Impaired ability of aged human dendritic cells to maintain mucosal tolerance

描述（由申请人提供）：随着年龄的增长，患呼吸系统疾病的风险明显增加。老年人更容易患流感和肺炎等肺部感染，以及哮喘和阻塞性肺病等慢性疾病。其潜在机制尚不清楚。气道不断暴露于各种各样的吸入抗原，其中大多数是无害的。树突状细胞（dc）是一种关键的先天免疫细胞，它对于启动和产生有效的免疫应答来抵抗入侵的病原体以及维持对无害吸入抗原的耐受性至关重要。维生素A代谢物视黄酸（RA）在呼吸道dc的耐受性诱导中起主要作用。我们的初步数据表明，老年受试者的dc对维甲酸的反应受损，导致耐受性丧失。此外，衰老dc还会影响气道上皮细胞的功能，诱导CXCL-10、cccl -26、cccl -20等多种趋化因子的分泌，吸引其他细胞进入气道，增强炎症反应。因此，我们假设来自老年人的dc在维持呼吸道表面耐受性的能力上受损，从而导致慢性炎症和气道重塑，并增加老年人对呼吸道疾病的易感性。我们提案的具体目的是-1)研究老年人dc对RA反应受损的机制；2)确定老年dc中RA代谢降低的功能后果；3)探讨老年DC RA反应改变对DC-上皮细胞串扰的影响。世界范围内的老年人口正在增加，需要更好地了解老年人对呼吸系统疾病易感性增加的机制，以设计新的和更有效的治疗方法。

DESCRIPTION (provided by applicant): The risk of respiratory diseases increases significantly with advancing age. Elderly people are more prone to lung infections such as influenza and pneumonia and chronic illnesses such as asthma and obstructive pulmonary disease. The underlying mechanisms are not well understood. Airways are continuously being exposed to a wide variety of inhaled antigens majority of which are harmless. Dendritic cells (DCs) are key innate immune cells which are critical for initiation and generation of an effective immune response against invading pathogens as well as for maintaining tolerance against harmless inhaled antigens. Vitamin A metabolite, Retinoic acid (RA) plays a major role in inducing tolerance in respiratory DCs. Our preliminary data suggests that DCs from aged subjects are impaired in their response to retinoic acid resulting in loss of tolerance. Furthermore, aged DCs also affect the functions of airway epithelial cells to induce the secretion of various chemokines such as CXCL-10, CCL-26, and CCL-20 which can attract other cells into the airways and enhance inflammation. Therefore, we hypothesize that DCs from aged are impaired in their capacity to maintain tolerance at the respiratory surfaces which results in chronic inflammation and remodeling of the airways and increases the susceptibility of the elderly to respiratory illnesses. Our specific aims for the proposal are -1) to investigate the mechanisms responsible for impaired response of DCs from elderly to RA; 2) to determine the functional consequences of reduced RA metabolism in aged DCs; 3) to investigate the effect of altered RA response of aged DC on DC-epithelial cell crosstalk. Aged population is increasing worldwide and a better understanding of the mechanisms underlying the increased susceptibility of the elderly to respiratory diseases is required for design of novel and more effective treatment.