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: 8457980
• 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/8457980
• 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）：