Effects of IgE Blockade on T Cells in Food Allergy

IgE 阻断对食物过敏中 T 细胞的影响

• 批准号: 10199745
• 负责人: Kari C. Nadeau
• 金额: $ 39.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-16 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199745
• 关键词: ATAC-seq; Age; Allergens; Allergic; Allergic Reaction; Anaphylaxis; Antigens; Biological Assay; Biological Markers; Cell physiology; Cells; Chromatin Structure; Clinical; CpG Islands; Cytometry; DNA Methylation; Data; Development; Epigenetic Process; Exhibits; FOXP3 gene; Food; Food Hypersensitivity; Genes; Genetic Transcription; Hypersensitivity; IL4 gene; IgE; IgG4; Immune; Immunologic Markers; Immunologics; Immunophenotyping; Immunotherapy; Individual; Ingestion; Interferon Type II; Interleukin-10; Laboratories; Lead; Link; MHC Class II Genes; Mediating; Methods; Methylation; Molecular Cloning; Molecular Profiling; Outcome; Participant; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Play; Population; Protocols documentation; Randomized; Reaction; Regulatory T-Lymphocyte; Reporting; Resolution; Risk; Role; Safety; Sampling; Site; Surface; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transcript; Work; Xolair; anergy; anti-IgE; antigen-specific T cells; base; cohort; desensitization; efficacy evaluation; feeding; food allergen; innovation; insight; interest; novel; omalizumab; oral immunotherapy; peripheral blood; phase 2 study; pyrosequencing; sex; transcriptome sequencing

Project Summary: Effects of IgE Blockade on T Cells in Food Allergy Food allergies can lead to near-fatal or fatal anaphylaxis. Approximately 30% of food allergic individuals have multiple food allergies. Although many studies have evaluated the efficacy of oral immunotherapy (OIT) for single foods, studies evaluating OIT to multiple foods (multi-OIT) have been limited due to efficacy and safety concerns. Multifood allergic individuals could benefit from treatment, and omalizumab (anti-IgE blockade therapy) potentially mitigates their risk for IgE-mediated allergic reactions. A few groups, including ours, have demonstrated important immunophenotypic and functional biomarker changes induced by single-allergen OIT in T cell subsets. The salient findings from these reports show: increases in the numbers and function of regulatory T cells (Treg); reprogramming of T helper 2 cells (Th2) to the T helper 1 (Th1) subtype; and anergy in allergen-specific Th2 cells. It is of great interest to identify T cell immune biomarker changes while multi-OIT is given to multi-allergic individuals to track desensitization, a lack of clinical reactivity with regular antigen (Ag) exposure, as distinct from sustained unresponsiveness, in which the patient exhibits a long-term and perhaps permanent loss of reactivity to Ag that is independent of continued Ag exposure. Therefore, we have performed a randomized, controlled, phase 2 study in a cohort of multifood allergic participants (Multi Immunotherapy to Test Tolerance and Xolair, ClinicalTrials.gov Identifier: NCT02626611, n=70 participants): peripheral blood mononuclear cells and plasma samples were collected and stored throughout the duration of study. We propose to use these samples and two sets of matched controls for this project. Our main hypothesis is that multi-OIT results in marked downmodulation of Th2 function and concomitant enhancement in Th1 and Treg function, and that these changes will be associated with sustained unresponsiveness and, to a lesser extent, desensitization. To test this hypothesis, we propose to: (Aim 1) Characterize the immunophenotypic and functional changes induced by multi-OIT in total and allergen-specific T cell populations in multi-allergic study participants; (Aim 2) Use MHC class II multimer-based methods to sort allergen-specific single cells, and perform targeted RNA-Seq to investigate their molecular signatures and clonal ancestry at single-cell resolution; and (Aim 3) Quantify epigenetic changes (i.e., methylation of CpG islands) in key genes (i.e., FOXP3, IL4, IFNg, IL10) to assess possible links between the methylation and the desensitization and sustained unresponsiveness resulting from OIT. The results from this study of T cell phenotype, function and epigenetics will enable us: to identify which of these immune features will be most useful as signatures of multi-OIT-induced desensitization and sustained unresponsiveness; to identify patterns of changes in T cells that are associated with these distinct clinical outcomes of multi-OIT; and to determine how these patterns are modified by adding treatment with omalizumab to the multi-OIT protocol.

