Impact of chronic infection in the aged on the response to vaccination

描述（申请人提供）：随着年龄的增长，免疫系统的功能发生了深刻的变化。最重要的临床变化之一是，疫苗效力在老年人中显著下降，使他们更容易感染流感和肺炎等传染病。这种下降导致整体抗体（Ab）滴度降低以及Ab功能降低。此外，衰老个体的炎症和慢性炎症感染发生率增加，这两种情况都可能对初级免疫反应的结果产生重大影响。我们目前尚不清楚老年人炎症和感染发生率的增加是否导致他们对感染和疫苗接种的反应能力下降。在这方面，我们已经生成了两组数据，这些数据促使我们在这个R21应用程序中处理这个问题。利用T细胞受体转基因（TCR Tg） CD4 T细胞的新型过继转移模型，我们已经证明，与年轻的CD4 T细胞相比，来自老年人的幼稚CD4 T细胞对疫苗接种促进Ab反应的能力降低。此外，在初步数据中，我们发现老年宿主表达能够产生炎症细胞因子IL-17的细胞频率增加，并且这种频率在分枝杆菌感染的存在下进一步增加。这些观察结果促使我们提出这样的假设：CD4 T细胞的启动和同源功能受到慢性感染的影响，而T细胞和宿主的年龄都加剧了这种影响。为了验证这一假设，我们概述了4个目标，以确定感染和炎症对CD4 T细胞对疫苗反应的影响。目的1。老年宿主的慢性感染在多大程度上影响年轻初始CD4 T细胞的启动？目标2。慢性感染在多大程度上影响老化CD4 T细胞的启动？目标3。慢性感染在多大程度上影响老年CD4 T细胞的同源辅助功能？目标4。慢性感染在多大程度上影响CD4 T细胞记忆的发育和表达？我们将使用TCR Tg T细胞提供足够数量的均匀幼稚T细胞和低毒力但炎症性分枝杆菌感染（BCG），以在年轻和老年宿主中提供可重复的炎症水平增加。我们可以跟踪T细胞和B细胞对疫苗接种的反应，从而确定感染在多大程度上调节了这两组细胞的反应。这些实验与人类健康有关，因为确定炎症对疫苗接种反应的影响将使我们能够改善老年人的疫苗接种。

DESCRIPTION (provided by applicant): The function of the immune system changes profoundly with age. One of the most clinically important changes is that vaccine efficacy significantly declines in the elderly, leaving them more susceptible to infectious diseases such as influenza and pneumonia. This decline leads to lower overall antibody (Ab) titers as well as reduced Ab function. In addition, aging individuals have an increased incidence of inflammation and chronic inflammatory infections, both of which can potentially have a significant impact on the outcome of a primary immune response. We currently do not know whether the increased incidence of inflammation and infection in the elderly contributes to their reduced ability to respond to infection and vaccination. In this regard we have generated two sets of data that have prompted us to pursue this issue in this R21 application. Using a novel adoptive transfer model with T cell receptor transgenic (TCR Tg) CD4 T cells, we have shown that naive CD4 T cells from aged individuals exhibit a reduced ability to promote Ab responses to vaccination compared to young CD4 T cells. In addition, in the preliminary data, we show that aged hosts express an increased frequency of cells capable of producing the inflammatory cytokine IL-17, and that this frequency is further increased by the presence of mycobacterial infection. These observations prompted us to propose the hypothesis that the priming and cognate function of CD4 T cells is influenced by chronic infection and that age of both T cells and host exacerbate this influence. To test this hypothesis, we have outlined 4 aims that will determine the impact of infection and inflammation on the CD4 T cell response to vaccination. Aim 1. To what extent does chronic infection in the aged host influence the priming of young naive CD4 T cells? Aim 2. To what extent does chronic infection influence the priming of aged CD4 T cells? Aim 3. To what extent does chronic infection influence the cognate helper function of aged CD4 T cells? Aim 4. To what extent does chronic infection influence the development and expression of CD4 T cell memory? We will use TCR Tg T cells to provide sufficient numbers of uniform naive T cells and a low-virulence yet inflammatory mycobacterial infection (BCG) to provide a reproducible increase in the level of inflammation in both young and aged hosts. We can follow both T and B cell responses to vaccination allowing us to determine the extent to which infection modulates the response of both sets of cells. These experiments are relevant to human health since determining the effect of inflammation on the response to vaccination will allow us to improve vaccination in the elderly.