Natural Killer Cell Subpopulations in COPD Exacerbations

COPD 恶化中的自然杀伤细胞亚群

• 批准号: 10578653
• 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/10578653
• 关键词: Acceleration; Accounting; Activated Natural Killer Cell; Acute; Address; Biological Markers; Cell physiology; Cell surface; Cells; Chronic; Chronic Obstructive Pulmonary 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; Inflammatory; Injury; Interferon Type II; Ligands; Longitudinal Studies; Lung; Lymphocyte; Molecular; Morbidity - disease rate; NCAM1 gene; Natural History; Natural Immunity; Natural Killer Cells; Patients; Phenotype; Population; Population Heterogeneity; Predisposition; Production; Proliferating; Quality of life; Recording of previous events; Research; Risk; Severities; Smoker; Smoking; Structure; Testing; Time; Veterans; adaptive immunity; cigarette smoke; cohort; cytokine; cytotoxicity; dimensional analysis; effective therapy; high dimensionality; immune function; individual variation; innovation; insight; longitudinal analysis; longitudinal, prospective study; 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.

尽管进行了数十年的研究，但没有有效的治疗方法来规避不可逆转的改变， 与COPD相关的肺功能。此外，COPD的并发症由急性和慢性炎症引起。 加重加重持续的损伤和重塑，增加发病率和死亡率。的 急性加重的病理生理学尚不清楚，但主要是由于感染引起的炎症。 一些患者更易发生急性加重，并代表与急性加重相关的“加重表型”。 先天性和适应性免疫的COPD依赖性变化。自然杀伤（NK）细胞是一种 在抵抗感染中起重要作用的淋巴细胞的异质群体。他们也是 参与通过细胞因子产生启动和指导主动免疫应答。NK细胞识别 病原体感染的细胞表达一系列活化和抑制受体的配体。的研究 我们的实验室和其他实验室确定了吸烟对NK细胞功能的多种影响，这表明这些变化是 在COPD急性加重的病理生理学中具有重要意义。传统上，NK细胞被分成未成熟的 以及基于CD 16和CD 56表达的成熟亚群。最近，高维分析 NK细胞显示出令人惊讶的高度表型多样性，每个人都有数千个 独特的NK细胞群。尽管各种NK细胞表面标志物的表达提供了线索 关于亚种群的功能，各种群的意义尚不清楚。因此，我们探测了 靶向NK细胞活化的非吸烟者、吸烟者和COPD患者队列的NK细胞表型 和抑制性受体。这些研究揭示了几种独特的NK细胞群体， 组进一步的分析表明，与既往急性发作相关的NK细胞亚群的大小 95%的信心。基于这些发现，我们假设吸烟改变了NK细胞的异质性 这导致了独特人群的出现，可以作为COPD风险增加的生物标志物 加重我们将用以下具体目标来检验这一假设：目标1：定义自然史 NK细胞的多样性和可塑性在从不吸烟者和吸烟者中的差异。NK细胞群的既往分析 随着时间的推移，基于有限的表型分析和NK细胞群体的高维分析已经成为 从一个时间点开始。进一步了解NK细胞群体的异质性 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 目前吸烟者无COPD。目标2.定义NK细胞群的变化是否先于或 在COPD急性加重后发生，以确定NK细胞表型作为生物标志物的有用性 未来的恶化。初步数据发现与COPD相关的NK细胞亚群变化 加重然而，我们不知道这些改变是否先于并预测未来的COPD加重 或因病情加重而出现。此外，如果COPD加重触发NK细胞的变化， 细胞群中，不知道这些紊乱是否永久或无限期地持续存在。目标3。定义 与COPD恶化相关的独特NK细胞群体的功能意义。我们证明了 只有15-30%的大量NK细胞响应细胞因子刺激以产生促炎细胞因子。这 指示特定亚群唯一能够产生响应。NK细胞具有 在免疫稳态中的重要性。因此，COPD急性加重的未来治疗选择 需要一种平衡的方法，反映需要保留/恢复必要的效应器功能， 解除或过度刺激整个NK细胞。这一目标将为我们的 了解COPD患者NK细胞的功能异质性，并揭示 与COPD急性加重相关的NK细胞亚群。