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）已成为一个主要的临床和公共卫生问题，全球范围内，由于戏剧性的 患病率增加，在大多数情况下终身持续存在，及其相关的危及生命的过敏性 反应PA发生的原因和精确的分子机制在很大程度上仍然是 未知现有的数据强调了早期的生命周期（即，在子宫内和生命的最初几年）作为关键的 PA的发育窗口，这也是适应性免疫的关键发育窗口 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中起着关键作用。 的PA。具体地说，CD 4 + T细胞通过与T细胞受体的结合来识别花生抗原 （TCR）。每个个体具有大的且高度可变的TCR库，其是免疫应答的主要决定因素。 对给定抗原的免疫反应。迄今为止，很少有研究纵向表征TCR库， 与PA有关的发展和动态，特别是在早期生命风险或保护因素的背景下， PA，如营养和代谢组学改变及其与PA发展的联合关联， 童年.这个建议，受到我们以前有趣的工作和有希望的初步数据的激励，将 利用先进的Adaptive immunoSEQ®技术对TCR β链（TCR γ）进行深度测序 在出生时（反映子宫内发育）和1-2岁时， （反映出生后发育）在300名儿童（150名花生过敏和150名非过敏，非致敏） 波士顿出生队列（BBC）是一个由NIH资助的美国城市，低资源 代表性不足的多族裔群体。通过利用BBC现有的生物标本，全基因组基因型 数据，代谢组学，广泛的流行病学和临床数据库，我们的目的是调查：（1） 早期TCR基因组发育与儿童PA风险的纵向相关性我们 假设TCR γ组库特征（即，组成、多样性和动态），1-2岁时 年，其纵向变化与儿童期PA的风险有关。我们会进一步确认花生- 具有富集的花生特异性CDR 3（ps-CDR 3）序列或基序的特异性CD 4 + T细胞亚群; 早期生活因素、代谢组学和TCRs库对PA儿童风险相互作用我们假设 生命早期的营养和代谢因素可能会影响TCR受体库的发育， 共同影响PA儿童风险。这一建议通过其前瞻性出生队列设计得到加强; 多学科协作团队，TCRs库与生命早期暴露于营养的新颖整合 和代谢组学;并侧重于代表性不足，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为PA的早期风险评估确定新的生物标志物， 在最早的发展窗口期进行干预的目标。总之，这项研究代表了一种独特的 有机会推进该领域，并打开大门，有前途的新方向，以解开PA的奥秘。