Aging and Immunity to Infections

描述（由申请人提供）：衰老和免疫感染。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，定义这些缺陷的潜在本质是极其困难的，因为人类的基因是多样化的，需要大量的实验对象，而且不容易操纵。小鼠模型使我们能够精确地确定单个细胞亚群是否受损，哪些机制受到损害以及如何逆转缺陷。这些模型已经在CD4 T细胞中发现了一个深刻的、与年龄相关的缺陷，它减少了初级效应物的产生、记忆的产生和抗体的产生。我们计划研究衰老对CD4和CD8 T细胞对病毒反应的影响。我们将确定哪些反应受到衰老的损害，什么机制导致缺陷，以及佐剂或细胞因子是否可以增强反应和/或克服已知缺陷。这些研究将产生重要的信息，阐明随着年龄增长而出现的T细胞免疫缺陷，并有助于未来制定有效的老年人疫苗接种策略。本计划包括4个项目：1.；衰老和CD4对流感病毒的免疫，将决定衰老如何影响幼稚CD4 T细胞的体内反应，佐剂是否可以挽救衰老幼稚CD4 T细胞的反应，以及克服其不良反应的潜在机制。2. 增强衰老CD4细胞与细胞因子的同源功能，将决定衰老CD4 T细胞缺陷对其为B细胞提供同源帮助的能力的影响，从而影响Ab的产生，并将决定促炎细胞因子是否可以改善衰老CD4 T细胞对蛋白质抗原的体内功能。3. 衰老对CD8记忆T细胞亚群的影响，将研究年龄对记忆CD8 T细胞的影响，包括不同记忆亚群的分布和周转，它们的功能特征，以及疫苗诱导的CD8记忆群的稳定性。4. 衰老对持续病毒免疫控制的影响将确定衰老对潜伏小鼠y-疱疹病毒的细胞和体液免疫的影响，以及老年人对该病毒免疫控制的后果。

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.