Mechanisms to augment primary immunity in aging

描述（由申请人提供）：临床研究表明，老年人更容易患多种疾病，包括癌症、自身免疫和感染，并对疫苗接种反应减弱。这意味着老年人有异常的免疫反应。尽管一些早期的研究表明，衰老会损害T细胞功能，但这些研究大多是在免疫系统的先天臂被认识之前进行的。Toll样受体（TLR）是树突状细胞（DC）上的关键先天性免疫受体，其代表对特定微生物基序应答的最强大的抗原呈递细胞。在TLR连接后，DC对于有效引发未处理的CD4+和CD8+ T细胞是必需的。然而，衰老对DC依赖性免疫功能的影响尚不清楚。如果我们要开发有效的治疗方法来改善老年人的免疫功能，回答这个基本问题至关重要。由于西方国家的老年人口迅速增加，对我们的医疗资源构成沉重负担，这一问题日益紧迫。我们使用实验同种异体小鼠模型的初步数据提供了新的证据，即髓样DCs中的TLR免疫反应随着年龄的增长而保持不变，以响应广泛的TLR激动剂。因此，在这项提议中，我们处于有利地位，以测试这一假设，即衰老特异性地损害适应性内在CD8+ T细胞免疫反应的病毒感染与保留先天DC依赖性TLR免疫启动。具体而言，我们将采用鼠LCMV感染模型来辨别衰老是否损害先天DC依赖性TLR免疫引发或适应性内在CD8+抗病毒免疫（目的1和2）。在目标3中，我们将测试特定TLR激动剂增加促炎细胞因子环境并增强老年宿主中的初级抗病毒CD8+ T免疫的假设。在选定的病例中，我们将使用替代病原体来检查我们的发现是否适用于其他病毒感染。因此，该提议将提供关于衰老是否在病毒感染期间损害先天性DC依赖性TLR免疫或适应性内在CD8+ T细胞免疫应答的关键的基本信息，并且将提供关于TLR激动剂是否可以充当佐剂并恢复老年宿主中的初级免疫的见解。由此产生的信息对于加速临床相关的治疗方案至关重要，这些方案将增强免疫反应并帮助老年人恢复健康。

DESCRIPTION (provided by applicant): Clinical studies have shown that older persons are more susceptible to multiple diseases including cancer, autoimmunity and infections and manifest an impaired response to vaccinations. This implies that the elderly have aberrant immune responses. Although several earlier studies have shown that aging impairs T cell function, most of these studies were performed prior to the appreciation of the innate arm of the immune system. The Toll like receptors (TLRs) are critical innate immune receptors on dendritic cells (DCs), which represent the most powerful antigen presenting cells that respond to specific microbial motifs. Upon TLR ligation DCs are essential for effective priming of both na'i've CD4+ and CD8+ T cells. However, the impact of aging on DC-dependent immune function is unclear. It is critical to answer this fundamental question if we are to develop effective therapies to improve immune function in older people. The urgency of this issue is rising since the elderly subpopulation in western countries is rapidly increasing and posing a heavy burden on our health care resources. Our preliminary data using experimental allogeneic murine models provide novel evidence that TLR immunity in myeloid DCs remains preserved with aging in response to a broad range of TLR agonists. Therefore, in this proposal, we are in a strong position to test the hypothesis that aging specifically impairs adaptive intrinsic CD8+ T cell immune responses to viral infection with preserved innate DC-dependent TLR immune priming. Specifically, we will employ a murine LCMV infection model to discern if aging impairs either innate DC-dependent TLR immune priming or adaptive intrinsic CD8+ anti-viral immunity (aims 1 and 2). In aim 3 we will test the hypothesis that specific TLR agonists augment the proinflammatory cytokine milieu and boost primary anti-viral CD8+ T immunity in the aged host. In selected cases we will use alternate pathogens to examine if our findings are applicable to other viral infections. Therefore, this proposal will provide critical, fundamental information as to whether aging impairs innate DC- dependent TLR immunity or adaptive intrinsic CD8+ T cell immune responses during viral infection and will provide insights as to whether TLR agonists can act as adjuvants and restore primary immunity in the aged host. The resulting information will be essential to accelerate clinically relevant therapeutic protocols that will augment the immune response and help restore health in older people.