MECHANISMS OF INTERSTITIAL PNEUMONITIS IN MURINE AIDS

间质性肺炎(IP)在 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的模型将对 探讨该病的致病机制。我们 最近发表的小鼠艾滋病逆转录病毒模型(女佣)， 由LP-BM5小鼠白血病病毒引起，表现为弥漫性间质 肺炎的特征是T细胞、B细胞和 巨噬细胞，弥散能力下降和随后的发育 肺纤维化和血管性肺动脉高压疾病。这 小鼠艾滋病逆转录病毒模型将用于检测以下内容 假设。逆转录病毒诱导的间质性肺炎 免疫缺陷是由病毒特异的或激活的 自身免疫T细胞和巨噬细胞进入肺部，导致慢性 细胞因子的分泌和效应细胞的原位功能。时间变化 在T和B淋巴细胞亚群的发育过程中会出现IP 通过流式细胞仪和免疫组织学研究进行分析。综合 T细胞和巨噬细胞因子与Lp-BM5的复制 肺内逆转录病毒在间质炎症发展过程中会 用酶联免疫吸附试验、生物测定法和聚合酶链式反应进行分析。这个 淋巴细胞亚群对IP发展的贡献将是 通过将淋巴细胞过继转移到遗传易感人群中进行分析 C57B1/6小鼠和淋巴细胞缺陷SCID小鼠。以确定是否 女佣感染小鼠肺T和B淋巴细胞的特异性 病毒或自身免疫，抗原诱导的细胞因子体外分泌和 支气管肺泡灌洗抗体与肺组织切片的结合将是 分析过了。淋巴细胞归巢受体与血管的表达 将通过流式细胞术来确定MAIDS相关IP中的地址， 免疫组织学及这些黏附分子在IP中的作用 将通过体内抗体阻断来分析发育情况。是否肺 T细胞诱导分泌的巨噬细胞衍生细胞因子将被 由体外组织培养研究和病毒感染的SCID确定 老鼠。最后，细胞因子在女佣IP发生中的作用 感染的小鼠将通过体内阻断研究来确定 细胞因子抗体。这些研究的结果将确定该角色 抗原特异性淋巴细胞在IP发病中的作用及特性 特定的细胞黏附分子和细胞因子的机制 导致免疫缺陷相关的间质性肺炎 小鼠艾滋病逆转录病毒模型。

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.