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.

摘要 花生过敏(PA)已经成为世界范围内的一个主要的临床和公共卫生问题，原因是 患病率增加，在大多数情况下持续终生，并与其相关的危及生命的过敏反应 回应。PA发生的原因和确切的分子机制在很大程度上仍然存在 未知。现有数据强调早期生命阶段(即宫内和生命最初几年)是关键 PA发展的窗口，这也是获得性免疫的关键发展窗口 系统。越来越多的证据表明，T细胞在调节对花生的耐受性和风险方面发挥着关键作用 宾夕法尼亚州。具体地说，CD4+T细胞通过与T细胞受体的结合识别花生抗原 (TCR)。每个人都有一个庞大且高度可变的TCR曲目，这是决定 对特定抗原的免疫反应。到目前为止，很少有研究纵向描述TCR曲目 与PA有关的发展和动态，特别是在早期生命风险或保护性因素的背景下 PA的营养和代谢改变及其与PA发育的联合关系 童年。这项提案的动机是我们以前有趣的工作和有希望的初步数据，它将 利用尖端的自适应免疫序列®技术对TCR？链(TCR？)进行深度测序 互补决定区3(CDR3)在出生时(反映子宫内发育)和1-2岁时 (反映出生后发育)300名儿童(150名对花生过敏，150名不过敏，非致敏) 儿童)，来自未来的波士顿出生队列(BBC)，NIH资助的美国城市，低资源 未被充分代表的多民族群体。通过利用英国广播公司现有的生物样本、全基因组基因 数据，代谢组，以及广泛的流行病学和临床数据库，我们的目标是调查：(1) 早期Tcrü谱系发育与PA儿童风险的纵向关联。我们 假设Tcr？曲目在1-2岁出生时具有特征(即组成、多样性和动态) 其纵向变化与儿童患PA的风险相关。我们将进一步鉴定花生- 富含花生特异性CDR3(PS-CDR3)序列或基序的特异性CD4+T细胞亚群； 早期生活因素、新陈代谢组和TCRü谱系对儿童PA风险的相互作用。我们假设 早期生活中的营养和代谢因素可能会影响Tcr？谱系的发育，进而可能 共同影响儿童患PA的风险。这一建议因其预期出生队列设计而得到加强；一个强有力的 多学科协作团队，TCR？曲目与早期营养暴露的新集成 和代谢组；重点关注代表性不足、学习不足、高风险、主要是少数族裔儿童。 该项目的成功完成将为PA和NEW的早期风险评估确定新的生物标志物 在最早的发育窗口期的干预目标。简而言之，这项研究代表了一种独特的 有机会推进这一领域，并打开大门，打开有希望的新方向，解开PA的神秘面纱。