Role of T Cells in Lung Disease in Systemic Sclerosis

描述（由申请人提供）：肺纤维化是硬皮病的主要死亡原因。硬皮病的进行性肺纤维化是某些患者肺部正在进行的成熟、稳定的病理网络的一部分，而不是单向级联的终点。这种病理包括多种成分，以多种方式联系在一起。初步研究表明，CD8+ T细胞可能是这一病理网络的重要组成部分。本研究的假设是，T细胞对硬皮病进行性肺纤维化至关重要，通过促纤维化细胞因子和生长因子的产生，以及刺激tgf - β的产生和活化，巨噬细胞的替代活化和肺部炎症导致肺纤维化。该策略是删除T细胞，监测体内促纤维化途径的变化，以及对肺功能的临床益处。这些实验将包括深入分析T细胞对纤维化途径的影响，在基因表达、蛋白质表达和信号转导水平上进行评估。预期的结果是，T细胞的耗竭会减少T细胞产生IL-4和其他促纤维化生长因子，减少tgf - β的产生和激活。它将减少肺泡巨噬细胞的选择性活化和肺部炎症。这些变化将伴随着肺纤维化的停止。在本例中，患者将接受12个月的阿列克谢治疗，并在第0、6和12个月时进行支气管肺泡灌洗。alfacept是一种人源LFA-3/IgG1融合蛋白，它通过凋亡而不激活T细胞，从而消耗CD2+细胞（主要是T细胞）。给出了具体的目的：1)表明阿霉素治疗会消耗硬皮病患者肺中的T细胞，T细胞的消耗会稳定肺纤维化；2)表明两种主要的促纤维化途径- IL-4的产生和信号传导以及tgf - β的产生、激活和信号传导-在硬皮病中是T细胞依赖的过程；3)表明在硬皮病中，巨噬细胞的交替激活和肺部炎症是T细胞依赖的过程。新信息的获得将推进知识的t细胞依赖机制的肺纤维化硬皮病。

DESCRIPTION (provided by applicant): Pulmonary fibrosis is a major cause of death in scleroderma. Progressive pulmonary fibrosis in scleroderma is part of a mature, stable pathologic network that is ongoing in the lungs of certain patients, rather than the end of a unidirectional cascade. This pathology includes multiple components, linked in multiple ways. Preliminary work suggests that CD8+ T cells may be an essential component in this pathologic network. The hypothesis of this work is that T cells are essential to progressive pulmonary fibrosis in scleroderma, causing lung fibrosis through production of pro-fibrotic cytokines and growth factors as well as stimulation of TGF-betaa production and activation, alternative activation of macrophages and lung inflammation. The strategy is to delete T cells and monitor changes in profibrotic pathways in vivo, as well as clinical benefit on lung function. These experiments will include in-depth analyses of the effects of T cells on profibrotic pathways, assessed at the level of gene expression, protein expression and signal transduction. The expected outcome is that depletion of T cells will reduce T cell production of IL-4 and other profibrotic growth factors and reduce production and activation of TGF-beta. It will reduce alternative activation of alveolar macrophages and lung inflammation. These changes will be accompanied by arrest of pulmonary fibrosis. In this application, patients will receive alefacept therapy for 12 months, with bronchoalveolar lavage done at time 0, 6, and 12 months. Alefacept is a humanized LFA-3/IgG1 fusion protein that depletes CD2+ cells, which are largely T cells, through apoptosis, without T cell activation. The specific aims are given: 1) Show that alefacept therapy depletes T cells in the lungs of scleroderma patients and that T cell depletion stabilizes lung fibrosis; 2) Show that two major profibrotic pathways - IL-4 production and signaling and TGF-beta production, activation and signaling - are T cell-dependent processes in scleroderma lung disease; and 3) Show that alternative activation of macrophages and lung inflammation are T cell-dependent processes in scleroderma lung disease. The new information that is gained will advance knowledge of T-cell dependent mechanisms of pulmonary fibrosis in scleroderma.