MECHANISMS OF CELL-MEDIATED LUNG INJURY

T淋巴细胞在多种人肺组织中浸润 以急性和慢性肺损伤为特征的疾病。的 诱导肺损伤的潜在机制，以及由此产生的 对肺生理学影响仍不清楚。T细胞能够 表达多种效应子功能，包括直接溶细胞活性 以及许多可溶性炎症介质的分泌。它 肺的T细胞浸润可能导致肺实质损伤， 细胞通过几种直接和间接的机制。这项建议的目的是 了解T细胞直接损伤肺的具体机制， 特别是肺泡上皮细胞。这次受伤对 还将分析呼吸生理学。一种转基因小鼠模型， 已经为此目的而开发，其中T细胞针对模型靶点， 抗原在体外活化，并过继转移到转基因细胞中。 在肺中表达该靶抗原的受体。重度间质性 肺炎是由活化的CD 8 + T细胞的过继转移产生的， 导致严重的肺损伤并在一周内死亡。似乎 由CD 8 + T细胞表达的TNF-α是T细胞增殖的重要贡献者。 细胞介导的肺损伤这也表明特异性T细胞识别 肺泡上皮细胞上的抗原触发了 靶细胞和炎症趋化因子表达，这是一个主要的 伤害严重程度的决定因素。为了研究特定的机制 CD 8 + T细胞识别诱导肺泡损伤，以及 生理损伤的后果，以下具体目标将是 解决了：1）表征TNF-α中和肺的影响， CD 8 + T细胞转移引发的损伤; 2）分析特异性相互作用 体外CD 8 + T淋巴细胞与肺泡上皮细胞之间的关系;和3） 分析TNF依赖性CD 8 + T细胞介导的体内损伤机制。

T lymphocytes infiltrate the lung in a variety of human lung diseases which are characterized by acute and chronic lung injury. The mechanisms underlying the induction of injury to the lung, and the resultant impact on pulmonary physiology remain obscure. T cells are capable of expressing a variety of effector functions, including direct cytolytic activity as well as the secretion of a number of soluble mediators of inflammation. It is likely that T cell infiltration of the lung results in damage to parenchymal cells by several direct and indirect mechanisms. The aim of this proposal is to understand the specific mechanisms by which T cells directly injure the lung, particularly the alveolar epithelial cell. The impact of this injury on respiratory physiology will also be analyzed. A transgenic murine model has been developed for this purpose, in which T cells directed to a model target antigen are activated in vitro, and adoptively transferred into a transgenic recipient which expresses that target antigen in the lung. Severe interstitial pneumonitis is generated by the adoptive transfer of activated CD8+ T cells, resulting in significant lung injury and death within one week. It appears that TNF-alpha expressed by CD8+ T cells is an important contributor to T cell-mediated lung injury. It also appears that specific T cell recognition of antigen on alveolar epithelial cells triggers active transcription in the target cell and expression of inflammatory chemokines, which are a primary determinant of the severity of injury. To investigate the specific mechanisms by which CD8+ T cell recognition induces alveolar injury, as well as the physiologic consequences of injury, the following specific aims will be addressed: 1) to characterize the impact of TNF-alpha neutralization of lung injury initiated by CD8+ T cell transfer; 2) to analyze specific interactions between CD8+ T lymphocyte and alveolar epithelial cells in vitro; and 3) to analyze the mechanisms of TNF-dependent CD8+ T cell-mediated injury in vivo.