Exercise-induced immunomodulation in the aged: Mechanisms

描述（由申请人提供）：随着年龄的增长，免疫反应性显著降低。免疫衰老的临床后果包括对感染性疾病的易感性和/或严重性增加。已经提出了几种干预策略来恢复免疫功能。体育锻炼是研究得最少的提高免疫反应的方法之一。本研究小组的长期研究目标是阐明适度运动诱导的适应性增强老年人群对传染病的免疫反应的机制。在本申请中，一个目标是确定由运动诱导的机械适应，其影响参与识别病毒感染的初始途径，从而导致IFN α产生增强。第二个目标是确定哪些途径可以由IFN α触发，从而改善病毒清除和减少免疫病理学。具体目标是：1）鉴定老年动物的运动训练在流感病毒攻击后增加IFN α产生的机制，2）确定运动诱导的IFN α增加调节树突细胞和CD 8+细胞应答的程度，3）鉴定运动改变的IFN α应答中涉及的途径，和4）通过确定肺内促炎/抗炎细胞因子之间的平衡和随后对免疫病理学介导的组织损伤的影响，进一步定义运动的影响，鉴定产生这些细胞因子的细胞，并确定IFN α作为这些效应的介导者的作用。将使用流感病毒感染的小鼠模型。将老年BALB/c小鼠分配到中度运动组10周或非运动组。在运动训练后，一些实验将涉及体内病毒攻击以检查在完整动物中发生的免疫应答，而其他实验将涉及从运动训练后的小鼠收集细胞，并暴露于体外病毒攻击。将使用不同的技术来识别响应挑战的细胞类型以及所涉及的多种途径。在完成这些研究后，我们希望确定参与细胞防御病毒感染的运动诱导的适应，随后形成不断发展的免疫反应，从而改善病毒清除和减少免疫病理学。

DESCRIPTION (provided by applicant): A significant decrease in immune responsiveness occurs with advancing age. The clinical consequences of immunosenescence include an increased susceptibility to and/or severity of infectious disease. Several intervention strategies have been proposed to restore immune function. One of the least well-studied approaches to improve immune response is physical exercise. The long term research objectives of our research group are to elucidate the mechanisms underlying the adaptations induced by moderate exercise that enhance immune responsiveness to infectious disease in aged populations. In this application, one goal is to determine the mechanistic adaptations induced by exercise that affect the initial pathways involved in recognition of viral infection that result in enhanced IFNalpha production. A second goal is to identify which of the pathways that can be triggered by IFNalpha lead to improved viral clearance and reduced immunopathology. The specific aims are: 1) Identify the mechanism(s) by which exercise training of aged animals increases IFNalpha production after influenza virus challenge, 2) Determine the extent to which the exercise-induced increase in IFNalpha regulates responses of dendritic cells and CD8+cells, 3) Identify the pathways involved in the response to IFNalpha that are altered by exercise, and 4) Further define the impact of exercise by determining the balance between pro-inflammatory / anti-inflammatory cytokines within the lungs and the subsequent effect on immunopathologically-mediated tissue damage, identify the cells producing these cytokines, and establish the role of IFNalpha as a mediator of these effects. A mouse model of influenza viral infection will be used. Aged BALB/c mice will be assigned to a moderate exercise group for 10 weeks or a non-exercise group. After exercise training, some experiments will involve an in vivo viral challenge to examine immune responses that occur in the intact animals, whereas other experiments will involve the collection of cells from mice after exercise training, and exposure to viral challenge in vitro. Different techniques will be used to identify the type of cells responding to challenge as well as the multiple pathways involved. Upon completion of these studies, we expect to indentify the exercise-induced adaptations involved in cellular defense against viral infection that subsequently shape the evolving immune response resulting in improved viral clearance and reduced immunopathology.