Alveolar host defense to Pneumocytis carinii

描述（由申请人提供）：卡氏肺孢子虫是 典型的机会致病菌仅卡氏肺孢子虫肺炎 发生严重的免疫抑制，其特征通常是 T和B淋巴细胞的功能或绝对缺陷。肺泡 巨噬细胞（AM）是肺泡的常驻免疫调节细胞， 间隙，并负责从肺中清除卡氏肺孢子虫。 诱导免疫抑制的相同因素，如感染（艾滋病毒）或 药物（细胞毒疗法或皮质类固醇）直接或间接损害AM 功能和清除机会性感染如卡氏肺孢子虫的能力。 激活AM功能的重要免疫调节剂包括细胞因子，例如， 干扰素-γ（IFN-g）或肿瘤坏死因子-α（TNF-α）常常缺乏 在免疫缺陷期间。多项研究表明，T 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 这些细胞进入免疫缺陷动物和恢复宿主防御。的 AM在响应中的关键作用经常被假定或忽略。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。 该提案将测试以下假设：宿主对 感染如卡氏肺孢子虫部分是由于AM功能的缺陷， 调节AM功能的因素;相反，纠正这些缺陷将 恢复正常肺泡宿主反应并控制感染。具体目标 将包括：I .证明正常或活化AM的重建 将恢复接受者SCID或免疫缺陷的局部肺泡宿主防御 小鼠; 2.为了确定重组AM是否显著增强 卡氏肺孢子虫的附着/吞噬/杀死和肺泡 感染/肺炎; 3.为了确定促炎细胞因子在 重组AM附着/吞噬/杀死卡氏肺孢子虫和 控制肺泡感染/肺炎; 4.为了确定离体基因治疗 对AM的作用纠正了肺泡宿主防御中的免疫缺陷并控制了P. 卡氏肺泡感染/肺炎。如果成功，这些研究可能表明 在免疫缺陷的小鼠中， 尽管进行全身免疫抑制。

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.