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

• 批准号: 7877001
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-16 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877001
• 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; 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; 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; public health relevance; research study; response; translational clinical trial

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）：肺炎胸藻肺炎（PCP）仍然是艾滋病，癌症，移植者或其他免疫促进性疾病的患者发病率和死亡的重要原因。尽管医疗实践和有效抗P的可用性有很多进展。 Carinii抗生素，Carinii P. carinii肺炎引起的发病率和死亡率在过去20年中发生了很少的变化，并且仍然无法接受。总体而言，非艾滋病患者的艾滋病患者的死亡率约为10％/发作，甚至更高，甚至高达40％/发作。这可能与以下事实有关：有效的抗生素介导的PC杀死不会立即减少PCP的严重免疫病理成分，而PCP的严重免疫病理成分是由肺中T细胞和PC抗原同时存在驱动的。在过去的9年中，我们确定了PC特异性免疫介导的炎症反应在与PCP相关的肺损伤的免疫发病中的作用。具体而言，我们已经证明了CD8+ T细胞在CD4+ T细胞耗尽宿主中这种炎症反应中的关键作用。我们的工作假设是，宿主的T细胞介导的对Carinii感染的免疫反应是PCP的发病率和死亡率的主要因素，并且了解这种损伤的进展对于有效控制这种反应并改善患者结果绝对至关重要。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久性中具有作用。这些事件包括通过NF-KB和MAPK的激活肺泡巨噬细胞（AMS），TNF-1的产生以及增强的细胞信号传导。我们的目标是进一步表征导致PCP期间肺损伤的细胞和分子事件，目的是确定特定的途径或组合，这些途径或组合将自己借给治疗干预。在我们的初步研究中，已经确定了“原理证明”和候选途径。我们很乐观地认为，此处概述的实验将导致NIH路线图中强调的转化临床试验。公共卫生相关性的发病率和死亡率在过去20年中由于肺炎肺炎而发生的变化很小，而且仍然不可接受。总体而言，非AIDS患者的艾滋病患者的死亡率约为10％/发作，甚至更高，甚至高达40％/发作。该提案中概述的实验旨在进行转化临床试验，旨在改善carinii肺炎患者的治疗。