项目摘要：IgE封锁对食物过敏中T细胞的影响 食物过敏会导致近乎致命或致命的过敏反应。大约30％的食物过敏患者有 多种食物过敏。尽管许多研究已经评估了口服免疫疗法（OIT）的功效 单一食品，评估OIT的多种食品（多OIT）的研究受到限制，这是由于功效和安全性而受到限制 关注。多病态过敏的人可以从治疗中受益，而omalizumab（抗IGE封锁 治疗）可能会减轻它们对IgE介导的过敏反应的风险。包括我们在内的几个小组 证明了由单过敏原OIT诱导的重要免疫表型和功能性生物标志物变化 在T细胞子集中。这些报告中的显着发现显示：增加的数量和功能 调节性T细胞（Treg）；将T辅助2细胞（Th2）重新编程为T辅助1（Th1）亚型；和Anergy In 过敏原特异性Th2细胞。识别T细胞免疫生物标志物变化而多OIT是非常有趣的 给予多过敏个体跟踪脱敏的脱敏，缺乏常规抗原（AG）的临床反应性 暴露与持续的无响应性不同，患者长期表现出来 对AG的反应性永久丧失，与持续AG暴露无关。因此，我们有 在多病态过敏参与者队列中进行了随机，受控的2阶段研究 免疫疗法测试耐受性和Xolair，临床。 在整个持续时间内收集并存储外周血单核细胞和血浆样品 学习。我们建议将这些样本和两组匹配的控件用于此项目。 我们的主要假设是多OIT导致TH2功能和随之而来的显着下调 TH1和Treg功能的增强，这些变化将与持续 反应迟钝，并且在较小程度上脱敏。为了检验这一假设，我们建议：（目标1） 表征多OIT在总和特异性的多OIT引起的免疫表型和功能变化 多过敏性研究参与者的T细胞群体； （AIM 2）使用MHC II类基于多聚机的方法进行排序 过敏原特异性单细胞，并执行靶向RNA-Seq以研究其分子特征和 单细胞分辨率的克隆血统； （AIM 3）量化表观遗传变化（即CpG的甲基化 岛屿）中的关键基因（即Foxp3，IL4，IFNG，IL10）评估甲基化与甲基化之间的可能联系 OIT导致的脱敏和持续的无反应性。 这项T细胞表型，功能和表观遗传学研究的结果将使我们能够确定哪些 这些免疫特征将是多OIT诱导的脱敏和持续的特征 反应迟钝；确定与这些不同临床相关的T细胞变化模式 多OIT的结果；并通过添加处理方法来确定如何修改这些模式 Omalizumab到多OIT方案。

项目成果

Early peanut introduction wins over the HLA-DQA1*01:02 allele in the interplay between environment and genetics.

• DOI: 10.1172/jci155609
• 发表时间: 2022-01-04
• 期刊: The Journal of clinical investigation
• 作者: Manohar M;Nadeau KC;Kasowski M
• 通讯作者: Kasowski M

The importance of the 2S albumins for allergenicity and cross-reactivity of peanuts, tree nuts, and sesame seeds.

• DOI: 10.1016/j.jaci.2020.11.004
• 发表时间: 2021-04
• 期刊: The Journal of allergy and clinical immunology
• 作者: Dreskin SC;Koppelman SJ;Andorf S;Nadeau KC;Kalra A;Braun W;Negi SS;Chen X;Schein CH
• 通讯作者: Schein CH

Cytometric analysis reveals an association between allergen-responsive natural killer cells and human peanut allergy.

• DOI: 10.1172/jci157962
• 发表时间: 2022-10-17
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Zhou, Xiaoying;Yu, Wong;Dunham, Diane M.;Schuetz, Jackson P.;Blish, Catherine A.;DeKruyff, Rosemarie H.;Nadeau, Kari C.
• 通讯作者: Nadeau, Kari C.

A positive feedback loop reinforces the allergic immune response in human peanut allergy.

• DOI: 10.1084/jem.20201793
• 发表时间: 2021-07-05
• 期刊: The Journal of experimental medicine
• 作者: Zhou X;Yu W;Lyu SC;Macaubas C;Bunning B;He Z;Mellins ED;Nadeau KC
• 通讯作者: Nadeau KC