Alveolar host defense to Pneumocytis carinii

描述(申请人提供)：卡氏肺孢子虫是 肺部有典型的机会性病原体。仅限卡氏肺炎杆菌 出现严重的免疫抑制，其特征通常是 T和B淋巴细胞的功能性或绝对缺陷。牙槽骨 巨噬细胞是肺泡的常驻免疫调节细胞。 并负责清除肺部的卡氏肺孢子虫生物。 导致免疫抑制的相同因素，如感染(HIV)或 药物(细胞毒治疗或皮质类固醇)直接或间接损害AM 功能及其清除卡氏肺孢子虫等机会性感染的能力。 激活AM功能的重要免疫调节剂包括细胞因子，如 干扰素-g或肿瘤坏死因子-a经常缺乏。 在免疫缺陷期间。多项研究已经证明了T的重要性 和B淋巴细胞在宿主对卡氏肺孢子虫的反应中，通常通过重组 这些细胞转化为免疫缺陷动物并恢复宿主防御。这个 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来评估空管系统在 活体在肺泡宿主防御中。 这一提议将检验以下假设：宿主对 像卡氏肺孢子虫这样的感染部分是由于AM功能和 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，控制感染。具体目标 将包括：i.演示正常或激活的AM的重建 将恢复受体SCID或免疫缺陷患者的局部肺泡宿主防御 小鼠；2.测定重组AM是否显著增强 卡氏肺孢子虫附着/吞噬/杀灭与肺泡控制 感染/肺炎；3.确定促炎细胞因子在 重组AM黏附/吞噬/杀灭卡氏肺孢子虫和 控制肺泡感染/肺炎；4.确定体外基因治疗 TO AM纠正了肺泡宿主防御的免疫缺陷，控制了P。 卡氏肺泡感染/肺炎。如果成功，这些研究可能会表明 免疫缺陷患者的局部肺泡宿主防御是可能的 尽管正在进行全身免疫抑制，但仍是宿主。

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.