P. carinii Pneumonia Lung Damage: CD8-driven Cellular and Molecular Events

卡氏疟原虫肺炎肺损伤：CD8 驱动的细胞和分子事件

基本信息

批准号：
8269027
负责人：
Francis Gigliotti
金额：
$ 38.5万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-16 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269027
关键词：
AIDS-Related Pneumocystis Carinii Pneumonia Acquired Immunodeficiency Syndrome Adrenal Cortex Hormones Affect Alveolar Macrophages Antibiotics Antigens Basic Science CD4 Positive T Lymphocytes CD8B1 gene Cells Characteristics Clinic Clinical Trials Design Dose Environment Event Failure Generations Goals Health Immune Immune response Immune system Immunocompromised Host Infection Inflammation Inflammatory Inflammatory Response Injury Integrins Intervention Lead Lung MAP Kinase Gene MAPK8 gene MAPK9 gene Malignant Neoplasms Mediating Medical Modeling Molecular Morbidity - disease rate Mus NF-kappa B Nature Outcome Pathogenesis Pathway interactions Patients Pattern Pneumocystis carinii Pneumocystis carinii Pneumonia Pneumonia Production Role Severities Signal Pathway Signal Transduction Steroids System T cell response T-Cell Activation T-Lymphocyte TNF gene Testing Therapeutic Intervention Tissues Translating Transplant Recipients United States National Institutes of Health Work cell injury cell mediated immune response design human disease immunopathology immunosuppressed improved killings lung injury meetings mortality mouse model research study response translational clinical trial

项目摘要

DESCRIPTION (provided by applicant): Pneumocystis carinii pneumonia (PcP) continues to be a significant cause of morbidity and mortality among patients with AIDS, cancer, transplant recipients, or other immunocompromising illnesses. Despite the many advances in medical practice and the availability of effective anti-P. carinii antibiotics, the morbidity and mortality due to P. carinii pneumonia has changed little in the last 20 years and remains unacceptably high. Overall, mortality is about 10%/episode in AIDS patients and even higher, up to 40%/episode, in non- AIDS patients. This is likely related to the fact that effective antibiotic-mediated killing of Pc does not immediately reduce the severe immunopathological component of PcP that is driven by the concurrent presence of T cells and Pc antigen in the lung. We have established, over the past 9 years, the role of the Pc-specific immune-mediated inflammatory response in the immunopathogenesis of lung injury associated with PcP. Specifically, we have demonstrated a critical role for CD8+ T cells in the initiation of this inflammatory response in the CD4+ T cell depleted host. Our working hypothesis is that the host's T cell-mediated immune response to infection by P. carinii is a major contributor to the morbidity and mortality of PcP, and that understanding how this injury progresses is absolutely critical to the effective control of this response and improving patient outcomes. In addition to targeting T cells, we have identified specific inflammatory events downstream of T cell activation that may have roles in the generation and persistence of PcP-related inflammatory lung injury. These events include the activation of alveolar macrophages (AMs), the production of TNF-1, and enhanced cell signaling through NF-kB and MAPK. Our goal is to further characterize the cellular and molecular events leading to lung injury during PcP for the purpose of identifying specific pathways or combinations of pathways that lend themselves to therapeutic intervention. "Proof of principle" and candidate pathways have been identified during our initial studies. We are optimistic that the experiments outlined herein will lead to translational clinical trials as emphasized in the NIH roadmap. PUBLIC HEALTH RELEVANCE The morbidity and mortality due to P. carinii pneumonia has changed little in the last 20 years and remains unacceptably high. Overall, mortality is about 10%/episode in AIDS patients and even higher, up to 40%/episode, in non-AIDS patients. The experiments outlined in this proposal are designed to lead to a translational clinical trial designed to improve the management of patients with P. carinii pneumonia.

描述（由申请人提供）：卡氏肺孢子虫肺炎（PcP）仍然是艾滋病、癌症、移植受者或其他免疫功能低下疾病患者发病和死亡的重要原因。尽管医学实践取得了许多进步并且有效的抗P.尽管卡氏疟原虫肺炎的发病率和死亡率在过去 20 年中变化不大，但仍然高得令人无法接受。总体而言，艾滋病患者的死亡率约为 10%/发作，非艾滋病患者的死亡率甚至更高，高达 40%/发作。这可能与以下事实有关：有效的抗生素介导的 Pc 杀伤并不能立即减少 PcP 的严重免疫病理学成分，而 PcP 是由肺中同时存在的 T 细胞和 Pc 抗原驱动的。在过去的 9 年里，我们已经确定了 Pc 特异性免疫介导的炎症反应在 PcP 相关肺损伤的免疫发病机制中的作用。具体来说，我们已经证明 CD8+ T 细胞在 CD4+ T 细胞耗尽的宿主中引发这种炎症反应中发挥着关键作用。我们的工作假设是，宿主对卡氏疟原虫感染的 T 细胞介导的免疫反应是导致 PcP 发病和死亡的主要原因，了解这种损伤如何进展对于有效控制这种反应和改善患者的结果。除了靶向 T 细胞外，我们还确定了 T 细胞激活下游的特定炎症事件，这些事件可能在 PcP 相关炎症性肺损伤的产生和持续中发挥作用。这些事件包括肺泡巨噬细胞 (AM) 的激活、TNF-1 的产生以及通过 NF-kB 和 MAPK 增强细胞信号传导。我们的目标是进一步表征 PcP 期间导致肺损伤的细胞和分子事件，以确定有助于治疗干预的特定途径或途径组合。在我们的初步研究中已经确定了“原理证明”和候选途径。我们乐观地认为，本文概述的实验将导致转化临床试验，正如 NIH 路线图所强调的那样。公共卫生相关性卡氏疟原虫肺炎的发病率和死亡率在过去 20 年中变化不大，仍然高得令人无法接受。总体而言，艾滋病患者的死亡率约为 10%/次，非艾滋病患者的死亡率甚至更高，高达 40%/次。该提案中概述的实验旨在开展一项转化性临床试验，旨在改善卡氏疟原虫肺炎患者的治疗。