Predictive Molecular Profiling in Human Pulmonary Allografts

对于大多数晚期肺部疾病，肺移植（LTx）提供了唯一的治疗选择。尽管全世界范围内同种异体肺移植的5年存活率几乎为50%，但这一点仍然成立，而其他移植物，如肺移植。G.肾脏，在近80%的患者中保持功能。其主要原因是由于所谓的闭塞性细支气管炎（BO）导致的进行性器官衰竭，这被认为是慢性移植物功能障碍的标志。BO被定义为小气道的闭塞性重塑，由产生过量细胞外基质的活化肌成纤维细胞主导。不幸的是，由于BO病变在肺实质中分布不均匀，主要影响小细支气管，因此经支气管活检检测BO的灵敏度较低。由于这些原因，在排除感染或急性排斥反应后，临床功能测试的恶化已被确定为所谓的BO综合征（BOS）。这些标准也缺乏敏感性，因为在临床症状出现之前，必须有大量的肺功能丧失，在临床实践中还没有建立起弥合这种敏感性差距和提高基于组织的检测价值以预测/诊断气道闭塞或对药物治疗的反应性的生物标志物。最近，我们已经确定了一组分子标志物，过度表达，这是与随后的发展BO，即使在不显眼的biopsies.We的目的是验证我们最近建立的分子标志物的发展BO的预后能力，使用临床数据和结果的患者从LTx监测计划的MHH作为参考。此外，我们打算使用新的动物模型系统和体外培养的肌成纤维细胞实验来确定预测BO患者对药物治疗的反应性的标志物。

For most terminal lung diseases, lung transplantation (LTx) provides the only therapeutic option. This holds true despite a 5-year survival rate of lung allografts of hardly 50% on a worldwide scale, while other grafts, e. g. kidneys, remain functional in almost 80% of patients. The major reason for this is the progressive organ failure due to so-called bronchiolitis obliterans (BO), which is considered the hallmark of chronic graft dysfunction. BO is defined as the obliterative remodeling of small airways, dominated by activated myofibroblasts which produce excessive extracellular matrix. Unfortunately, the sensitivity of transbronchial biopsies for their detection is low, as BO lesions are unevenly distributed in the lung parenchyma and affect mainly the small bronchioli. For these reasons, the deterioration of clinical functional tests after excluding infection or acute rejection has been established to define the so-called BO-Syndrome (BOS). These criteria lack sensitivity also, as a significant amount of lung function has to be irrevocably lost, before clinical symptoms develop.Biomarkers bridging this sensitivity gap and improving the value of tissue-based testing to predict/diagnose airway obliteration or responsiveness to medical treatment have not yet been established in clinical practice. Recently, we have identified a set of molecular markers, overexpression of which was associated with subsequent development of BO, even in inconspicuous biopsies.We aim to validate the prognostic power of our recently established molecular markers for the development of BO, using clinical data and outcome of patients from the LTx surveillance program of the MHH as a reference. Furthermore, we intend to determine markers predicting the responsiveness of BO patients to medical therapy using novel animal model systems and in vitro experiments with cultured myofibroblasts.