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Lymphendothel in terminaler Herzinsuffizienz und nach Herz- und Lungentransplantation
Lymphendothel in terminaler Herzinsuffizienz und nach Herz- und Lungentransplantation
The lymphatic endothelium is relevant for the pathogenesis of various cardiac and pulmonary diseases. However, the knowledge about the functions and role of lymphatic endothelium in the setting of transplantation is very limited. Therefore it was the main focus of this study. The study investigated the changes of lymphatic endothelial phenotype in patients with terminal heart failure and during the time course after heart and lung transplantation. These observations of the lymphatic phenotype are the first of their kind and provide the evidence, that acute allograft rejection after heart and lung transplantation in human patients is associated with significant changes in the phenotype of lymphatic endothelium. To show the exact mechanistic role of lymphatic endothelium in acute organ rejection and to clarify the cause-effect relation between allograft rejection and lymphatic endothelium, the experimental studies involving heterotopic heart transplantation in rat and mouse were conducted. The results demonstrated that ischemiareperfusion injury induced the activation of lymphatic endothelial cells in rat cardiac allografts. The process was mediated by interaction in the VEGF-C-VEGFR-3 axis and had direct consequences for the development of alloimmune responses. Further, specific perioperative single-dose VEGF-C inhibiting strategies demonstrated beneficial effects on lymphatic vessel activation, antigenpresenting cell trafficking and subsequent development of alloimmune responses in rat cardiac allografts. VEGF-C/D trapping in donor heart prevented acute lymphatic vessel activation and led to homing of VEGFR-3+ dendritic cells in cardiac allograft. Intracoronary ex-vivo perfusion with VEGFC/D trap also improved rat cardiac allograft survival and inhibited the development of cardiac fibrosis, allograft vasculopathy and inflammation. The results of the study, thus, demonstrate the significance of VEGF-C-VEGFR-3 signaling in alloimmunity and suggest VEGF-C/D inhibiting strategies as an alternative clinically feasible immunomodulatory approach targeting lymphatic vessels.
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Dashkevich, Alexey
2017
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Dashkevich, Alexey (2017): Lymphendothel in terminaler Herzinsuffizienz und nach Herz- und Lungentransplantation. Habilitationsschrift, LMU München: Faculty of Medicine
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Abstract

The lymphatic endothelium is relevant for the pathogenesis of various cardiac and pulmonary diseases. However, the knowledge about the functions and role of lymphatic endothelium in the setting of transplantation is very limited. Therefore it was the main focus of this study. The study investigated the changes of lymphatic endothelial phenotype in patients with terminal heart failure and during the time course after heart and lung transplantation. These observations of the lymphatic phenotype are the first of their kind and provide the evidence, that acute allograft rejection after heart and lung transplantation in human patients is associated with significant changes in the phenotype of lymphatic endothelium. To show the exact mechanistic role of lymphatic endothelium in acute organ rejection and to clarify the cause-effect relation between allograft rejection and lymphatic endothelium, the experimental studies involving heterotopic heart transplantation in rat and mouse were conducted. The results demonstrated that ischemiareperfusion injury induced the activation of lymphatic endothelial cells in rat cardiac allografts. The process was mediated by interaction in the VEGF-C-VEGFR-3 axis and had direct consequences for the development of alloimmune responses. Further, specific perioperative single-dose VEGF-C inhibiting strategies demonstrated beneficial effects on lymphatic vessel activation, antigenpresenting cell trafficking and subsequent development of alloimmune responses in rat cardiac allografts. VEGF-C/D trapping in donor heart prevented acute lymphatic vessel activation and led to homing of VEGFR-3+ dendritic cells in cardiac allograft. Intracoronary ex-vivo perfusion with VEGFC/D trap also improved rat cardiac allograft survival and inhibited the development of cardiac fibrosis, allograft vasculopathy and inflammation. The results of the study, thus, demonstrate the significance of VEGF-C-VEGFR-3 signaling in alloimmunity and suggest VEGF-C/D inhibiting strategies as an alternative clinically feasible immunomodulatory approach targeting lymphatic vessels.