Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease

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-relap...

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Autores: García-Bernal, D., Palomo, Marta|||0000-0002-3261-6577, Martínez, C. M., Millán-Rivero, J. E., García-Guillén, A. I., Blanquer, M., Diaz-Ricart, Maribel|||0000-0003-1122-0052, Sackstein, Robert, Carreras, Enric|||0000-0002-3134-9964, Moraleda, J. M.
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:236631
Acceso en línea:https://ddd.uab.cat/record/236631
https://dx.doi.org/urn:doi:10.1111/jcmm.15434
Access Level:acceso abierto
Palabra clave:Acute GvHD
Defibrotide
Hematopoietic stem cell transplantation
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spelling Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host diseaseGarcía-Bernal, D.Palomo, Marta|||0000-0002-3261-6577Martínez, C. M.Millán-Rivero, J. E.García-Guillén, A. I.Blanquer, M.Diaz-Ricart, Maribel|||0000-0003-1122-0052Sackstein, RobertCarreras, Enric|||0000-0002-3134-9964Moraleda, J. M.Acute GvHDDefibrotideHematopoietic stem cell transplantationAllogeneic 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.Universitat Autònoma de Barcelona 22020-01-0120202020-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/236631https://dx.doi.org/urn:doi:10.1111/jcmm.15434reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PIE15-00027Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 RD16-0011-0001open accesshttp://purl.org/coar/access_right/c_abf2Aquest 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.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2366312026-06-06T12:50:31Z
dc.title.none.fl_str_mv Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
title Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
spellingShingle Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
García-Bernal, D.
Acute GvHD
Defibrotide
Hematopoietic stem cell transplantation
title_short Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
title_full Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
title_fullStr Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
title_full_unstemmed Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
title_sort Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease
dc.creator.none.fl_str_mv García-Bernal, D.
Palomo, Marta|||0000-0002-3261-6577
Martínez, C. M.
Millán-Rivero, J. E.
García-Guillén, A. I.
Blanquer, M.
Diaz-Ricart, Maribel|||0000-0003-1122-0052
Sackstein, Robert
Carreras, Enric|||0000-0002-3134-9964
Moraleda, J. M.
author García-Bernal, D.
author_facet García-Bernal, D.
Palomo, Marta|||0000-0002-3261-6577
Martínez, C. M.
Millán-Rivero, J. E.
García-Guillén, A. I.
Blanquer, M.
Diaz-Ricart, Maribel|||0000-0003-1122-0052
Sackstein, Robert
Carreras, Enric|||0000-0002-3134-9964
Moraleda, J. M.
author_role author
author2 Palomo, Marta|||0000-0002-3261-6577
Martínez, C. M.
Millán-Rivero, J. E.
García-Guillén, A. I.
Blanquer, M.
Diaz-Ricart, Maribel|||0000-0003-1122-0052
Sackstein, Robert
Carreras, Enric|||0000-0002-3134-9964
Moraleda, J. M.
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Acute GvHD
Defibrotide
Hematopoietic stem cell transplantation
topic Acute GvHD
Defibrotide
Hematopoietic stem cell transplantation
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2
2020-01-01
2020
2020-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/236631
https://dx.doi.org/urn:doi:10.1111/jcmm.15434
url https://ddd.uab.cat/record/236631
https://dx.doi.org/urn:doi:10.1111/jcmm.15434
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PIE15-00027
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 RD16-0011-0001
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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