Identification of Metabolic and Immune Deficits in the Aged Population and Their Restoration to Achieve Youthful Anti-Influenza Vaccine Responsiveness

项目摘要 流感是老年人死亡的主要原因，目前的疫苗只能保护一小部分人 尽管有广泛的疫苗接种计划和专门的制剂。更好地理解分子 迫切需要控制免疫老化的机制，以便新设计的疫苗，佐剂 和药物干预可以用来恢复年轻的抗体（Ab）反应，在老年人 人口我们的首要目标是确定衰老对免疫细胞的影响， 抗流感抗体疫苗的反应。我们将进行综合全面的评估， 循环T滤泡辅助（Tfh）、T滤泡调节（Tfr）细胞和B细胞以及它们的亚群， 年轻人和老年人在季节性流感疫苗接种之前和之后。我们将检验一个假设， 年龄增长的结果是Tfh/Tfr细胞的个体亚群的分布改变， 代谢重编程和缺陷B细胞引起流感疫苗应答。我们的综合分析 包括在生物体和细胞水平上研究代谢途径中与年龄相关的下降， 例如线粒体生物发生和一碳代谢缺陷，并确定这些变化是否 导致免疫功能障碍。最后，从这些研究中获得的知识将用于执行 在体外进行概念验证拯救实验，以恢复最佳流感疫苗反应性。支持 在这些研究中，将使用来自153名参与者（年龄21-76岁， 包括15名≥ 65岁的个体），在四价血凝素注射后第0、7和32天献血 (HA)预防针我们计划有针对性地扩大该队列，招募另外100名≥ 65岁的供体， 年龄和一组25名年轻成人（≤ 40岁，n=25）进行单细胞基因组学和代谢组学研究， 新鲜血液样本我们将暂时跟踪流感疫苗反应，并比较年轻人和老年人 组具体来说，在目标1中，我们将研究亚群组成和代谢重编程的改变 在年轻人和老年人的滤泡T细胞中。这些研究的完成将使我们了解 与衰老相关的体液免疫缺陷是否由Tfh和Tfr亚群的变化介导， 固有功能性或两者。在目标2中，我们将评估抗体应答的特征，并确定 年轻和老年个体中B细胞群的组成和代谢变化。完成时 通过这些研究，我们还将了解导致免疫印记的变化。在第三章中，我们将分析年龄- 体外应答流感疫苗抗原的Tfh、Tfr和B细胞的相关功能障碍。Tfh/B细胞共培养 将接受免疫调节剂和小分子治疗，以恢复免疫和代谢功能， 克服疫苗反应中与年龄相关的缺陷。我们组建了一个高素质的团队 这些研究的目标是测试新的范式，并建立一个可操作的路线图， 提高老年人的疫苗反应性。

Project Summary Influenza is a leading cause of death in the elderly and current vaccines only protect a fraction of this population despite widespread vaccination programs and specialized formulations. A better understanding of the molecular mechanisms that control immunological aging is urgently needed so that newly designed vaccines, adjuvants and pharmacologic interventions can be employed to restore youthful antibody (Ab) responses in the older population. Our overarching goals are focused on determining the effects of aging on immune cells that mediate the anti-influenza Ab vaccine response. We will perform an integrated and comprehensive evaluation of circulating T follicular helper (Tfh), T follicular regulatory (Tfr) cells and B cells as well as their subsets from young and older individuals prior to and after seasonal influenza vaccination. We will test the hypothesis that a consequence of advancing age is an altered distribution of individual subsets of Tfh/Tfr cells resulting in metabolic reprogramming and defective B cell elicited influenza vaccine responses. Our integrated analysis includes studies to investigate at the organismal and cellular level age-related declines in metabolic pathways, such as defective mitochondrial biogenesis and one carbon metabolism and to determine if these changes contribute to the immune dysfunction. Finally, knowledge gained from these studies will be used to perform proof of concept rescue experiments in vitro to restore optimal influenza vaccine responsiveness. To support these studies, samples will be used from a seasonal influenza vaccinee cohort of 153 participants (ages 21-76, including 15 individuals ≥ 65yr) who have donated blood at days 0, 7 and 32 after quadrivalent hemagglutinin (HA) vaccination. We plan a targeted expansion of this cohort to recruit an additional 100 donors ≥ 65 years of age and a group of 25 younger adults (≤ 40yr, n=25) for single cell genomic and metabolomic studies that require fresh blood samples. We will temporally follow the influenza vaccine response and compare young and older groups. Specifically, in Aim 1 we will examine alterations in subset composition and metabolic reprogramming in follicular T cells in young and aged individuals. The completion of these studies will allow us to understand whether defects in humoral immunity associated with aging are mediated by changes in Tfh and Tfr subsets, intrinsic functionality, or both. In Aim 2 we will assess characteristics of the Ab response and determine composition and metabolic changes in B cell populations in young and aged individuals. At the completion of these studies we will also understand changes that result in immune imprinting. In Aim 3 we will analyze age- related dysfunction of Tfh, Tfr and B cells in vitro in response to influenza vaccine antigens. Tfh/B cell co-cultures will be treated with immune modulators and small molecules to restore immunologic and metabolic function to overcome age-related defects in vaccine responses. We have assembled a highly accomplished team to carry out these studies with the goal of testing new paradigms and establishing an actionable roadmap on how to improve vaccine responsiveness in the elderly.