Natural Killer Cell Subpopulations in COPD Exacerbations

COPD 恶化中的自然杀伤细胞亚群

• 批准号: 10012049
• 负责人: Michael Borchers
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012049
• 关键词: Accounting; Acute; Address; Biological Markers; Cell physiology; Cell surface; Cells; Chronic; Chronic Obstructive Airway Disease; Complex; Data; Data Analyses; Disease; Disease Progression; Environmental Exposure; Exhibits; FCGR3B gene; Failure; Flow Cytometry; Functional disorder; Future; Heart failure; Heterogeneity; Homeostasis; Immune; Immune response; Immune system; Individual; Infection; Inflammation; Injury; Interferon Type II; Lead; Ligands; Longitudinal Studies; Longitudinal prospective study; Lung; Lymphocyte; Molecular; Morbidity - disease rate; NCAM1 gene; Natural History; Natural Immunity; Natural Killer Cells; Patients; Phenotype; Population; Population Heterogeneity; Predisposition; Production; Quality of life; Recording of previous events; Research; Risk; Severities; Smoker; Smoking; Structure; Testing; Time; Veterans; adaptive immunity; base; cigarette smoke; cohort; cytokine; cytotoxicity; dimensional analysis; effective therapy; high dimensionality; immune function; individual variation; innovation; insight; longitudinal analysis; military veteran; mortality; never smoker; non-smoker; novel; pathogen; preservation; prospective; pulmonary function; pulmonary function decline; receptor; response

Despite decades of research, no effective therapies exist to circumvent the irreversible alterations in lung function associated with COPD. Further, complications of COPD arise from acute and chronic exacerbations that amplify ongoing injury and remodeling that increase morbidity and mortality. The pathophysiology of exacerbations is poorly understood, but is primarily due to inflammation from infections. Some patients are more susceptible to exacerbations and represent an `exacerbator phenotype' associated with COPD-dependent changes in innate and adaptive immunity. Natural killer (NK) cells are a heterogeneous population of lymphocytes that are important in the defense against infections. They are also involved in initiating and directing active immune responses through cytokine production. NK cells recognize pathogen-infected cells expressing ligands for an array of activating and inhibitory receptors. Research by our lab and others identified multiple effects of smoking on NK cell function that suggest these changes are significant in the pathophysiology of COPD exacerbations. Traditionally, NK cells were divided into immature and mature subpopulations based on CD16 and CD56 expression. Recently, high-dimensional analysis of NK cells revealed a surprisingly high degree of phenotypic diversity and that each individual has thousands of unique populations of NK cells. Although the expression of various NK cell surface markers provides clues about the function of subpopulations, the significance of each populations is unknown. Therefore, we probed NK cell phenotypes from a cohort of non-smokers, smokers, and COPD patients targeting NK cell activating and inhibitory receptors. These studies revealed several unique NK cell populations that differed between groups. Further analyses showed that the size of NK cell subsets associated with a previous exacerbation with 95% confidence. Based on these findings, we hypothesized that smoking alters NK cell heterogeneity which leads to the emergence of unique populations that can serve as biomarkers of increased risk of COPD exacerbations. We will test this hypothesis with the following Specific Aims: Aim 1: Define the natural history of NK cell diversity and plasticity in never smokers and smokers. Previous analyses of NK cell populations over time are based on limited phenotyping and high-dimensional analyses of NK cell populations have been derived from a single time point. To advance our understanding of the heterogeneity of NK cell populations over time, we will conduct a 3-year prospective longitudinal analysis of NK cell plasticity in never smokers and current smokers without COPD. Aim 2. Define whether alterations in NK cell populations precede or occur following exacerbations in COPD to determine the usefulness of NK cell phenotyping as a biomarker of future exacerbations. Preliminary data identify alterations in NK cell subsets associated with COPD exacerbations. However, we do not know if these alterations precede and predict future COPD exacerbations or if they arise as a consequence of exacerbations. Further, if COPD exacerbations trigger changes in NK cell populations, it is not known if these derangements persist finitely or indefinitely. Aim 3. Define the functional significance of unique NK cell populations associated with COPD exacerbations. We show that only 15-30% of bulk NK cells respond to cytokine stimulation to elaborate proinflammatory cytokines. This indicates that a specific subpopulation(s) is uniquely capable of generating a response. NK cells have obvious importance in immune homeostasis. Therefore, future treatment options for COPD exacerbations require a balanced approach reflecting the need to preserve/restore necessary effector functions without disarming or overstimulating the entirety of the NK cells. This Aim will provide a critical advance in our understanding of the functional heterogeneity of NK cells in COPD and reveal insight into the significance of the NK cell subpopulations associated with COPD exacerbations.

