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，但尚无有效的疗法来规避不可逆转的改变 与COPD相关的肺功能。此外，COPD的并发症来自急性和慢性 加剧持续的伤害和重塑，增加发病率和死亡率。这 恶化的病理生理学知之甚少，但主要是由于感染引起的炎症。 一些患者更容易受到加重的影响，并代表了相关的“恶化表型” 与COPD依赖于先天和适应性免疫的变化。天然杀手（NK）细胞是一个 在防御感染中很重要的淋巴细胞种群。他们也是 参与通过细胞因子产生来引发和指导主动免疫反应。 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 我们的实验室和其他人确定了吸烟对NK细胞功能的多种影响，这表明这些变化是 COPD加重的病理生理学意义重大。传统上，NK细胞分为不成熟 以及基于CD16和CD56表达的成熟亚群。最近，对 NK细胞显示出令人惊讶的高度表型多样性，并且每个人都有数千个 NK细胞的独特种群。尽管各种NK细胞表面标记的表达提供了线索 关于亚群的功能，每个人群的重要性尚不清楚。因此，我们探测了 来自非吸烟者，吸烟者和COPD患者的NK细胞表型，靶向NK细胞激活的患者 和抑制受体。这些研究揭示了几个独特的NK细胞群体之间的不同 组。进一步的分析表明，NK细胞子集的大小与先前的恶化相关 有95％的信心。基于这些发现，我们假设吸烟改变了NK细胞异质性 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 恶化。我们将以以下特定目的检验这一假设：目标1：定义自然历史 Never and烟民和吸烟者的NK细胞多样性和可塑性。对NK细胞群体的先前分析 随着时间的流逝，基于有限的表型和NK细胞群体的高维分析是 源自一个时间点。促进我们对NK细胞种群异质性的理解 随着时间的流逝，我们将对Never Sugmers的NK细胞可塑性进行3年的前瞻性纵向分析 目前没有COPD的吸烟者。 AIM 2。定义NK细胞种群的改变还是在 在COPD中加重后发生，以确定NK细胞表型作为生物标志物的有用性 未来加重。初步数据确定了与COPD相关的NK细胞子集的变化 恶化。但是，我们不知道这些更改是否先于并预测未来的COPD加剧 或者，由于加剧而出现。此外，如果COPD加剧触发NK的变化 细胞群体，尚不清楚这些扰动是否有限或无限期地存在。目标3。定义 与COPD恶化有关的独特NK细胞群体的功能意义。我们表明 只有15-30％的散装NK细胞对细胞因子刺激反应，对细胞因子的刺激产生了促进的促炎性细胞因子。这 表明特定的亚群（S）具有唯一能够产生响应的能力。 NK细胞具有 在免疫稳态中显而易见的重要性。因此，COPD加剧的未来治疗选择 需要平衡的方法，以反映无需保留/恢复必要效应功能的需求 解除或过度刺激NK细胞。这个目标将在我们的 了解COPD中NK细胞的功能异质性，并揭示了对 与COPD加重有关的NK细胞亚群。