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

AuthorsCaballero-Velázquez, Teresa; Sánchez-Abarca, Luis Ignacio; Gutiérrez-Cosío, S.; Blanco, Belén; Calderón-Cabrera, Cristina; Herrero-Rodríguez, Carmen; Carrancio, Soraya; Cañizo, María Consuelo del; San Miguel, Jesús F. ; Pérez-Simón, José A.
Issue Date2012
PublisherFerrata Storti Foundation
CitationHaematologica 97(9): 1329-1337 (2012)
Abstract[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.
DescriptionThis is an open-access paper.
Publisher version (URL)http://dx.doi.org/10.3324/haematol.2011.058677
Identifiersissn: 0390-6078
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