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

描述(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受损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，有效的抗P。在过去20年里，卡氏肺孢子虫肺炎的发病率和死亡率几乎没有变化，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%/例，非艾滋病患者的死亡率甚至更高，高达40%/例。这可能与这样一个事实有关，即有效的抗生素介导的Pc杀伤并不能立即减少PCP的严重免疫病理成分，这种严重的免疫病理成分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特异性免疫介导性炎症反应在PCP相关肺损伤的免疫发病机制中的作用。具体地说，我们已经证明了CD8+T细胞在CD4+T细胞耗尽的宿主中启动这种炎症反应的关键作用。我们的工作假设是宿主对卡氏肺孢子虫感染的T细胞介导的免疫反应是PCP发病率和死亡率的主要贡献因素，了解这种损伤是如何发展的对于有效控制这种反应和改善患者预后是绝对关键的。除了以T细胞为靶点外，我们还发现了T细胞激活下游的特定炎症事件，这些事件可能在PCP相关炎性肺损伤的发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，肿瘤坏死因子-1的产生，以及通过核因子-kB和MAPK增强的细胞信号。我们的目标是进一步确定PCP过程中导致肺损伤的细胞和分子事件的特征，以确定适合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“原则证明”和候选路径。我们乐观地认为，这里概述的实验将导致NIH路线图中强调的转化性临床试验。公共卫生相关性在过去20年中，卡氏肺孢子虫肺炎的发病率和死亡率几乎没有变化，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%/例，非艾滋病患者的死亡率甚至更高，高达40%/例。这项提案中概述的实验旨在导致一项旨在改善卡氏肺孢子虫肺炎患者管理的转化性临床试验。

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.