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Mechanistic Study of Stroke-induced Immune Suppression and Identification of Immune Modulatory Targets for Stroke-associated Pneumonia

中风引起的免疫抑制机制研究及中风相关肺炎免疫调节靶点的鉴定

基本信息

批准号：
10217167
负责人：
EDWIN CHI KEUNG WAN
金额：
$ 29.99万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-08 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10217167
关键词：
Acute Adoptive Transfer Alveolar Macrophages Animal Model Anti-Bacterial Agents Antibiotic Therapy B-Lymphocytes Bacterial Antibiotic Resistance Bacterial Infections Brain Brain Ischemia CCL2 gene CCL22 gene Cell Separation Cell physiology Cells Centers of Research Excellence Chemotactic Factors Clinical Congenic Strain Coupled Data Dendritic Cells Event Goals Gold Host Defense ITGAM gene Immune Immunity Immunosuppression Impairment Incidence Infection Infiltration Inflammatory Innate Immune Response Ischemic Stroke Kinetics Label Lung Lung infections Lymphocyte Lymphocyte Count Mediator of activation protein Middle Cerebral Artery Occlusion Molecular Mouse Strains Multi-site clinical study Mus Natural Immunity Natural Killer Cells Organ Outcome Outcome Study PTPRC gene Pathway interactions Patients Peripheral Phagocytes Phase Pneumonia Predisposition Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pulmonary Pathology RANTES Reporter Research Role Severities Site Stroke T-Lymphocyte Testing Transgenic Organisms Universities Urinary tract infection Virus West Virginia acquired immunodeficiency antigen-specific T cells bactericide cell type chemokine congenic cytokine functional disability improved ineffective therapies macrophage monocyte mortality mouse model neutralizing antibody neutrophil new therapeutic target novel therapeutic intervention post stroke prophylactic recruit small molecule inhibitor stroke event stroke patient stroke therapy time use trafficking

项目摘要

Project Summary/Abstract Stroke-associated pneumonia (SAP) is the major cause of mortality in patients who have suffered from acute ischemic stroke. Multi-center clinical studies suggested that prophylactic antibiotic treatments do not reduce the incidence of mortality or SAP. Moreover, the emergence of antibiotic resistant bacteria renders the “gold standard” antibiotic treatments ineffective. Therefore, novel therapeutic strategies are needed to improve clinical outcomes. Studies utilizing animal models of focal brain ischemia demonstrated that stroke-induced immune suppression is one of the causes of SAP. The overall goal of this proposal is to understand the cause of stroke-induced immune suppression and identify novel therapeutic targets for SAP. Innate immune cells including neutrophils, monocytes, macrophages, and dendritic cells (DCs) are the first line of lung immune defense, which is followed by subsequent recruitment and activation of the antigen-specific T and B cells. In phase one of the Stroke CoBRE, we used transient middle cerebral artery occlusion (tMCAO), a mouse model of focal brain ischemia, to analyze immune cell niches in the brain and the lungs, as well as determined the expression of inflammatory cytokines and chemokines in the lungs after ischemic stroke induction. Our preliminarily data demonstrate that 1) ischemic stroke increases the number of alveolar macrophages, CD11b+ DCs, and neutrophils in the lungs, but monocyte number remains unchanged despite an increased expression of monocyte chemoattractant CCL2; 2) monocyte number is significantly increased in the brain after ischemic stroke induction; 3) ischemic stroke decreases the number of T cells, B cells, and NK cells in the lungs, correlating with the reduction of chemokines CCL5 and CCL22. These observations suggest that ischemic stroke events alter the immune cell niches in the lungs and potentially impair their functions. Using tMCAO coupled with P. aeruginosa infection, we propose to further test our hypothesis that SAP is caused by the impairment of the lung-specific, anti-bacterial innate immunity. Our hypothesis will be tested in three aims. In Aim 1, we will determine the phagocytic and bactericidal activities of innate immune cells in the lungs following tMCAO and P. aeruginosa infection. In Aim 2, we will test our hypothesis that monocyte infiltration to the brain after ischemic stroke impedes their infiltrating to the lungs, and thereby contributes to SAP. We will test this hypothesis by adoptive transfer of purified monocytes from B6 CD45.2 mice to the B6 CD45.1 congenic strain recipient mice, followed by tMCAO and P. aeruginosa infection. In Aim 3, we will investigate the protective role of CCL5 and CCL22 in SAP by determining if intratracheal administration of these chemokines restores lymphocyte availability and reduces severity of SAP. We are hopeful that this research will identify key immune cell types, molecular pathways, and downstream mediators that are critical for the host defense against lung infections following ischemic stroke, and ultimately improve clinical outcomes.

项目总结/文摘