Mechanisms to augment primary immunity in aging

描述(申请人提供)：临床研究表明，老年人更容易感染多种疾病，包括癌症、自身免疫和感染，并对疫苗接种表现出受损的反应。这意味着老年人有异常的免疫反应。虽然早期的几项研究表明，衰老会损害T细胞的功能，但这些研究大多是在评价免疫系统的固有手臂之前进行的。Toll样受体(TLRs)是树突状细胞(DC)上的重要先天免疫受体，树突状细胞是对特定微生物基序作出反应的最强大的抗原提呈细胞。在TLR结扎后，DC对于初始的CD4+和CD8+T细胞的有效启动是必不可少的。然而，衰老对DC依赖的免疫功能的影响尚不清楚。如果我们要开发有效的疗法来改善老年人的免疫功能，回答这个根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，给我们的卫生保健资源带来了沉重的负担，这一问题的紧迫性正在上升。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，表明髓系树突状细胞中的TLR免疫随着年龄的增长而保持不变，以应对广泛的TLR激动剂。因此，在这一提议中，我们处于有利地位，可以通过保存的先天DC依赖的TLR免疫启动来检验这一假设，即衰老特异性地损害病毒感染的适应性内在CD8+T细胞免疫反应。具体地说，我们将使用小鼠LCMV感染模型来辨别衰老是否损害了先天DC依赖的TLR免疫启动或适应性内在CD8+抗病毒免疫(目标1和2)。在目标3中，我们将测试特定的TLR激动剂增加促炎细胞因子环境和增强老年宿主的初级抗病毒CD8+T细胞免疫的假设。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，这一建议将提供关于衰老是否损害病毒感染期间先天DC依赖的TLR免疫或适应性内在CD8+T细胞免疫反应的关键的基本信息，并将为TLR激动剂是否可以作为佐剂而恢复老年宿主的初级免疫提供深入的见解。由此产生的信息将是加快临床相关治疗方案的关键，这些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.