build on our innovation of assaying time series of blood samples from children undergoing double-blind, placebo-controlled food challenges to study subjects of all thresholds before and after OIT to identify in vivo mechanisms of reaction severity. ROSETTA will leverage integrative transcriptomics and systems biology to uncover mechanisms underlying reaction severity, OIT, and endotypes of OIT response. IMPALA will complement this effort with cell- and pathway-specific studies to expand our understanding of innate immunity in anaphylaxis. Our integrated program will enrich mechanistic understandings, advance personalized medicine, and identify new therapeutic targets for peanut allergy.