尽管进行了几十年的研究，但目前还没有有效的疗法来绕过心脏不可逆的变化。 与COPD相关的肺功能。此外，慢性阻塞性肺病的并发症由急性和慢性引起。 加剧持续的损伤和重塑，增加发病率和死亡率。这个 病情恶化的病理生理学还知之甚少，但主要是由于感染引起的炎症。 一些患者更容易恶化，并表现出与之相关的“恶化表型”。 COPD依赖的先天免疫和获得性免疫的改变。自然杀伤(NK)细胞是一种 在防御感染中起重要作用的异质淋巴细胞群体。他们也是 参与通过细胞因子的产生启动和引导主动免疫反应的。NK细胞识别 病原体感染的细胞表达一系列激活和抑制受体的配体。研究人员： 我们的实验室和其他人发现了吸烟对NK细胞功能的多种影响，表明这些变化是 在慢性阻塞性肺疾病恶化的病理生理学方面具有重要意义。传统上，NK细胞被分为未成熟的 以CD16、CD56表达为主的成熟亚群。最近，高维分析对 NK细胞显示出惊人的高度表型多样性，每个人有数千个 独特的自然杀伤细胞群体。尽管各种NK细胞表面标志的表达提供了线索 关于亚居群的功能，每个居群的意义尚不清楚。因此，我们探索了 非吸烟者、吸烟者和COPD患者中以NK细胞活化为靶点的NK细胞表型 和抑制性受体。这些研究揭示了几个独特的NK细胞群体，它们之间存在差异 组。进一步的分析表明，NK细胞亚群的大小与先前的病情恶化有关 带着95%的信心。基于这些发现，我们假设吸烟会改变NK细胞的异质性。 这导致了独特人群的出现，这些人群可以作为COPD风险增加的生物标志物 病情加重。我们将通过以下具体目标来检验这一假设：目标1：定义自然历史 从不吸烟者和吸烟者的NK细胞多样性和可塑性。以往对自然杀伤细胞群的分析 随着时间的推移，基于有限的表型和NK细胞群体的高维分析已经被 从单个时间点派生的。为了增进我们对NK细胞群体异质性的理解 随着时间的推移，我们将对从不吸烟者的NK细胞可塑性进行为期3年的前瞻性纵向分析 以及目前没有慢性阻塞性肺病的吸烟者。目标2.确定NK细胞群体的变化是先于还是 在COPD病情恶化后发生，以确定NK细胞表型作为生物标志物的有用性 未来病情恶化的可能性。初步数据确定与COPD相关的NK细胞亚群的变化 病情加重。然而，我们不知道这些改变是否先于和预测未来COPD的恶化 或者如果它们是由于病情恶化而出现的。此外，如果慢性阻塞性肺疾病的恶化引发NK的变化 对于细胞群体，目前还不知道这些错乱是有限的还是无限期的。目标3.定义 与COPD加重相关的独特NK细胞群的功能意义。我们证明了 只有15%-30%的NK细胞对细胞因子刺激有反应，从而产生致炎细胞因子。这 表示特定的亚群(S)是唯一能够产生响应的。NK细胞有 对免疫动态平衡的重要性显而易见。因此，未来COPD恶化的治疗选择 需要一种平衡的方法来反映保存/恢复必要的效应器功能的需要 解除或过度刺激整个NK细胞。这一目标将为我们的 了解慢性阻塞性肺疾病患者NK细胞功能的异质性 自然杀伤细胞亚群与COPD病情加重相关。