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Cell Therapy & Immunotherapy
Endothelial damage and dysfunction in acute graft-versus-host disease
Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2147-2160
Steffen Cordes,1 Zeinab Mokhtari,2 Maria Bartosova,3 Sarah Mertlitz,1 Katarina Riesner,1 Yu Shi,1 Jörg Mengwasser,1,4 Martina Kalupa,1 Aleixandria McGeary,1 Johanna Schleifenbaum,5,6 Jens Schrezenmeier,1 Lars Bullinger,1 Maribel Diaz- Ricart,7 Marta Palomo,7,8 Enric Carreras,8 Gernot Beutel,9 Claus Peter Schmitt, 3Andreas Beilhack2 and Olaf Penack1
1Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Campus Virchow Clinic, Berlin, Germany; 2Department of Medicine II, Würzburg University Hospital, Interdisciplinary Center for Clinical Research (IZKF), Laboratory for Experimental Stem Cell Transplantation, Würzburg, Germany; 3Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany; 4Department of Surgery, Charité Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow Clinic, Berlin, Germany; 5Experimental and Clinical Research Center (ECRC) - a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany; 6Charité Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany; 7Department of Hematopathology, Hospital Clinic of Barcelona, Biomedical Diagnosis Centre (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; 8Josep Carreras Leukemia Research Institute, Hospital Clinic/University of Barcelona Campus, Barcelona, Spain and 9Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
ABSTRACT
Clinical studies have suggested a potential involvement of endothe- lial dysfunction and damage in the development and severity of acute graft-versus-host disease (aGvHD). Accordingly, we found an increased percentage of apoptotic caspase 3 positive blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGvHD. In murine experimental aGvHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompa- nied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. During intes- tinal aGvHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. As recent data demon- strated an association of endothelium-related factors and steroid refrac- tory aGvHD (SR-aGvHD), we analyzed human biopsies and murine tis- sues from SR-aGvHD. We found extensive tissue damage but low levels of alloreactive T-cell infiltration in target organs, providing the rationale for T-cell independent SR-aGvHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGvHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Therapeutic intervention by endotheli- um-protecting agents is an attractive approach for SR-aGvHD comple- menting current anti-inflammatory treatment options.
Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only cur- ative treatment option for many patients suffering from hematological malignan- cies. A major complication of allo-HSCT is acute graft-versus-host disease (aGvHD), an inflammatory condition primarily affecting the skin, liver, and intes- tines. aGvHD occurs in more than two thirds of patients undergoing allo-HSCT.1
Correspondence:
OLAF PENACK
olaf.penack@charite.de
Received: March 27, 2020. Accepted: July 13, 2020. Pre-published: July16,2020.
https://doi.org/10.3324/haematol.2020.253716
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haematologica | 2021; 106(8)
2147
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