Endothelial damage and dysfunction in acute graft-versus-host disease
Cordes, Steffen (Charité - Universitätsmedizin Berlin)
Mokhtari, Zeinab (Department of Medicine II. Würzburg University Hospital. Interdisciplinary Center for Clinical Research (IZKF). Laboratory for Experimental Stem Cell Transplantation)
Bartosova, Maria (Pediatric Nephrology. Center for Pediatric and Adolescent Medicine. University Hospital Heidelberg)
Mertlitz, Sarah (Charité - Universitätsmedizin Berlin)
Riesner, Katarina (Charité - Universitätsmedizin Berlin)
Shi, Yu (Charité - Universitätsmedizin Berlin)
Mengwasser, Jörg (Department of Surgery. Charité Universitätsmedizin Berlin)
Kalupa, Martina (Charité - Universitätsmedizin Berlin)
McGeary, Aleixandria (Charité - Universitätsmedizin Berlin)
Schleifenbaum, Johanna (Institute of Vegetative. Charité Universitätsmedizin Berlin)
Schrezenmeier, Jens (Charité - Universitätsmedizin Berlin)
Bullinger, Lars (Charité - Universitätsmedizin Berlin)
Diaz-Ricart, Maribel (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Palomo, Marta (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Carreras, Enric (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Beutel, Gernot (Hannover Medical School)
Schmitt, Claus Peter (Center for Child and Adolescent Medicine (Heidelberg, Alemanya))
Beilhack, Andreas (Würzburg University Hospital)
Penack, Olaf (Charité - Universitätsmedizin Berlin)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	Clinical studies have suggested a potential involvement of endothelial 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 accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. During intestinal aGvHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. As recent data demonstrated an association of endothelium-related factors and steroid refractory aGvHD (SR-aGvHD), we analyzed human biopsies and murine tissues 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 endothelium-protecting agents is an attractive approach for SR-aGvHD complementing current anti-inflammatory treatment options.
Ajuts:	European Commission 287813
Nota:	Altres ajuts: Deutsche Forschungsgemeinschaft (DFG) TRR221 (B11 Z02), TRR225 (B08)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Animals ; Endothelial Cells ; Endothelium ; Graft vs Host Disease ; Humans ; Mice ; Steroids ; T-Lymphocytes
Publicat a:	Haematologica, Vol. 106 Núm. 8 (august 2021) , p. 2147-2160, ISSN 1592-8721

DOI: 10.3324/haematol.2020.253716
PMID: 32675225

14 p, 2.8 MB

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