Alveolar host defense to Pneumocytis carinii

肺泡宿主对卡氏肺孢子虫的防御

• 批准号: 6721249
• 负责人: William J Martin
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721249
• 关键词: Pneumocystis carinii; Pneumocystis pneumonia; SCID mouse; alveolar macrophages; cytokine; disease /disorder model; gene therapy; host organism interaction; leukocyte activation /transformation; microorganism immunology; nonhuman therapy evaluation

DESCRIPTION (provided by the applicant): Pneumocystis carinii is the prototypical opportunistic pathogen in the lung. P. carinii pneumonia only occurs with profound immunosuppression that is often characterized by functional or absolute deficiencies in T and B lymphocytes. Alveolar macrophages (AMs) are the resident immunoregulatory cells of the alveolar spaces and are responsible for clearance of P. carinii organisms from the lung. The same factors that induce immunosuppression such as infections (HIV) or drugs (cytotoxic therapy or corticosteroids) directly and indirectly impair AM function and their ability to clear opportunistic infection such as P. carinii. Important immunomodulators that activate AM function include cytokines e.g. interferon-gamma (IFN-g) or tumor necrosis actor-a (TNF-a) are often deficient during immunodeficiency. Multiple studies have demonstrated the importance of T and B lymphocytes in the host response to P. carinii, often by reconstituting these cells into immunodeficient animals and restoring host defense. The critical role of the AM in the response is often assumed or ignored. We have developed new experimental approaches to assess the critical role of the AMs in vivo in alveolar host defense. This proposal will test the following hypothesis: Host susceptibility to infections such as P. carinii is due in part to deficiencies in AM function and factors that regulate AM function; conversely, correction of these defects will restore normal alveolar host response and control infection. The Specific Aims will include: I .To demonstrate that reconstitution of normal or activated AMs will restore local alveolar host defense in recipient SCID or immunodeficient mice; 2. To determine if reconstituted AM significantly enhance attachment/phagocytosis/killing of P. carinii and control of alveolar infection/pneumonia; 3. To determine the role of proinflammatory cytokines on the ability of reconstituted AMs to attach/phagocytose/kill P. carinii and to control alveolar infection/pneumonia; 4. To determine if ex vivo gene therapy to AMs corrects immune deficiencies in alveolar host defense and controls P. carinii alveolar infection/pneumonia. If successful, these studies may suggest it is possible to restore local alveolar host defense in an immunodeficient host despite ongoing systemic immunosuppression.

描述（由申请人提供）：肺炎雄杆菌是 肺中的原型机会病原体。仅P. carinii肺炎 以深刻的免疫抑制发生，通常以 T和B淋巴细胞中的功能或绝对缺陷。牙槽 巨噬细胞（AMS）是肺泡的常驻免疫调节细胞 空间，并负责从肺部清除Carinii生物。 诱导免疫抑制的相同因素，例如感染（HIV）或 药物（细胞毒性疗法或皮质类固醇）直接和间接损害AM 功能及其清除机会性感染（例如Carinii）的能力。 激活AM功能的重要免疫调节剂包括细胞因子，例如 干扰素 - γ（IFN-G）或肿瘤坏死Actor-A（TNF-A）通常不足 在免疫缺陷期间。多项研究表明了T的重要性 通常通过重新建立，宿主对carinii的宿主反应中的B淋巴细胞 这些细胞进入免疫缺陷动物并恢复宿主防御。这 AM在响应中的关键作用通常被假定或忽略。我们有 开发了新的实验方法，以评估AMS的关键作用 肺泡宿主防御中的体内。 该建议将检验以下假设：宿主对 诸如Carinii之类的感染部分是由于AM功能和 调节AM功能的因素；相反，对这些缺陷的纠正将 恢复正常的肺泡宿主反应和对照感染。具体目标 将包括：i。证明正常或激活的AM的重建 将在受体SCID或免疫缺陷中恢复本地肺泡宿主防御 小鼠； 2。确定重组是否显着增强 carinii的附着/吞噬作用/杀死肺泡的控制 感染/肺炎； 3。确定促炎细胞因子在 重组AMS连接/吞噬/杀死P. carinii的能力 控制肺泡感染/肺炎； 4。确定离体基因治疗是否 为了纠正肺泡宿主防御和控制中的免疫缺陷。 Carinii肺泡感染/肺炎。如果成功，这些研究可能表明 可以在免疫缺陷中恢复局部肺泡宿主防御 尽管有持续的系统性免疫抑制，但宿主。