Aging and Immunity to Infection

描述（由申请人提供）：传染病，如流感，导致老年人群的高发病率和死亡率。此外，疫苗对老年人的效力也大大降低，使他们更容易受到感染。虽然众所周知，对流感感染和免疫的适应性免疫应答随着年龄的增长而下降，但T细胞功能中特定年龄相关变化的影响仍有待阐明。确定人类群体中免疫应答与衰老的潜在缺陷是极其困难的。幸运的是，小鼠模型使我们能够精确地检查免疫系统中与年龄相关的变化，并确定这些变化对特定病原体反应的影响。因此，该计划的重点是评估T细胞功能中与年龄相关的变化的发展，确定导致这些缺陷的机制，并确定它们是否也参与了人类免疫系统的下降。项目1“老化对CD 4免疫力的影响”将研究年龄对CD 4 T细胞主要和记忆反应的影响，以及是否可以增强这种影响。项目2“衰老对T滤泡辅助细胞（Tfh）的影响”将重点研究与年龄相关的CD 4 T细胞同源辅助功能变化对体液应答的作用，以及这如何影响疫苗接种后保护性抗体的产生。项目3“年龄对CD 8 + T细胞免疫对呼吸道感染的影响”将研究CDS T细胞记忆的产生和功能，这可能是由于记忆T细胞亚群的稳态变化而随着年龄的增长而急剧减少。项目4“衰老对T细胞库和对流感病毒的细胞免疫的影响”将研究CD 4和CDS T细胞库中与年龄相关的变化以及这些变化如何影响对流感感染的反应能力。所产生的知识将使未来的战略发展，以克服这些缺陷，提高疫苗的老年人的效力。项目5“老化对T细胞对流感疫苗接种的反应的影响”将把小鼠模型中的发现扩展到对来自不同年龄组接种疫苗的成年人的人类幼稚和记忆T细胞的研究。 公共卫生相关性：虽然已知对流感的适应性免疫应答随着年龄的增长而下降，但T细胞中特定年龄相关变化的影响及其在免疫应答降低中的作用仍有待阐明。因此，该计划的重点是评估T细胞功能和库中与年龄相关的变化的发展，以及这些变化如何导致动物和人类模型中免疫力下降。这将使未来的发展战略，以克服这些缺陷，提高疫苗的效力，为老年人。 审查可持续发展项目的各个组成部分 核心A：行政; Laura Haynes博士，核心负责人（CL） 描述（由申请人提供）行政核心将为项目主任和项目中的每位研究者提供行政支持和服务。项目总监负责监督项目并协调研究者之间的互动，并需要该核心人员的协助才能履行此职能。该计划的监督和协调将通过几种机制来实现，包括每月计划会议，与计划咨询委员会的会议以及我们进展情况的内部介绍。核心小组还将提供统计支持，安排旅行，协调受邀研讨会发言人的安排，安排内部研讨会和会议，编写进度报告，协调调查员之间和外部论坛上的介绍。协调会议和数据交换的功能对于实现该计划的目标尤为重要，该计划旨在全面了解衰老对传染病免疫反应的影响，以及我们最终试图找到克服这些缺陷的策略。 公共卫生相关性：老年人感染流感后发病率和死亡率的增加被认为在很大程度上是由于免疫系统中与年龄相关的变化。因此，我们需要更好地了解免疫系统中与年龄相关的缺陷如何导致疫苗效力降低，以及这些缺陷是否可以克服。该项目研究了年龄对T细胞和体液对流感感染和疫苗接种的反应的影响。该行政核心将为项目负责人和项目中的每位研究者提供行政支持和服务。

DESCRIPTION (provided by applicant): Infectious diseases, such as influenza, lead to high morbidity and mortality in elderly populations. In addition, the efficacy of vaccines is also significantly reduced for elderly populations, leaving them much more vulnerable to infection. While it is well known that the adaptive immune response to influenza infection and immunization declines with aging, the impact of specific age-related changes in T cell function remains to be elucidated. Defining the underlying defects in the immune response with aging in human populations is extremely difficult. Fortunately, mouse models allow us to precisely examine age-related changes in the immune system and determine the effect of these changes on a response to a particular pathogen. Thus, the key focus of this program is to assess the development of age-related changes in T cell function, define the mechanisms responsible for these defects and determine if they are also involved in declines in the human immune system. Project 1 "Impact of aging on CD4 immunity to flu" will examine the impact of age on CD4 T cell primary and memory responses and if this can be enhanced. Project 2 " Influence of aging on T follicular helper (Tfh) cells" will focus on examining the role of age-related changes in CD4 T cel cognate helper function for humoral responses and how this impacts the production of protective antibodies following vaccination. Project 3 "Impact of age on CD8+ T cell immunity to respiratory infection " will examine CDS T cell memory generation and function, which is dramatically reduced with aging possibly due to changes in homeostasis of memory T cell subsets. Project 4 "Impact of aging on the T cell repertoire and cellular immunity to influenza virus" will examine age- related changes in CD4 and CDS T cell repertoire and how these influence the ability to respond to influenza infection. The knowledge generated will allow the future development of strategies to overcome these defects and enhance vaccine efficacy for the elderly. Project 5 "Impact of aging on T cell responses to influenza vaccination" will translat findings in mouse models to studies in human naive and memory T cells from different age groups of vaccinated adults. PUBLIC HEALTH RELEVANCE: While it is known that the adaptive immune response to influenza declines with aging, the impact of specific age-related changes in T cells and the role that they play in reduced immune responses remain to be elucidated. Thus, the key focus of this program is to assess the development of age-related changes in T cell function and repertoire and how these contribute to reduced immunity in animal and human models. This will allow the future development of strategies to overcome these defects and enhance vaccine efficacy for the elderly. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATION; Dr. Laura Haynes, Core Leader (CL) DESCRIPTION (provided by applicant) The Administrative Core will provide administrative support and services to the Program Director and each Investigator in the program. The Program Director is responsible for supervising the Program and coordinating interactions between the Investigators, and will need the assistance of this Core to carry out this function. Oversight and coordination of this Program will be achieved by several mechanisms including monthly program meetings, meetings with the program's advisory committee and in house presentations of our progress. The Core will also provide statistical support, arrange travel, coordinate arrangements for invited seminar speakers, arrange internal seminars and meetings, prepare Progress Reports and coordinate presentations among the Investigators and in outside forums. The function of coordinating meetings and data exchange is particularly crucial to achieving the goals of the program to develop a comprehensive understanding of the impact of aging on the immune response to infectious disease and our ultimate attempts to find strategies to overcome those defects. PUBLIC HEALTH RELEVANCE: Increased morbidity and mortality seen in elderly populations following influenza infection are thought to be due in large part to age-associated changes in the immune system. Thus, we need to better understand how age-related defects in the immune system contribute to reduced vaccine efficacy and if those defects can be overcome. This program examines the impact of age on T cell and humoral responses to influenza infection and vaccination. This Administrative Core will provide administrative support and services to the Program Director and each Investigator in the program.