Clark J G, Madtes D K, Hackman R C, Chen W, Cheever M A, Martin P J
Department of Medicine, University of Washington, Seattle 98195, USA.
J Immunol. 1998 Aug 15;161(4):1913-20.
We have investigated a murine model of acute lung injury caused by i.v. administration of a T cell clone (CD4+, Th1 phenotype) that recognizes Ly5, a polymorphic cell surface glycoprotein expressed on hemopoietic cells. Alloreactive cloned T cells, specific for host Ly5 Ag, cause a mononuclear cell pulmonary vasculitis and interstitial pneumonitis. In further studies of the cellular mechanisms involved in this model, we found that mature host T cells or B cells are not required, since lung injury was comparable in transgenic host mice that lack these cells (RAG-1 knockout). Cloned T cells labeled in vitro with bromodeoxyuridine were localized in inflammation foci in lung, but the majority of cells in the foci were not labeled. Using transgenic mice that constitutively express lacZ, we determined that the mononuclear cell vasculitis is of host cell origin. Alveolar macrophages (AM) from T cell-treated mice spontaneously secreted TNF-alpha in culture, whereas TNF-alpha was not detected in AM cultures from control mice. TNF-alpha production in response to LPS stimulation was significantly higher in AM cultures derived from T cell-treated mice than in those from control mice. Challenge with sublethal doses of LPS resulted in 50% mortality in T cell-treated mice and was associated with augmented AM TNF-alpha production and protein in bronchoalveolar lavage fluid. We conclude that immune activation of T cells of the Th1 phenotype can initiate lung injury characterized by a host-derived mononuclear cell inflammation and activation of AM.
我们研究了一种急性肺损伤的小鼠模型，该模型由静脉注射一种识别Ly5的T细胞克隆（CD4 +，Th1表型）引起，Ly5是一种在造血细胞上表达的多态性细胞表面糖蛋白。对宿主Ly5抗原具有特异性的同种反应性克隆T细胞会导致单核细胞肺血管炎和间质性肺炎。在对该模型所涉及的细胞机制的进一步研究中，我们发现成熟的宿主T细胞或B细胞并非必需，因为在缺乏这些细胞的转基因宿主小鼠（RAG - 1基因敲除小鼠）中，肺损伤情况相当。体外用溴脱氧尿苷标记的克隆T细胞定位于肺内的炎症病灶，但病灶中的大多数细胞未被标记。使用组成性表达lacZ的转基因小鼠，我们确定单核细胞血管炎源自宿主细胞。来自经T细胞处理的小鼠的肺泡巨噬细胞（AM）在培养物中自发分泌肿瘤坏死因子-α（TNF-α），而在对照小鼠的AM培养物中未检测到TNF-α。经T细胞处理的小鼠的AM培养物中，对脂多糖（LPS）刺激产生的TNF-α反应明显高于对照小鼠的培养物。用亚致死剂量的LPS攻击导致经T细胞处理的小鼠死亡率达50%，并与AM中TNF-α产生增加以及支气管肺泡灌洗液中的蛋白质增加有关。我们得出结论，Th1表型的T细胞的免疫激活可引发以宿主来源的单核细胞炎症和AM激活为特征的肺损伤。
