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

• 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
• 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

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 由于戏剧性的 在大多数情况下，患病率的增加，其终身持久性及其危及生命的过敏反应 回复。 PA开发的基础的原因和精确的分子机制仍然很大程度上 未知。可用数据强调了早期生命时期（即生命的最初几年）作为关键 PA开发的窗口，这也是自适应免疫的关键发展窗口 越来越多的证据表明，T细胞在调节花生的容忍度和风险中起着关键作用 PA。特别是，CD4+ T细胞通过T细胞受体的参与识别花生抗原 （TCR）。每个人都有一个较大且高度可变的TCR曲目，这是 对给定抗原的免疫反应。迄今为止，很少有研究纵向表征TCR曲目 与PA有关的发展和动态，尤其是在早期生活风险或保护因素的背景下 PA，例如营养和代谢组改变及其与PA发展的联合关联 童年。这项提案是由我们有趣的先前工作和有前途的初步数据的动机的，将 利用尖端的自适应免疫素技术来深度序列TCRβ链（TCRß） 互补性确定出生时区域3（CDR3）（反映UTERO内发育）和1-2岁时 （反映产后发育）300名儿童（150个花生过敏和150个非过敏性，非敏感性 儿童）来自前瞻性波士顿出生队列（BBC），这是NIH资助的美国城市低资源的 代表性不足的多种族队列。通过利用英国广播公司现有的生物传播，全基因组基因型 数据，代谢组以及广泛的流行病学和临床数据库，我们的目的是研究：（1） 早期生活的纵向关联TCRß曲目发展与儿童的风险。我们 假设出生时TCRß曲目特征（即组成，多样性和动力学），年龄为1-2 几年，他们的纵向变化与PA的儿童时期风险有关。我们将进一步确定花生 特定的CD4+ T细胞亚群，具有富集花生特异性CDR3（PS-CDR3）序列或基序； （2） 早期生命因素，代谢组和TCRß曲目的相互作用涉及儿童的风险。我们假设这一点 早期生活营养和代谢因素可能会影响TCRß曲目的发展，反过来又可能 共同影响儿童的PA风险。该提议的前瞻性出生队列设计得到了加强。强壮 多学科合作团队，TCRß曲目的新颖集成与早期寿命的营养 和代谢组；并专注于代表性不足，研究的高风险，主要是少数族裔。 该项目的成功完成将确定新颖的生物标志物，以提早对PA和新的风险评估 在最早的发育窗口中进行干预的目标。简而言之，这项研究代表了一个独特的 有机会推进田野并打开大门，承诺新的方向解锁PA的奥秘。