Impaired ability of aged human dendritic cells to maintain mucosal tolerance

衰老的人类树突状细胞维持粘膜耐受性的能力受损

• 批准号: 8927521
• 负责人: Anshu Agrawal
• 金额: $ 30.72万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927521
• 关键词: Affect; Age; Air; All-Trans-Retinol; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Asthma; B-Lymphocytes; Bacteria; Blood; Body Surface; Breathing; Cell Aging; Cell physiology; Cells; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Cytokine Activation; Data; Defect; Dendritic Cells; Elderly; Enzyme Gene; Enzymes; Epithelial Cells; Esophagus; Food; Gene Expression; Generations; Genes; Genital system; Goals; Health; Human; Immune; Immune response; Immune system; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Influenza; Integrins; Interferon Type I; Interleukin-10; Invaded; Leukocytes; Lung; Lung diseases; Lymphoid; Maintenance; Metabolism; Morbidity - disease rate; Mucous Membrane; Mus; Organ; Pathway interactions; Play; Pneumonia; Population; Predisposition; Production; RXR; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Respiratory Mucosa; Respiratory System; Respiratory Tract Infections; Retinoic Acid Receptor; Risk; Role; Signal Pathway; Skin; Surface; T cell response; T-Lymphocyte; TSLP gene; Therapeutic Intervention; Time; Toxic Environmental Substances; Tretinoin; Up-Regulation; Vitamin A; aged; airway inflammation; airway remodeling; autocrine; base; cell age; chemokine; cytokine; design; effective therapy; gastrointestinal system; human subject; migration; mortality; mucosal site; novel; pathogen; prevent; programs; respiratory; response

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.

描述（由申请人提供）：随着年龄的增长，呼吸系统疾病的风险显着增加。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。其基本机制尚不清楚。呼吸道持续暴露于多种吸入抗原，其中大多数是无害的。树突状细胞 (DC) 是关键的先天免疫细胞，对于启动和产生针对入侵病原体的有效免疫反应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) 在诱导呼吸道 DC 耐受方面发挥着重要作用。我们的初步数据表明，老年受试者的树突状细胞对视黄酸的反应受损，导致耐受性丧失。此外，老化的DC还会影响气道上皮细胞的功能，诱导CXCL-10、CCL-26和CCL-20等多种趋化因子的分泌，这些趋化因子可以吸引其他细胞进入气道并增强炎症。因此，我们假设老年人的树突状细胞维持呼吸道表面耐受性的能力受损，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。我们该提案的具体目标是 -1) 研究导致老年人 DC 对 RA 反应受损的机制； 2) 确定衰老 DC 中 RA 代谢减少的功能后果； 3) 研究老化DC的RA反应改变对DC-上皮细胞串扰的影响。全球老年人口不断增加，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，以设计新颖且更有效的治疗方法。