Exercise-induced immunomodulation in the aged: Mechanisms

描述(由申请人提供)：随着年龄的增长，免疫反应性显著下降。免疫衰老的临床后果包括增加对传染病的易感性和/或严重性。已经提出了几种恢复免疫功能的干预策略。研究最少的提高免疫反应的方法之一就是体育锻炼。我们研究组的长期研究目标是阐明适度运动诱导的适应机制，以提高老年人群对传染病的免疫反应。在这项应用中，一个目标是确定运动诱导的机械性适应，这些适应影响识别病毒感染的初始途径，从而导致IFNpha产生增加。第二个目标是确定哪些途径可以由干扰素α触发，从而改善病毒清除和降低免疫病理学。其具体目标是：1)确定老年动物在流感病毒攻击后运动训练增加IFNα产生的机制(S)，2)确定运动诱导的IFNα增加调节树突状细胞和CD8+细胞反应的程度，3)确定运动改变对IFNα反应的途径，4)通过确定肺内促炎/抗炎细胞因子之间的平衡以及随后对免疫病理介导的组织损伤的影响来进一步确定运动的影响，确定产生这些细胞因子的细胞，并确定IFNα作为这些效应的介体的作用。将使用流感病毒感染的小鼠模型。将老龄BALB/c小鼠分为中度运动组和非运动组，每组10只。运动训练后，一些实验将涉及体内病毒挑战，以检查在完整动物中发生的免疫反应，而其他实验将涉及在运动训练后从小鼠身上收集细胞，并在体外暴露于病毒挑战。不同的技术将被用来识别对挑战做出反应的细胞类型以及涉及的多条途径。在这些研究完成后，我们希望确定运动诱导的适应涉及对病毒感染的细胞防御，从而塑造不断演变的免疫反应，从而改善病毒清除和降低免疫病理学。

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.