Role of T Cells in Lung Disease in Systemic Sclerosis

描述(申请人提供)：肺纤维化是硬皮病患者死亡的主要原因。硬皮病的进行性肺纤维化是一个成熟、稳定的病理网络的一部分，在某些患者的肺部正在进行，而不是单向级联的结束。这种病理包括多个组成部分，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。这项工作的假设是T细胞在硬皮病的进行性肺纤维化中是必不可少的，通过产生促纤维化的细胞因子和生长因子，以及刺激转化生长因子-β的产生和激活，巨噬细胞的交替激活和肺部炎症，从而导致肺纤维化。该策略是删除T细胞，并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细胞在促纤维化途径中的作用，从基因表达、蛋白质表达和信号转导的水平进行评估。预期的结果是，T细胞的耗尽将减少T细胞产生IL-4和其他促纤维化生长因子，并减少转化生长因子-β的产生和激活。它将减少肺泡巨噬细胞的交替激活和肺部炎症。这些变化将伴随着肺纤维化的停止。在这项应用中，患者将接受为期12个月的阿法塞普治疗，并在0、6和12个月时进行支气管肺泡灌洗。Alefacept是一种人源化的LFA-3/IgG1融合蛋白，它通过凋亡来耗尽CD2+细胞，而不是T细胞激活。CD2+细胞主要是T细胞。具体目的是：1)证明阿法塞普疗法消耗硬皮病患者肺中的T细胞，T细胞耗竭稳定肺纤维化；2)证明两条主要的促纤维化途径-IL-4的产生和信号以及转化生长因子-β的产生、激活和信号-是硬皮病肺部疾病中T细胞依赖的过程；以及3)表明巨噬细胞的交替激活和肺部炎症是硬皮病肺部疾病中T细胞依赖的过程。获得的新信息将促进对硬皮病肺纤维化T细胞依赖机制的了解。

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.