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

肺移植是终末期肺部疾病公认的治疗方法。然而，晚期同种异体移植排斥反应(闭塞性细支气管炎和血管病变)继续阻碍受者的预后。对移植肺纤维增生性转化的这一过程知之甚少。似乎，在慢性排斥反应的纤维增生期，病变对增强的免疫抑制不再有反应。因此，预防和治疗同种异体慢性排斥反应的新的治疗方法是有必要的。最近的研究发现，血小板衍生生长因子(PDGF)与慢性排斥反应的发生有关。伊马替尼是一种选择性酪氨酸激酶抑制剂，用于治疗慢性粒细胞白血病和胃肠道间质瘤。在先前的研究中，伊马替尼对PDGF受体的抑制预防/减轻了气管移植小鼠模型中闭塞性呼吸道疾病的发展，并在我们的正交异性大鼠肺移植模型中显示了良好的效果。尽管如此，仍然不清楚为什么一些动物对治疗没有反应。在此背景下，讨论了伪阻抗。急性时相蛋白α(1)-酸性糖蛋白(AGP)是一种与伊马替尼高亲和力的强血浆结合蛋白。在其他肺纤维化模型中，已经证明AGP是调节伊马替尼能力的重要调节因子。大环内酯类抗生素红霉素有能力逆转伊马替尼的作用。因此，联合应用伊马替尼和红霉素可能有助于治疗肺纤维化和慢性肺移植排斥反应。我们研究的第一个目的是检查是否有证据表明实验性大鼠肺移植后AGP导致伊马替尼假耐药。在此背景下，我们想要分析，伊马替尼和红霉素联合治疗慢性移植排斥反应是否能达到更好的效果。其次，已经描述了伊马替尼和免疫抑制物质埃博利莫斯的联合治疗显示出协同作用。在我们的大鼠肺移植模型的单独实验中，我们可以证实这些结果与肺移植后慢性排斥反应的发生有关。然而，肺移植时使用伊维洛韦会增加伤口愈合障碍的风险，并降低药物耐受性。在我们的大鼠肺移植模型中，临床数据和实验数据表明，由于肺移植后的长期疗效，霉酚酸酯(MMF)可能是一种更有效的治疗方法。参考这些数据，我们想要检查伊马替尼和MMF联合治疗在治疗慢性同种异体移植排斥反应中是否显示出协同作用。至少我们希望通过伊马替尼、MMF和红霉素的联合治疗来改善我们的结果。

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.