Functional and molecular changes in T cells in peanut allergy oral immunotherapy

花生过敏口服免疫治疗中 T 细胞的功能和分子变化

• 批准号: 8997970
• 负责人: Kari C. Nadeau
• 金额: $ 25.74万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8997970
• 关键词: Adult; Allergens; Allergic; Allergy to peanuts; Anaphylaxis; Autologous; Basophils; Biological Assay; Blood specimen; Cell Proliferation; Cell Separation; Cell physiology; Cells; Chemotaxis; Child; Clinical; Clinical Research; Control Groups; CpG Islands; DNA Methylation; Data; Development; Effector Cell; Epigenetic Process; Epithelial Cells; Epitopes; Exhibits; Exposure to; Favorable Clinical Outcome; Fire - disasters; Flow Cytometry; Food Hypersensitivity; Genes; Immune; Immune Tolerance; Immunologic Monitoring; Immunophenotyping; Immunotherapy; Individual; Instruction; Interferons; Interleukin-10; Interleukin-4; Intestines; Laboratories; Lead; Link; MHC Class II Genes; Maintenance; Measures; Memory; Methods; Methylation; Molecular; Outcome; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phase; Phase II Clinical Trials; Phenotype; Placebos; Population; Proteins; Protocols documentation; Reaction; Regulation; Regulatory T-Lymphocyte; Role; Safety; Site; Sorting - Cell Movement; Surface; T-Cell Immunologic Specificity; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Test Result; Testing; Time; Transcript; Work; anergy; base; cytokine; desensitization; food allergen; functional genomics; genetic analysis; improved; insight; interest; oral immunotherapy; oral tolerization; peripheral blood; phase 1 study; pyrosequencing; research study; response

PROJECT SUMMARY (See instructions): Peanut allergy (PA) Is an increasingly common form of food allergy associated with severe clinical reactions to peanut, Including fatal anaphylaxis. Recent studies in children (less than 18 years) have provided evidence that oral immunotherapy (OIT) can reduce the sensitivity of PA patients to peanut. However, it is not yet clear to what extent such patients have developed desensitization/non-tolerance, defined as a lack of clinical reactivity to peanut that requires ongoing exposure to peanut for this muted clinical reactivity to peanut to be maintained, as oppose to tolerance, in which the patient exhibits a long term and perhaps permanent loss of reactivity to peanut^"^. In the Phase 2 clinical trial of peanut OIT that will be conducted in Project 1 of this U19 proposal, we will determine which subjects develop desensitization/non-tolerance vs. tolerance to peanut. In this project, we will investigate changes in the T cell populations of PA subjects who respond to OIT, in order to identify changes that might contribute to the development of tolerance. We particularly will focus on changes in regulatory T cells (Treg) in PA patients who exhibit favorable responses to OIT. After characterizing and quantifying the modulation of T cell phenotype and function associated with peanut OIT, we will then test the results of these experiments for possible correlation with the development of tolerance vs. non-tolerance in PA patients who respond favorably to peanut OIT. Our main hypothesis is that memory T effector cells (Teff) specific to peanut allergen are converted Into Treg through epigenetic changes in the FOXPS locus that increase FOXPS expression, resulting In improved Treg function, as reflected In a Treg-dependent reduction of Teff proliferation in response to peanut. To test this hypothesis, we propose to: (Aim 1) Characterize the immunophenotypic and functional changes induced by OIT in specific T cell populations in patients with PA; (Aim 2) Quantify epigenetic changes (I.e., methylation of CpG islands) in key loci (i.e., F0XP3) to assess whether such changes are associated with enhancement of Treg function and favorable clinical outcomes in OIT; and (Aim 3) Use MHC class II multimer-based methods to characterize the specificity of T cell recognition of peanut peptides. If we achieve these aims, we expect our results to provide new insights into the mechanisms underlying tolerance to food allergens, and to Improve understanding ofthe immune changes that contribute to the durability and safety of oral Immunotherapy.

项目摘要（请参阅说明）： 花生过敏（PA）是一种越来越普遍的食物过敏形式，与包括致命过敏反应在内的花生的严重临床反应有关。最近对儿童（不到18岁）的研究提供了证据，表明口服免疫疗法（OIT）可以降低PA患者对花生的敏感性。 However, it is not yet clear to what extent such patients have developed desensitization/non-tolerance, defined as a lack of clinical reactivity to peanut that requires ongoing exposure to peanut for this muted clinical reactivity to peanut to be maintained, as oppose to tolerance, in which the patient exhibits a long term and perhaps permanent loss of reactivity to peanut^"^. In the Phase 2 clinical trial of peanut OIT that will be conducted在该U19的建议中，我们将确定哪些受试者在该项目中发展脱敏/不耐受性与耐受性。随后，我们将测试与花生OIT相关的T细胞表型和功能的调节，然后测试这些实验的结果，以与对花生OIT反应良好的PA患者的耐受性与不耐受性的发展相关。我们的主要假设是，特定于花生过敏原特异性的记忆T效应细胞（TEFF）通过FOXPS基因座的表观遗传变化转化为Treg，从而增加FOXPS表达，从而改善Treg功能，这反映在Treg依赖于Teff增殖的响应中，这反映了对花生的响应。为了检验这一假设，我们建议：（ AIM 1）表征PA患者在特定T细胞群体中OIT引起的免疫表型和功能变化； （AIM 2）量化关键基因座（即F0XP3）的表观遗传变化（即CpG岛的甲基化），以评估此类变化是否与Treg功能的增强和OIT中有利的临床结果有关； （AIM 3）使用MHC II类基于多聚机的方法来表征T细胞识别花生肽的特异性。如果我们实现这些目标，我们希望我们的结果可以为食物过敏原耐受性提供新的见解，并提高对有助于口服免疫疗法的耐用性和安全性的免疫变化的理解。