Prävention und Frühtherapie der chronischen Abstoßung nach orthotoper unilateraler Lungentransplantation in der Ratte

• Applicant: Professor Dr. Stephan Hirt
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34200951

Lung transplantation is an accepted therapy for end-stage lung disease. However, recipient outcomes continue to be hindered by late allograft rejection (bronchiolitis obliterans and vasculopathy). This process of fibroproliferative transformation of lung allograft is poorly understood. It seems that, during the fibroproliferative phase of chronic rejection lesion is no longer responsive to augmented immunosuppression. Therefore, new therapeutic approaches for the prevention and treatment of chronic allograft rejection are warranted. Recent observations have linked platelet-derived growth factor (PDGF) to the development chronic rejection. Imatinib is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. In previous studies, the inhibition of PDGF receptors by Imatinib prevented/attenuated the development of obliterative airway disease in a tracheal transplantation mouse model and showed promising effects in our orthotropic rat lung transplantation model. Nonetheless it still remains unclear, why some animals have not responded to therapy. In this context, pseudoresistances were discussed. The acute phase protein alpha(1)-acid glycoprotein (AGP) is a strong plasma binding protein with high-affinity to Imatinib. In other pulmonary fibrosis models it has already been shown that AGP is an important regulatory factor modulating the ability of Imatinib. The macrolide antibiotic Erythromycin has the capacity to reverse the effect of imatinib. Therefore, a combination therapy with imatinib and Erythromycin might be useful for treatment of pulmonary fibrosis and chronic lung allograft rejection.The first aim of our study is to examine, if there is evidence of an Imatinib pseudoresistance caused by AGP after experimental rat lung transplantation. In this context, we want to analyze, if a combined treatment with Imatinib and Erythromycin can reach better results in the treatment of chronic allograft rejection. Secondly, is has been described, that a combination therapy with Imatinib and the immunosuppressive substance Everolimus showed synergistic effects. In separate experiments in our rat lung transplantation model we could confirm these results for the development of chronic rejection after lung transplantation. However treatment of everolimus at the time of lung transplantation increased the risk of disorders for wound healing and reduced drug tolerance. Clinical data, as well as experimental data in our rat lung transplantation model suggest that Mycophenolat mofetil (MMF) might be a more effective therapy due to long term outcome after lung transplantation. Referring to these data, we would like to examine, if a combination therapy of Imatinib and MMF show synergistic effects in the therapy of chronic allograft rejection. At least we would like to improve our results with a combination therapy of Imatinib, MMF and Erythromycin.

• DFG Programme: Research Grants
• Participating Person: Dr. Thomas Pühler