Natural Killer Cell Subpopulations in COPD Exacerbations

COPD 恶化中的自然杀伤细胞亚群

基本信息

项目摘要

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.
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项目成果

期刊论文数量(0)
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会议论文数量(0)
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Michael Borchers其他文献

Michael Borchers的其他文献

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{{ truncateString('Michael Borchers', 18)}}的其他基金

Molecular and Cellular Pathogenesis of Pulmonary Langerhans Cell Histiocytosis
肺朗格汉斯细胞组织细胞增多症的分子和细胞发病机制
  • 批准号:
    10658208
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Natural Killer Cell Subpopulations in COPD Exacerbations
COPD 恶化中的自然杀伤细胞亚群
  • 批准号:
    10316151
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Natural Killer Cell Subpopulations in COPD Exacerbations
COPD 恶化中的自然杀伤细胞亚群
  • 批准号:
    10578653
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Natural Killer Cell Functions in Lymphangioleiomyomatosis
自然杀伤细胞在淋巴管平滑肌瘤病中的功能
  • 批准号:
    10323021
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Clec5a regulation of Macrophage function in COPD
Clec5a 对 COPD 巨噬细胞功能的调节
  • 批准号:
    8696486
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Clec5a regulation of Macrophage function in COPD
Clec5a 对 COPD 巨噬细胞功能的调节
  • 批准号:
    9040253
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Clec5a regulation of Macrophage function in COPD
Clec5a 对 COPD 巨噬细胞功能的调节
  • 批准号:
    9247243
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Novel Reagents in Mouse Models of Autoimmune COPD
自身免疫性慢性阻塞性肺病小鼠模型中的新型试剂
  • 批准号:
    8166497
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Novel Reagents in Mouse Models of Autoimmune COPD
自身免疫性慢性阻塞性肺病小鼠模型中的新型试剂
  • 批准号:
    8313878
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Shared Mechanisms of Pulmonary Lymphocyte Activation by Bacteria and Toxicants
细菌和毒物激活肺淋巴细胞的共同机制
  • 批准号:
    7163144
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:

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