Frontiers in Immunology (Oct 2019)
Acute Graft-vs.-Host Disease-Associated Endothelial Activation in vitro Is Prevented by Defibrotide
- Julia Martinez-Sanchez,
- Julia Martinez-Sanchez,
- Julia Martinez-Sanchez,
- Hannah Hamelmann,
- Hannah Hamelmann,
- Hannah Hamelmann,
- Marta Palomo,
- Marta Palomo,
- Marta Palomo,
- Enrique Mir,
- Enrique Mir,
- Enrique Mir,
- Ana Belen Moreno-Castaño,
- Sergi Torramade,
- Montserrat Rovira,
- Ginés Escolar,
- Steffen Cordes,
- Steffen Cordes,
- Steffen Cordes,
- Martina Kalupa,
- Martina Kalupa,
- Martina Kalupa,
- Sarah Mertlitz,
- Sarah Mertlitz,
- Sarah Mertlitz,
- Katarina Riesner,
- Katarina Riesner,
- Katarina Riesner,
- Enric Carreras,
- Enric Carreras,
- Olaf Penack,
- Olaf Penack,
- Olaf Penack,
- Maribel Diaz-Ricart,
- Maribel Diaz-Ricart
Affiliations
- Julia Martinez-Sanchez
- Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
- Julia Martinez-Sanchez
- Department of Hematopathology, Biomedical Diagnosis Center (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Julia Martinez-Sanchez
- Barcelona Endothelium Team, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Hannah Hamelmann
- Hematology, Oncology and Tumor Immunology Department, Charité Universitätsmedizin Berlin, Berlin, Germany
- Hannah Hamelmann
- Berlin-Brandenburg Center for Regenerative Therapies, Charité Medical University of Berlin, Berlin, Germany
- Hannah Hamelmann
- Department of Hematology and Oncology, Berlin Institute of Health, Berlin, Germany
- Marta Palomo
- Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
- Marta Palomo
- Department of Hematopathology, Biomedical Diagnosis Center (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Marta Palomo
- Barcelona Endothelium Team, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Enrique Mir
- Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
- Enrique Mir
- Department of Hematopathology, Biomedical Diagnosis Center (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Enrique Mir
- Barcelona Endothelium Team, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Ana Belen Moreno-Castaño
- Department of Hematopathology, Biomedical Diagnosis Center (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Sergi Torramade
- Department of Hematopathology, Biomedical Diagnosis Center (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Montserrat Rovira
- Stem Cell Transplantation Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain
- Ginés Escolar
- Department of Hematopathology, Biomedical Diagnosis Center (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Steffen Cordes
- Hematology, Oncology and Tumor Immunology Department, Charité Universitätsmedizin Berlin, Berlin, Germany
- Steffen Cordes
- Berlin-Brandenburg Center for Regenerative Therapies, Charité Medical University of Berlin, Berlin, Germany
- Steffen Cordes
- Department of Hematology and Oncology, Berlin Institute of Health, Berlin, Germany
- Martina Kalupa
- Hematology, Oncology and Tumor Immunology Department, Charité Universitätsmedizin Berlin, Berlin, Germany
- Martina Kalupa
- Berlin-Brandenburg Center for Regenerative Therapies, Charité Medical University of Berlin, Berlin, Germany
- Martina Kalupa
- Department of Hematology and Oncology, Berlin Institute of Health, Berlin, Germany
- Sarah Mertlitz
- Hematology, Oncology and Tumor Immunology Department, Charité Universitätsmedizin Berlin, Berlin, Germany
- Sarah Mertlitz
- Berlin-Brandenburg Center for Regenerative Therapies, Charité Medical University of Berlin, Berlin, Germany
- Sarah Mertlitz
- Department of Hematology and Oncology, Berlin Institute of Health, Berlin, Germany
- Katarina Riesner
- Hematology, Oncology and Tumor Immunology Department, Charité Universitätsmedizin Berlin, Berlin, Germany
- Katarina Riesner
- Berlin-Brandenburg Center for Regenerative Therapies, Charité Medical University of Berlin, Berlin, Germany
- Katarina Riesner
- Department of Hematology and Oncology, Berlin Institute of Health, Berlin, Germany
- Enric Carreras
- Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
- Enric Carreras
- Barcelona Endothelium Team, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Olaf Penack
- Hematology, Oncology and Tumor Immunology Department, Charité Universitätsmedizin Berlin, Berlin, Germany
- Olaf Penack
- Berlin-Brandenburg Center for Regenerative Therapies, Charité Medical University of Berlin, Berlin, Germany
- Olaf Penack
- Department of Hematology and Oncology, Berlin Institute of Health, Berlin, Germany
- Maribel Diaz-Ricart
- Department of Hematopathology, Biomedical Diagnosis Center (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Maribel Diaz-Ricart
- Barcelona Endothelium Team, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- DOI
- https://doi.org/10.3389/fimmu.2019.02339
- Journal volume & issue
-
Vol. 10
Abstract
Angiogenesis and endothelial activation and dysfunction have been associated with acute graft-vs.-host disease (aGVHD), pointing to the endothelium as a potential target for pharmacological intervention. Defibrotide (DF) is a drug with an endothelium-protective effect that has been approved for the treatment of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Clinical data suggest that DF also reduces the incidence of aGVHD; however, the mechanisms of DF-mediated aGVHD regulation have not been examined. To investigate possible DF-mediated prophylactic and therapeutic mechanisms in aGVHD, we performed in vitro studies using endothelial cell (EC) lines. We found that DF significantly and dose-dependently suppressed EC proliferation and notably reduced their ability to form vascular tubes in Matrigel. To explore whether DF administered prophylactically or therapeutically has a significant effect on aGVHD endothelial dysfunction, ECs were exposed to media containing sera from patients with aGVHD (n = 22) in the absence or presence of DF and from patients that did not develop aGVHD (n = 13). ECs upregulated adhesion molecules (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), the adherence junction protein VE-cadherin, von Willebrand factor (VWF), and Akt phosphorylation in response to aGVHD sera. These responses were suppressed upon treatment with DF. In summary, DF inhibits vascular angiogenesis and endothelial activation induced by sera from aGVHD patients. Our results support the view that DF has notable positive effects on endothelial biology during aGVHD.
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