The effects of immune-age on immune-response and the molecular mechanisms which drive it

免疫年龄对免疫反应的影响及其驱动的分子机制

• 批准号: 10491680
• 负责人: Shai Shlomo Shen-Orr
• 金额: $ 64.49万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491680
• 关键词: Adaptive Immune System; Adult; Affect; Age; Aging; Algorithms; Antibodies; Antibody Repertoire; Antibody Response; Antibody Specificity; Automobile Driving; Cells; Clinical; Complex; Data; Data Set; Databases; Elderly; Environment; Epigenetic Process; Epitopes; Etiology; Experimental Designs; Gene Expression; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunologics; In Vitro; Individual; Infection; Inflammatory; Influenza; Influenza vaccination; Knowledge; Lead; Maps; Measures; Modification; Molecular; Outcome; Pattern; Physiological; Play; Positioning Attribute; Process; Recording of previous events; Resolution; Resources; Risk; Role; Sampling; Serology test; Specificity; System; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; Testing; Time; Translating; Twin Multiple Birth; Vaccination; Vaccines; Variant; World Health; aged; base; cell type; cohort; cytokine; design; environmental change; flu; glycosylation; healthy aging; high dimensionality; immune function; improved; influenza virus vaccine; insight; inter-individual variation; metabolomics; middle age; novel; programs; response; seasonal influenza; vaccination strategy; vaccine response; young adult

PROJECT SUMMARY The immune system is a complex system which continuously changes as it responds to the internal and external environments, making it very difficult to understand the variation between individuals and its functional implications. Our SELA derived trajectory captures the variation in immune-cell composition between individuals, thus describes the conserved cascade of cell compositional changes occurring during healthy aging. An individual’s high-dimensional immune cell composition can be translated into a quantitative measure describing its position along this immune-aging cascade reflecting the immune-age. Individuals’ immune-age alters as they advance at different rates along this patterned trajectory, resulting in high inter-individual variation at baseline. We hypothesize that the immune-aging trajectory is conserved between individuals due to epigenetic cell-specific alterations that are induced through an interaction with common physiological and environmental changes that occur with age. Furthermore, we hypothesize that this the baseline variation in immune-age between individuals has functional implications during immune response, which ultimately may lead to variability in clinical outcome, which is observed for the majority of insults and therapies. Project 1 is designed to enrich and refine our immune age metric by expanding our cohort (adding 40-60 years-old twins) and by measuring in addition immune cell types, factors (cytokines, epigenetic modifications, and metabolomics) found to be in correlation with immune aging. Furthermore, we will identify factors that drive progression along the immune age trajectory. In addition, we will gain comprehensive insight into the way age and immune history affect adaptive (B and T) responses elicited by annual influenza vaccination in the old. Lastly, leveraging the 12+ years of bio-banked SELA samples pre and post seasonal influenza vaccination we will test the hypothesis that molecular immune responses differ as a function of baseline immune-age and decouple immune dynamics that are caused by different vaccine compositions from those that are caused by immune-age. We will combine the latter molecular features correlated with immune age with data on flu specific adaptive responses to obtain, for the first-time comprehensive understanding of vaccine responses in older adults, a risk group for infection. We hope that combining immune-age with B and T flu history, will allow to predict influenza vaccine response from baseline, an unsolved problem of high concern for world health.

项目摘要 免疫系统是一个复杂的系统，它在响应内部和外部时不断变化 环境，很难理解个人与其功能之间的差异 含义。我们的SELA衍生轨迹捕获了个体之间免疫细胞组成的变化， 描述了在健康衰老期间发生的一系列细胞组成变化。一个 个人的高维免疫细胞组成可以转化为描述的定量测量 它沿着这种反映免疫年龄的免疫级联级联反应的位置。个人的免疫年龄变化 沿着这种模式的轨迹以不同的速度提高，导致基线时个体间变化很高。 我们假设由于表观遗传细胞特异 通过与常见的身体和环境变化互动引起的改变 随着年龄的增长而发生。此外，我们假设这是个体之间免疫年龄的基线变化 在免疫反应过程中具有功能含义，这最终可能导致临床结果的变化， 这是大多数侮辱和疗法的观察。项目1旨在丰富和完善我们的免疫力 通过扩展我们的队列（增加40 - 60年的双胞胎）和测量免疫细胞，通过扩展年龄度量 发现与免疫相关的类型，因子（细胞因子，表观遗传修饰和代谢组学） 老化。此外，我们将确定沿免疫年龄轨迹进展的因素。此外， 我们将对年龄和免疫历史影响适应性（B和T）的反应的方式进行全面了解 通过年度影响力疫苗接种在旧的情况下引起。最后，利用生物银行的Sela样品的12年以上 季节前后的影响我们将检验以下假设：分子免疫反应不同 作为基线免疫年龄和脱致免疫动力学的函数，这些动力学是由不同的疫苗引起的 由免疫年龄引起的成分。我们将结合后来的分子特征 与免疫年龄相关，与流感特异性自适应反应的数据相关，以获得首次 全面了解老年人的疫苗反应，这是感染的风险组。我们希望那样 将免疫年龄与B和T流感史相结合，可以预测基线的影响力疫苗反应， 对世界卫生的高度关注的尚未解决的问题。