The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

Background We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reducegraft-vers...

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Autores: Caballero Velázquez, Teresa, Sánchez-Abarca, Luis Ignacio, Gutiérrez-Cosío, Silvia, Blanco, Belén, Calderón, Cristina, Herrero, Carmen, Carrancio, Soraya, Serrano, Concepción, del Cañizo, Consuelo, San Miguel, Jesús F., Pérez Simón, José Antonio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/156842
Acceso en línea:https://hdl.handle.net/11441/156842
https://doi.org/10.3324/haematol.2011.058677
Access Level:acceso abierto
Palabra clave:Allogeneic transplant
Sirolimus
Bortezomib
Graft-versus-host
Graft-versusleukemia
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spelling The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantationCaballero Velázquez, TeresaSánchez-Abarca, Luis IgnacioGutiérrez-Cosío, SilviaBlanco, BelénCalderón, CristinaHerrero, CarmenCarrancio, SorayaSerrano, Concepcióndel Cañizo, ConsueloSan Miguel, Jesús F.Pérez Simón, José AntonioAllogeneic transplantSirolimusBortezomibGraft-versus-hostGraft-versusleukemiaBackground We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reducegraft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. Design and Methods We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. Results The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. Conclusions The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.Ferrata Storti FoundationInstituto de Biomedicina de Sevilla (IBIS)Medicina2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/156842https://doi.org/10.3324/haematol.2011.058677reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésHaematologica, 97 (9), 1329-1337.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436233/info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1568422026-06-17T12:51:07Z
dc.title.none.fl_str_mv The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
title The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
spellingShingle The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
Caballero Velázquez, Teresa
Allogeneic transplant
Sirolimus
Bortezomib
Graft-versus-host
Graft-versusleukemia
title_short The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
title_full The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
title_fullStr The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
title_full_unstemmed The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
title_sort The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
dc.creator.none.fl_str_mv Caballero Velázquez, Teresa
Sánchez-Abarca, Luis Ignacio
Gutiérrez-Cosío, Silvia
Blanco, Belén
Calderón, Cristina
Herrero, Carmen
Carrancio, Soraya
Serrano, Concepción
del Cañizo, Consuelo
San Miguel, Jesús F.
Pérez Simón, José Antonio
author Caballero Velázquez, Teresa
author_facet Caballero Velázquez, Teresa
Sánchez-Abarca, Luis Ignacio
Gutiérrez-Cosío, Silvia
Blanco, Belén
Calderón, Cristina
Herrero, Carmen
Carrancio, Soraya
Serrano, Concepción
del Cañizo, Consuelo
San Miguel, Jesús F.
Pérez Simón, José Antonio
author_role author
author2 Sánchez-Abarca, Luis Ignacio
Gutiérrez-Cosío, Silvia
Blanco, Belén
Calderón, Cristina
Herrero, Carmen
Carrancio, Soraya
Serrano, Concepción
del Cañizo, Consuelo
San Miguel, Jesús F.
Pérez Simón, José Antonio
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Biomedicina de Sevilla (IBIS)
Medicina
dc.subject.none.fl_str_mv Allogeneic transplant
Sirolimus
Bortezomib
Graft-versus-host
Graft-versusleukemia
topic Allogeneic transplant
Sirolimus
Bortezomib
Graft-versus-host
Graft-versusleukemia
description Background We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reducegraft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. Design and Methods We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. Results The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. Conclusions The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.
publishDate 2012
dc.date.none.fl_str_mv 2012
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/156842
https://doi.org/10.3324/haematol.2011.058677
url https://hdl.handle.net/11441/156842
https://doi.org/10.3324/haematol.2011.058677
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Haematologica, 97 (9), 1329-1337.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436233/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Ferrata Storti Foundation
publisher.none.fl_str_mv Ferrata Storti Foundation
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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