Predictive Molecular Profiling in Human Pulmonary Allografts

• Applicant: Professor Dr. Danny David Jonigk
• Subject Area: Pathology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213074196

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.

• DFG Programme: Research Grants
• Participating Person: Dr. Florian Peter Länger