Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
García-Bernal, D. (Internal Medicine Department. Medicine School. University of Murcia)
Palomo, Marta (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Martínez, C. M. (Instituto Murciano de Investigación Biosanitaria)
Millán-Rivero, J. E. (Internal Medicine Department. Medicine School. University of Murcia)
García-Guillén, A. I. (Hospital Universitario Virgen de la Arrixaca (Múrcia))
Blanquer, M. (Internal Medicine Department. Medicine School. University of Murcia)
Diaz-Ricart, Maribel (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Sackstein, R. (Department of Translational Medicine. and the Translational Glycobiology Institute. Herbert Wertheim College of Medicine. Florida International University)
Carreras, Enric (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Moraleda, J. M. (Internal Medicine Department. Medicine School. University of Murcia)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective therapy for the treatment of high-risk haematological malignant disorders and other life-threatening haematological and genetic diseases. Acute graft-versus-host disease (aGvHD) remains the most frequent cause of non-relapse mortality following allo-HCT and limits its extensive clinical application. Current pharmacologic agents used for prophylaxis and treatment of aGvHD are not uniformly successful and have serious secondary side effects. Therefore, more effective and safe prophylaxis and therapy for aGvHD are an unmet clinical need. Defibrotide is a multi-target drug successfully employed for prophylaxis and treatment of veno-occlusive disease/sinusoidal obstruction syndrome. Recent preliminary clinical data have suggested some efficacy of defibrotide in the prevention of aGvHD after allo-HCT. Using a fully MHC-mismatched murine model of allo-HCT, we report here that defibrotide, either in prophylaxis or treatment, is effective in preventing T cell and neutrophil infiltration and aGvHD-associated tissue injury, thus reducing aGvHD incidence and severity, with significantly improved survival after allo-HCT. Moreover, we performed in vitro mechanistic studies using human cells revealing that defibrotide inhibits leucocyte-endothelial interactions by down-regulating expression of key endothelial adhesion molecules involved in leucocyte trafficking. Together, these findings provide evidence that defibrotide may represent an effective and safe clinical alternative for both prophylaxis and treatment of aGvHD after allo-HCT, paving the way for new therapeutic approaches.
Grants:	Instituto de Salud Carlos III PIE15-00027 Instituto de Salud Carlos III RD16-0011-0001
Note:	Altres ajuts: This study has been funded by Josep Carreras Leukaemia Foundation (Grant 11R/2016 and 03R/2019).
Rights:	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, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Acute GvHD ; Defibrotide ; Hematopoietic stem cell transplantation
Published in:	Journal of Cellular and Molecular Medicine, Vol. 24 Núm. 14 (january 2020) , p. 8031-8044, ISSN 1582-4934

DOI: 10.1111/jcmm.15434
PMID: 32519822

14 p, 2.2 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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