Alveolar host defense to Pneumocytis carinii

描述（由申请人提供）： 卡氏肺囊虫是 肺部典型的机会性病原体。仅卡氏疟原虫肺炎 伴随严重的免疫抑制而发生，其特征通常是 T 和 B 淋巴细胞功能或绝对缺陷。肺泡 巨噬细胞（AM）是肺泡内常驻的免疫调节细胞 空间并负责从肺部清除卡氏疟原虫生物体。 引起免疫抑制的相同因素，例如感染（HIV）或 药物（细胞毒疗法或皮质类固醇）直接或间接损害 AM 功能及其清除机会性感染（例如卡氏疟原虫）的能力。 激活 AM 功能的重要免疫调节剂包括细胞因子，例如细胞因子。 干扰素-γ (IFN-g) 或肿瘤坏死因子-a (TNF-a) 经常缺乏 免疫缺陷期间。多项研究证明了 T 的重要性 宿主对卡氏疟原虫的反应中的 B 淋巴细胞，通常通过重构 这些细胞进入免疫缺陷动物体内并恢复宿主防御。的 AM 在响应中的关键作用经常被假设或忽略。我们有 开发了新的实验方法来评估 AM 的关键作用 体内肺泡宿主防御。 该提案将检验以下假设： 宿主对 卡氏疟原虫等感染的部分原因是 AM 功能缺陷和 调节 AM 功能的因素；相反，纠正这些缺陷将 恢复正常的肺泡宿主反应并控制感染。具体目标 将包括： I. 证明正常或激活的 AM 的重构 将恢复受者 SCID 或免疫缺陷患者的局部肺泡宿主防御 老鼠； 2. 确定重组AM是否显着增强 P. carinii 的附着/吞噬/杀死和肺泡的控制 感染/肺炎； 3. 确定促炎细胞因子的作用 重组 AM 附着/吞噬/杀死卡氏疟原虫的能力 控制肺泡感染/肺炎； 4. 确定是否进行离体基因治疗 AMs 可以纠正肺泡宿主防御中的免疫缺陷并控制 P. 卡里尼肺泡感染/肺炎。如果成功的话，这些研究可能表明 有可能恢复免疫缺陷患者的局部肺泡宿主防御 尽管正在进行全身性免疫抑制，但宿主仍然存在。

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.