Interplay of the T Cell Repertoire Development and Early Life Exposure on Incident Risk of Peanut Allergy

T 细胞库发育和生命早期接触对花生过敏事件风险的相互作用

基本信息

批准号：
10742029
负责人：
Xiumei Hong
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-03 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10742029
关键词：
Adaptive Immune System Adult Affect Age Alleles Allergens Allergic Allergy to peanuts Antigens Attention Bar Codes Biological Assay Birth Black race Boston Breast Breast Feeding CD4 Positive T Lymphocytes Cells Child Childhood Clinical Cohort Studies DNA Data Databases Development Epidemiology Ethics Exposure to Folic Acid Food Hypersensitivity Funding Genetic Risk Genotype Goals HLA Antigens Haplotypes Histocompatibility Antigens Class II Hypersensitivity Immune response Immunity Individual Infant Intervention Investigation Joints Latinx Life Mediating Metabolic Metabolism Molecular Monitor Not Hispanic or Latino Nutritional Nutritional status Peripheral Blood Mononuclear Cell Play Population Prevalence Probability Public Health Regulatory T-Lymphocyte Reporting Research Resources Risk Risk Assessment Risk Factors Role Sampling Sorting Specificity Systems Development T cell receptor repertoire sequencing T-Cell Activation T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Technology Thymus Gland Time United States National Institutes of Health Vitamin D Work beta Chain Antigen T Cell Receptor biological specimen archives clinical database cohort complementarity-determining region 3 cost design early childhood early detection biomarkers early life exposure effective intervention effector T cell feeding genetic variant genome wide association study genome-wide high risk in utero metabolome metabolomics minority children multi-ethnic multidisciplinary multiple omics novel novel marker nutrition postnatal development prospective protective factors response risk prediction

项目摘要

ABSTRACT Peanut allergy (PA) has emerged as a major clinical and public health problem worldwide, due to the dramatic increase in prevalence, its life-long persistence in most cases, and its associated life-threatening anaphylactic response. The causes and precise molecular mechanisms underlying the development of PA remain largely unknown. Available data underscore the early life period (i.e., in-utero and first few years of life) as the critical window in the development of PA, which is also the critical developmental window for the adaptive immune system. There is increasing evidence that T cells play a critical role in modulating tolerance to peanut and risk of PA. Specifically, CD4+ T cells recognize peanut antigens through the engagement of T cell receptors (TCRs). Each individual has a large and highly variable TCR repertoire which is a major determinant in the immune response to a given antigen. To date, few studies have longitudinally characterized TCR repertoire development and dynamics in relation to PA, especially in the context of early life risk or protective factors of PA such as nutrition and metabolomic alteration and their joint associations with PA development during childhood. This proposal, motivated by our intriguing previous work and promising preliminary data, will harness the cutting-edge Adaptive immunoSEQ® technology to deep sequence the TCR ß-chain (TCRß) complementarity determining region 3 (CDR3) at birth (reflecting in-utero development) and at age 1-2 years (reflecting postnatal development) in 300 children (150 peanut allergic and 150 non-allergic, non-sensitized children) from the prospective Boston Birth Cohort (BBC), a NIH-funded U.S. urban, low-resourced underrepresented multi-ethnic cohort. By leveraging the BBC’s existing biospecimen, genome-wide genotype data, metabolome, and extensive epidemiological and clinical databases, we aim to investigate: (1) Longitudinal associations of early life TCRß repertoire development with child risk of PA. We hypothesize that TCRß repertoire features (i.e., composition, diversity, and dynamics) at birth, at age 1-2 years, and their longitudinal changes are associated with childhood risk of PA. We will further identify peanut- specific CD4+ T cell subsets with enriched peanut-specific CDR3 (ps-CDR3) sequences or motifs; (2) The interplay of early life factors, metabolome, and TCRß repertoire on child risk of PA. We hypothesize that early life nutritional and metabolic factors may influence TCRß repertoire development, and, in turn, may jointly affect child risk of PA. This proposal is strengthened by its prospective birth cohort design; a strong multi-disciplinary collaborative team, novel integration of TCRß repertoires with early life exposure to nutrition and metabolome; and focus on underrepresented, under-studied, high risk, predominantly minority children. Successful completion of this project will identify novel biomarkers for early risk assessment of PA and new targets for intervention during the earliest developmental windows. In short, this study represents a unique opportunity to advance the field and open doors to promising new directions to unlock the mystery of PA.

抽象的花生过敏（PA）已成为世界范围内的一个主要临床和公共卫生问题，因为患病率增加，大多数情况下其终生持续存在，以及相关的危及生命的过敏症 PA 发生的原因和精确的分子机制在很大程度上仍然存在。现有数据强调生命早期（即子宫内和生命的最初几年）是关键。 PA发育的窗口，也是适应性免疫的关键发育窗口越来越多的证据表明，T 细胞在调节花生耐受性和风险方面发挥着关键作用。具体来说，CD4+ T 细胞通过 T 细胞受体的结合识别花生抗原。（TCR）。每个人都有一个巨大且高度可变的 TCR 库，这是决定 TCR 的主要因素。迄今为止，很少有研究对 TCR 库进行纵向表征。与 PA 相关的发展和动态，特别是在早期生命风险或保护因素的背景下 PA，例如营养和代谢组的改变及其与 PA 发育的联合关联这项提议是受到我们之前有趣的工作和有希望的初步数据的推动。利用尖端的 AdaptiveimmunoSEQ® 技术对 TCR β 链 (TCRß) 进行深度测序出生时（反映子宫内发育）和 1-2 岁时的互补决定区 3 (CDR3) （反映产后发育）300 名儿童（150 名花生过敏和 150 名非过敏、非致敏）儿童）来自未来的波士顿出生队列（BBC），这是一个由 NIH 资助的美国城市，资源匮乏通过利用 BBC 现有的生物样本、全基因组基因型。数据、代谢组学以及广泛的流行病学和临床数据库，我们的目标是调查：(1) 生命早期 TCRß 功能发展与儿童 PA 风险的纵向关联。在出生时和 1-2 岁时培养 TCRß 曲目特征（即组成、多样性和动态）年，其纵向变化与儿童 PA 风险相关。具有丰富的花生特异性 CDR3 (ps-CDR3) 序列或基序的特定 CD4+ T 细胞亚群 (2) 早期生活因素、代谢组和 TCRß 库之间的相互作用对儿童 PA 风险的影响。生命早期的营养和代谢因素可能会影响 TCRß 功能的发展，进而可能强有力的前瞻性出生队列设计强化了该提案的共同影响。多学科协作团队，TCRß 库与生命早期营养暴露的新颖整合和代谢组学；并关注代表性不足、研究不足、高风险、主要是少数民族儿童。该项目的成功完成将确定新的生物标志物，用于 PA 的早期风险评估和新的简而言之，这项研究代表了一项独特的研究。推进该领域发展的机会，并为有希望的新方向打开大门，以解开 PA 的神秘面纱。