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，并且对疫苗接种的反应受损。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细胞的功能，但这些研究大多是在免疫系统固有臂的认识之前进行的。Toll样受体（TLRs）是树突状细胞（dc）上重要的先天免疫受体，树突状细胞是对特定微生物基元反应的最强大的抗原呈递细胞。在TLR连接后，dc对于有效启动na' s CD4+和CD8+ T细胞至关重要。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，回答这个基本问题是至关重要的。由于西方国家的老年人口正在迅速增加，并对我们的卫生保健资源造成沉重负担，因此这一问题的紧迫性正在上升。我们使用实验性同种异体小鼠模型的初步数据提供了新的证据，证明髓系dc中的TLR免疫对多种TLR激动剂的反应随着年龄的增长而保持不变。因此，在本研究中，我们可以通过保留的dc依赖性TLR免疫启动来验证衰老特异性损害CD8+ T细胞对病毒感染的适应性内在免疫应答的假设。具体来说，我们将采用小鼠LCMV感染模型来确定衰老是否会损害先天dc依赖性TLR免疫启动或适应性内在CD8+抗病毒免疫（目的1和2）。在目标3中，我们将验证特异性TLR激动剂增加促炎细胞因子环境并增强老年宿主的原发性抗病毒CD8+ T免疫的假设。在选定的情况下，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，这一建议将提供关键的、基本的信息，关于衰老是否会损害病毒感染期间DC依赖性TLR免疫或适应性CD8+ T细胞固有免疫反应，并将提供TLR激动剂是否可以作为佐剂并恢复老年宿主的初级免疫的见解。由此产生的信息对于加快临床相关的治疗方案至关重要，这些治疗方案将增强免疫反应并帮助恢复老年人的健康。

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.