Interactions of smoking, PD-1 and IL-10 in HIV-associated lung disease

吸烟、PD-1 和 IL-10 在 HIV 相关肺部疾病中的相互作用

• 批准号: 8743257
• 负责人: Thomas B. Campbell
• 金额: $ 66.85万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743257
• 关键词: Acquired Immunodeficiency Syndrome; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antigens; Bacterial Pneumonia; Blood; CD8B1 gene; Case-Control Studies; Cell physiology; Cells; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Cigarette Smoker; Clinical; Complication; Data; Development; Diagnostic radiologic examination; Frequencies; Functional disorder; Generations; HIV; HIV-1; Health; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Incidence; Individual; Infection; Inflammatory; Injury; Interleukin-10; Irrigation; Lead; Life Expectancy; Link; Lipopolysaccharides; Liquid substance; Lung; Lung diseases; Measures; Modeling; Morbidity - disease rate; Natural Immunity; Pathway interactions; Patients; Persons; Phenotype; Physiological; Physiology; Pneumonia; Population; Production; Property; Pulmonary Emphysema; Respiratory physiology; Risk; Secondary to; Signal Pathway; Smoker; Smoking; Specimen; T-Lymphocyte; T-Lymphocyte Subsets; TLR4 gene; TNF gene; Testing; Therapeutic; Time; Tumor Necrosis Factor-alpha; Viral; adaptive immunity; antiretroviral therapy; base; cigarette smoking; cigarette smoking; cytokine; disease phenotype; disorder control; exhaustion; experience; human TNF protein; human subject; immunoregulation; improved; lung development; lung injury; monocyte; mortality; non-smoker; pathogen; premature; programs; public health relevance; pulmonary function; receptor; respiratory; response; translational study

DESCRIPTION (provided by applicant): The lung has been recognized as one of the main targets of infectious and non-infectious complications of human immunodeficiency virus type 1 (HIV-1) infection. Despite the initiation of anti-retroviral therapy (ART), pulmonary complications of HIV-1/AIDS continue to be a major cause of morbidity and mortality in HIV-1-infected patients, with bacterial pneumonia and chronic obstructive pulmonary disease (COPD) being the most commonly identified pulmonary diseases. Following pneumonia, these individuals experience a decrement in lung function, which is not observed in HIV-1-uninfected populations, and a subset of HIV-1-infected smokers develop an accelerated form of emphysema. However, the mechanisms underlying the increased risk of pneumonia and COPD in HIV-1-infected individuals are not well understood. In this regard, smoking and COPD are associated with a re-programming of alveolar macrophages towards an immune phenotype associated with immunoregulation. In HIV-1-infected subjects, increased expression of the anti-inflammatory cytokine IL-10 in blood and bronchoalveloar lavage (BAL) fluid occurs. Our preliminary data show that alveolar macrophages (AMs) from HIV-1-infected smokers and nonsmokers secrete increased amounts of IL-10 in response to lipopolysaccharide (LPS) compared to uninfected individuals and that cigarette smoke exposure reduced LPS-induced TNF-alpha secretion from AMs. Importantly, a link between increased expression of the coinhibitory receptor programmed death 1 (PD-1) on blood monocytes and IL-10 secretion in HIV-1-infected subjects has been observed. PD-1 is upregulated on T cells in the setting of chronic antigen exposure, contributing to T cell dysfunction and an inability to clear HIV-1. Our preliminary data further show that HIV-1- specific CD4+ and CD8+ T cells in the lung have upregulated expression of PD-1 compared to T cells in blood, resulting in a dysfunctional T cell phenotype. Based on these findings, we hypothesize that the immunoregulatory consequences of increased IL-10 secretion from AMs, a dysfunctional T cell phenotype and HIV-1-induced immunosuppression combine to predispose the HIV-1-infected lung to infection and injury, thereby hastening the development of COPD in HIV-1-infected smokers. Using blood and BAL cells from smokers and nonsmokers with and without HIV-1 infection, we will determine the effects of HIV-1 and smoking on PD-1 expression and IL-10 production by AMs in specific aim 1. The second aim will evaluate the relationship between PD-1 and IL-10 expression on AMs and their effects on T cell function in the lung before and after ART. In specific aim 3, we will use a case-control study to evaluate AM and T cell function in relation to physiologic measures of lung function and COPD development. These studies will advance our understanding of the effects of cigarette smoking on innate and adaptive immunity in the HIV- 1-infected lung and the relationship of these responses to the development of chronic lung disease.

描述（由申请人提供）：肺已被公认为是人类免疫缺陷病毒1型（HIV-1）感染的传染性和非感染并发症的主要靶标之一。尽管开始了抗逆转录病毒疗法（ART），但肺部并发症 HIV-1/AIDS的主要原因是HIV-1感染患者发病率和死亡率的主要原因，细菌性肺炎和慢性阻塞性肺疾病（COPD）是最常见的肺部疾病。在肺炎之后，这些个体的肺功能降低，在HIV-1未感染的种群中未观察到，而HIV-1感染的吸烟者的一部分会形成一种加速的肺气肿。但是，尚不清楚HIV-1感染者肺炎和COPD风险增加的机制。在这方面，吸烟和COPD与对与免疫调节有关的免疫表型的肺泡巨噬细胞的重新编程有关。在HIV-1感染的受试者中，出现抗炎细胞因子IL-10在血液和支气管阿拉维洛尔灌洗（BAL）液中的表达增加。我们的初步数据表明，与未感染的个体相比，来自HIV-1感染的吸烟者的肺泡巨噬细胞（AMS）会增加IL-10的量增加IL-10，而香烟烟雾暴露降低了LPS诱发的TNF-Alpha诱导的TNF-Alpha分泌。重要的是，已经观察到已经观察到了HIV-1感染受试者对共抑制受体编程死亡1（PD-1）的表达增加与IL-10分泌之间的联系。在慢性抗原暴露的情况下，PD-1在T细胞上上调，导致T细胞功能障碍和无法清除HIV-1。我们的初步数据进一步表明，与血液中的T细胞相比，肺中HIV-1-特异性CD4+和CD8+ T细胞的表达上调，导致功能失调的T细胞表型。基于这些发现，我们假设增加了AMS的IL-10分泌的免疫调节后果，功能障碍的T细胞表型和HIV-1诱导的免疫抑制与HIV-1感染的HIV-1感染的肺对感染和受伤的结合，从而使COPD在HIV-1 Infefcted Infected Smokers In hiv-1烟雾中加速。使用有或没有HIV-1感染的吸烟者和非吸烟者的血液和BAL细胞，我们将确定HIV-1和吸烟对PD-1表达的影响，而AMS在特定目标1中由AMS产生的IL-10产生。第二个目标将评估PD-1和IL-10和IL-10表达对AMS的关系及其对AMS对T细胞在ART肺部功能的影响。在特定目标3中，我们将使用病例对照研究来评估与肺功能和COPD发育的生理测量有关的AM和T细胞功能。这些研究将提高我们对吸烟对艾滋病毒1感染的肺的先天和适应性免疫的影响以及这些反应对慢性肺部疾病发展的关系。