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Threshold, Severity, and Immunotherapy of Peanut Allergy

花生过敏的阈值、严重程度和免疫治疗

基本信息

批准号：
10635811
负责人：
Supinda Bunyavanich
金额：
$ 46.59万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-06 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10635811
关键词：
Address Adult Adverse effects Affect Allergic Allergic Reaction Allergy to eggs Allergy to peanuts Anaphylaxis B-Lymphocytes Basophils Biological Assay Blood Platelets Blood specimen CD4 Positive T Lymphocytes Caring Cells Characteristics Child Clinical Clinical Research Clinical Trials Communication Communities Complement Complex Data Dose Double-Blind Method Enrollment Flow Cytometry Food Food Hypersensitivity Gene Expression Genes Hypersensitivity Immune Immunotherapy Individual Innate Immune Response Interruption Investigation Link Metabolic Pathway Milk Milk Hypersensitivity Modeling Molecular Natural Immunity Oral Outcome Participant Pathway Analysis Pathway interactions Phase Phenotype Placebo Control Prevalence Proteins Quality of life Randomized Reaction Research Research Activity Research Project Grants Resources Role Safety Series Serious Adverse Event Serotonin Severities Shapes Study Subject Systems Biology Therapeutic Time desensitization design egg experience food challenge high dimensionality immune activation in vivo innate immune mechanisms innate immune pathways innovation insight multimodality neutrophil new therapeutic target novel oral immunotherapy peanut butter peripheral blood personalized medicine programs randomized, clinical trials response success synergism transcriptome transcriptomics translational study treatment response

项目摘要

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.

总结近几十年来，花生过敏的患病率增加了两倍，影响了美国一些地区高达5%的儿童。花生过敏通常是终身的，可能是致命的，并影响生活质量。这些因素支持我们的理论继续研究花生过敏症，以更新我们的AADCRC。我们的应用程序解决了几个未满足的花生过敏研究和护理的需求。花生过敏反应的不可预测的严重程度是一个负担为受影响的个人。目前的测定在预测反应严重性方面的效用有限。扩大我们对反应严重程度的机理理解是指导花生更好处理的必要步骤过敏尽管口服免疫疗法（OIT）正在获得脱敏的临床应用，但只有一种产品为低门槛儿童设计的药物获得批准，对治疗的反应是高度可变的。初步我们目前的AADCRC（2018-2023）中的一项随机临床试验的结果支持，容易治疗的高阈值花生过敏表型。所有完成高剂量花生在我们的试验中，黄油OIT显示了OIT后持续的无反应性，没有任何不良反应。方面的影响.类似于之前西奈山AADCRC对烤鸡蛋和烤面包的研究的革命性影响，牛奶对鸡蛋和牛奶过敏的治疗和理解，我们目前的AADCRC的研究结果可以改变全球范围内对花生过敏的方法，约50%的人患有高阈值花生过敏。这些研究结果还强调，需要进一步的研究来了解OIT和OIT的潜在机制在整个阈值范围内的响应。对比的结果激发了对所有人的检查阈值进行OIT，以识别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、双项目计划，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。我们将讨论我们的总体假设，循环细胞亚群、分子网络和代谢途径的动态变化，与花生反应的严重程度和对OIT的反应有关。我们会把西奈山的砍伐边缘临床OIT计划通过临床核心（路径）和行政核心，两个互补研究项目（ROSETTA和IMPALA），将扩大对反应严重性，阈值，花生过敏的免疫疗法我们将在分析血液样本时间序列的创新基础上从接受双盲、安慰剂对照食物挑战的儿童到所有阈值的研究受试者在OIT之前和之后，以确定反应严重程度的体内机制。ROSETTA将利用整合转录组学和系统生物学，以揭示反应严重性，OIT和内型的潜在机制的OIT响应。IMPALA将通过细胞和通路特异性研究来补充这一努力，以扩大我们的研究范围。对过敏反应中先天免疫的理解。我们的综合计划将丰富机械研究人员还发现，这些研究有助于提高认识，推进个性化医疗，并确定花生过敏症的新治疗靶点。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Predicting probability of tolerating discrete amounts of peanut protein in allergic children using epitope-specific IgE antibody profiling.

DOI：
10.1111/all.15477
发表时间：
2022-10
期刊：
ALLERGY
影响因子：
12.4
作者：
Suprun, Maria;Kearney, Paul;Hayward, Clive;Butler, Heather;Getts, Robert;Sicherer, Scott H.;Turner, Paul J.;Campbell, Dianne E.;Sampson, Hugh A.
通讯作者：
Sampson, Hugh A.

JAK1 inhibition with abrocitinib decreases allergen-specific basophil and T-cell activation in pediatric peanut allergy.

使用 abrocitinib 抑制 JAK1 可降低儿童花生过敏中过敏原特异性嗜碱性粒细胞和 T 细胞的活化。

DOI：
10.1016/j.jacig.2023.100103
发表时间：
2023
期刊：
The journal of allergy and clinical immunology. Global
影响因子：
0
作者：
Ramsey,Nicole;Kazmi,Wajiha;Phelan,Matthew;Lozano-Ojalvo,Daniel;Berin,MCecilia
通讯作者：
Berin,MCecilia

Acute FPIES reactions are associated with an IL-17 inflammatory signature.