MECHANISMS OF CELL-MEDIATED LUNG INJURY

T淋巴细胞在不同类型人肺组织中的浸润 以急性和慢性肺损伤为特征的疾病。这个 导致肺损伤的潜在机制以及由此产生的 对肺生理的影响仍不清楚。T细胞能够 表达多种效应器功能，包括直接细胞溶解活性 以及分泌一些可溶的炎症介质。它 可能是T细胞在肺内的渗透导致实质损伤 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， 尤其是肺泡上皮细胞。这种伤害对人类的影响 还将对呼吸生理学进行分析。一种转基因小鼠模型 为此目的而开发，其中T细胞指向模型靶 抗原在体外被激活，并过继地转移到转基因 在肺中表达该靶抗原的受体。重度间质 肺炎是通过过继转移激活的CD8+T细胞而产生的， 导致严重的肺损伤和一周内死亡。看起来， CD8+T细胞表达的肿瘤坏死因子-α是T细胞功能的重要组成部分 细胞介导的肺损伤。这也似乎表明，特异性T细胞识别 肺泡上皮细胞上的抗原在肺泡上皮细胞中激活转录 靶细胞和炎性趋化因子的表达是主要的 损伤严重程度的决定因素。探讨其具体作用机制 通过CD8+T细胞识别诱导肺泡损伤，以及 损伤的生理后果，将有以下具体目标 解决：1)描述肿瘤坏死因子-α中和对肺的影响 CD8+T细胞转移引起的损伤；2)分析特定的相互作用 CD8+T淋巴细胞与肺泡上皮细胞之间的相互作用 分析肿瘤坏死因子依赖的CD8+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.