Aging and Immunity to Infections

描述(申请人提供)：衰老和对感染的免疫力。传染病导致老年人的高发病率和死亡率，目前的疫苗往往无效。对人类来说，定义缺陷的潜在本质是极其困难的，因为人类群体是遗传多样性的，需要大量的受试者，而且不容易被操纵。小鼠模型使我们能够准确地确定细胞的个别亚群是否受损，哪些机制受到损害，以及缺陷可能如何逆转。这些模型已经确定了CD4T细胞中一种与年龄相关的深刻缺陷，这种缺陷会减少主要效应器的生成、记忆的生成和抗体的产生。我们计划研究衰老对CD4和CD8T细胞对病毒反应的影响。我们将确定哪些反应会因衰老而受损，什么机制导致这些缺陷，以及佐剂或细胞因子是否可以增强反应和/或克服已知的缺陷。这些研究将产生重要的信息，这些信息将阐明T细胞随年龄增长而出现的免疫缺陷，并有助于未来制定有效为老年人接种疫苗的策略。该计划包括4个项目：1.衰老和对流感病毒的CD4免疫，将确定衰老如何影响幼稚的CD4T细胞的体内反应，佐剂是否可以挽救老化的幼稚的CD4T细胞的反应，以及克服其低反应性的潜在机制。2.用细胞因子增强老年CD4T细胞的同源功能，将确定老年CD4T细胞缺陷对其为B细胞提供同源帮助的能力从而对抗体产生的影响，以及促炎细胞因子是否能改善老年CD4T细胞对蛋白质抗原的体内反应功能。3.衰老对CD8记忆T细胞亚群的影响，将研究年龄对CD8记忆T细胞亚群的影响，包括不同记忆亚群的分布和周转，其功能特征，以及疫苗诱导的CD8记忆群体的稳定性。4.老化对持久性病毒免疫控制的影响将决定衰老对潜伏的小鼠疱疹病毒的细胞和体液免疫的影响，以及对老年人病毒免疫控制的影响。

DESCRIPTION (provided by applicant): Aging and immunity to infections. Infectious disease results in high morbidity and mortality in the elderly and current vaccines are often ineffective. Defining the underlying nature of the defects is extremely difficult in man because the population is genetically diverse, requiring large numbers of subjects and cannot be readily manipulated. Mouse models allow us to determine precisely whether individual subsets of cells are impaired, what mechanisms are compromised and how defects might be reversed. Such models have identified a profound, age-related defect in CD4 T cells which reduces primary effector generation, memory generation and antibody production. We plan to study the impact of aging on responses of CD4 and CD8 T cells to viruses. We will determine which responses are compromised by aging, what mechanisms are responsible for the defects, and whether adjuvants or cytokines can enhance responses and/or overcome the known defects. These studies will generate important information that should elucidate immune defects that arise in T cells with aging and contribute in the future to the development of strategies to effectively vaccinate the elderly. The Program comprises 4 Projects: 1. Aging and CD4 Immunity to Influenza Virus, will determine how aging impacts the in vivo response of naive CD4 T cells, whether adjuvants can rescue the responses of aged naive CD4 T cells and what potential mechanisms are involved in overcoming their poor responsiveness. 2. Enhancing aged CD4 cognate function with cytokines, will determine the impact of aged CD4 T cell defects on their ability to provide cognate help for B cells and hence on Ab production and it will determine if proinflammatroy cytokines can improve the in vivo function of aged CD4 T cells responding to protein antigens. 3. Impact of Aging on CD8 Memory T Cell Subsets, will study the impact of age on memory CD8 T cells, including the distribution and turnover of distinct memory subsets, their functional characteristics, and the stability of vaccine-induced CD8 memory populations. 4. Impact of Aging on Immune Control of a Persistent Virus will determine the impact of aging on cellular and humoral immunity to a latent murine y-herpesvirus, and the consequences for immune control of the virus in aged individuals.