MECHANISMS OF INTERSTITIAL PNEUMONITIS IN MURINE AIDS

间质性肺炎（IP）在很大程度上导致了 成人和儿童艾滋病的非感染性肺部并发症。 动物 显示免疫缺陷相关IP的模型将是非常宝贵的， 对该病发病机制的研究。 我们 最近发表的研究表明，艾滋病的鼠逆转录病毒模型（MAIDS）， 由LP-BM 5鼠白血病病毒引起，表现为弥漫性间质性 以T细胞、B细胞和 巨噬细胞，扩散能力下降，随后发展 肺纤维化和血管性肺动脉高压疾病。 这 艾滋病的鼠逆转录病毒模型将用于测试以下内容 假说. 逆转录病毒引起的间质性肺炎 免疫缺陷是由病毒特异性或 自身免疫性T细胞和巨噬细胞进入肺部，导致慢性 原位细胞因子分泌和效应细胞功能。 时间变化 在IP发展过程中T和B淋巴细胞亚群的变化 通过流式细胞术和免疫组织学研究分析。 合成 T细胞和巨噬细胞细胞因子与LP-BM 5复制的关系 间质性炎症发展过程中肺中的逆转录病毒将 通过ELISA、生物测定和聚合酶链反应进行分析。 的 淋巴细胞亚群对IP发生的贡献将是 通过将淋巴细胞过继转移至遗传易感的 C57 B1/6小鼠和淋巴细胞缺陷的SCID小鼠中。 以确定是否 MAIDS感染小鼠肺T和B淋巴细胞特异性是抗- 体外病毒或自身免疫性抗原诱导的细胞因子分泌， 支气管肺泡灌洗抗体与肺组织切片的结合将被 分析了 淋巴细胞归巢受体的表达与血管生成 MAIDS相关IP中的地址素将通过流式细胞术测定， 免疫组织学和这些粘附分子在IP中的功能 将通过体内抗体阻断来分析显影。 是否肺 T细胞诱导巨噬细胞源性细胞因子的分泌将是 通过体外组织培养研究和在病毒感染的SCID中测定 小鼠 最后，细胞因子在MAIDS中IP发展中的作用 感染的小鼠将通过用抗- 细胞因子抗体 这些研究的结果将确定 抗原特异性淋巴细胞在IP发展中的作用， 特异性细胞粘附分子和细胞因子 导致免疫缺陷相关的间质性肺炎， 艾滋病的鼠逆转录病毒模型。

Interstitial pneumonitis (IP) contributes significantly to the noninfectious pulmonary complications in adult and pediatric AIDS. Animal models which display immunodeficiency-associated IP will be invaluable to investigations into the pathogenic mechanisms of this disease. We recently published that the murine retroviral model of AIDS (MAIDS), caused by the LP-BM5 murine leukemia virus, displays diffuse interstitial pneumonitis characterized by accumulation of T cells, B cells and macrophages, a decrease in diffusing capacity and subsequent development of pulmonary fibrosis and vascular pulmonary hypertensive disease. This murine retroviral model of AIDS will be used to test the following hypothesis. Interstitial pneumonitis in the setting of retroviral-induced immunodeficiency is caused by homing and activation of virus-specific or autoimmune T cells and macrophages to the lungs, leading to chronic cytokine secretion and effector cell function in situ. Temporal changes in T and B lymphocyte subsets during the development of IP will be analyzed by flow cytometric and immunohistological studies. The synthesis of T cell and macrophage cytokines and the replication of LP-BM5 retrovirus in lungs during development of interstitial inflammation will be analyzed by ELISA, bioassay and polymerase chain reaction. The contribution of lymphocyte subsets to the development of IP will be analyzed by adoptive transfer of lymphocytes into genetically susceptible C57B1/6 mice and in lymphocyte-deficient SCID mice. To ascertain whether pulmonary T and B lymphocyte specificity in MAIDS infected mice is anti- viral or autoimmune, antigen-induced cytokine secretion in vitro and binding of bronchoalveolar lavage antibody to lung tissue sections will be analyzed. The expression of lymphocyte homing receptors and vascular addressins in MAIDS-associated IP will be determined by flow cytometry, immunohistology and the function of these adhesion molecules in IP development will be analyzed by antibody blocking in vivo. Whether lung T cells induce secretion of macrophage-derived cytokines will be determined by in vitro tissue culture studies and in virus-infected SCID mice. Finally, the role of cytokines in the development of IP in MAIDS infected mice will be determined by blocking studies in vivo with anti- cytokine antibodies. The results of these studies will identify the role of antigen-specific lymphocytes in the development of IP and characterize the mechanism by which specific cellular adhesion molecules and cytokines contribute to immunodeficiency-associated interstitial pneumonitis in this murine retroviral model of AIDS.