Effect of Haemophilus influenzae infection on lung CD8+ T cells in COPD

流感嗜血杆菌感染对 COPD 肺 CD8 T 细胞的影响

• 批准号: 8698296
• 负责人: Christine M. Basmajian
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698296
• 关键词: Address; Affect; Animal Model; Antigen-Presenting Cells; Anxiety; Autologous; Biological Assay; Biological Models; CCR5 gene; CD8B1 gene; Cause of Death; Cells; Chronic Obstructive Airway Disease; Coculture Techniques; Consent; Data; Development; Disease; Disease Progression; Emotional; Excision; Family; Flow Cytometry; Goals; Healthcare; Hemophilus influenza infection; Histocompatibility; Human; In Vitro; Infection; Infiltration; Inflammatory; Ligands; Lung; Measures; Mediating; Mediator of activation protein; Medical; Membrane Proteins; Mental Depression; Nontypable Haemophilus influenza; Obstruction; Operative Surgical Procedures; Pathogenesis; Pathologic Processes; Patients; Peptides; Population; Production; Progressive Disease; Pulmonary Function Test/Forced Expiratory Volume 1; Recruitment Activity; Relative (related person); Resources; Respiratory physiology; Scanning; Shortness of Breath; Signal Transduction; Smoker; Specimen; Stable Disease; Structure of parenchyma of lung; Surface; T-Cell Receptor; T-Lymphocyte; TLR2 gene; Techniques; Therapeutic; Tissues; Toll-like receptors; Veterans; X-Ray Computed Tomography; airway remodeling; alveolar destruction; cell type; cytokine; density; drug development; innovation; insight; killings; macrophage; neutrophil; pathogen; prevent; pulmonary function; response

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the U.S., yet there are no current therapeutic treatments to halt the progression of this disease. COPD is characterized by airflow obstruction, variable degrees of airway remodeling and alveolar destruction, and an influx of lung inflammatory cells, including neutrophils, macrophages, and CD8+ T cells. The inverse correlation between numbers of airway CD8+ T cells and lung function, as determined by FEV1, implicates CD8+ T cells in COPD pathogenesis. CD8+ T cells can release inflammatory cytokines and mediators that could contribute to lung destruction. These effectors functions are augmented when lung CD8+ T cells are co-stimulated with synthetic bacterial ligands recognized by toll-like receptors (TLRs), in particular TLR2/1. TLR2/1 is known to recognize the outer membrane protein of nontypeable Haemophilus influenzae (NTHI), one of the predominant bacterial pathogens associated with airway infection in COPD, both in stable disease and as an important infectious trigger of exacerbations. The goal of this study is to determine whether lung CD8+ T cells will respond to NTHI co-stimulation by up-regulating their effector functions, such as secreting inflammatory cytokines, killing autologous lung cells, and recruiting additional CD8+ T cells. To carry out this objective, lung tissue from consented subjects undergoing clinically-indicated surgical resections will be used. Tissue will be obtained from both subjects with and without COPD. Isolated lung CD8+ T cells will be co-cultured with antigen- presenting cells and NTHI to determine what effect NTHI co-stimulation has on the production of effector molecules, which will be measured by flow cytometry. This will be correlated with measures of lung function. The co-culture assay will also be used to determine whether NTHI co-stimulation induces the lung CD8+ T cells to kill autologous lung cells. By isolating CD8+ T cells directly from human lung tissue and using them in vitro to study CD8 and NTHI interactions, we may gain unique insights into how COPD pathogenesis is initiated and progresses.

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）是美国第三大死亡原因，但目前尚无治疗方法可以阻止这种疾病的进展。 COPD 的特征是气流阻塞、不同程度的气道重塑和肺泡破坏以及肺部炎症细胞（包括中性粒细胞、巨噬细胞和 CD8+ T 细胞）的涌入。由 FEV1 确定的气道 CD8+ T 细胞数量与肺功能之间的负相关性表明 CD8+ T 细胞参与 COPD 发病机制。 CD8+ T 细胞可以释放炎症细胞因子和介质，从而导致肺部破坏。当肺 CD8+ T 细胞与 Toll 样受体 (TLR)（特别是 TLR2/1）识别的合成细菌配体共同刺激时，这些效应器功能会增强。 TLR2/1 已知可识别不可分型流感嗜血杆菌 (NTHI) 的外膜蛋白，NTHI 是与 COPD 气道感染相关的主要细菌病原体之一，无论是在疾病稳定期还是病情恶化的重要感染触发因素。本研究的目的是确定肺 CD8+ T 细胞是否会通过上调其效应功能（例如分泌炎症细胞因子、杀死自体肺细胞和招募额外的 CD8+ T 细胞）来对 NTHI 共刺激做出反应。为了实现这一目标，将使用来自接受临床指示手术切除的同意受试者的肺组织。将从患有和未患有慢性阻塞性肺病的受试者身上获取组织。分离的肺 CD8+ T 细胞将与抗原呈递细胞和 NTHI 共培养，以确定 NTHI 共刺激对效应分子产生的影响，这将通过流式细胞术测量。这将与肺功能的测量相关。共培养测定还将用于确定 NTHI 共刺激是否诱导肺 CD8+ T 细胞杀死自体肺细胞。通过直接从人肺组织中分离 CD8+ T 细胞，并在体外使用它们来研究 CD8 和 NTHI 相互作用，我们可能会获得关于 COPD 发病机制如何启动和进展的独特见解。