Artículo
The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
Autor/es | 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 |
Departamento | Instituto de Biomedicina de Sevilla (IBIS) Universidad de Sevilla. Departamento de Medicina |
Fecha de publicación | 2012 |
Fecha de depósito | 2024-04-12 |
Publicado en |
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Resumen | 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 ... 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. |
Cita | Caballero Velázquez, T., Sánchez-Abarca, L.I., Gutiérrez-Cosío, S., Blanco, B., Calderón, C., Herrero, C.,...,Pérez Simón, J.A. (2012). The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation. Haematologica, 97 (9), 1329-1337. https://doi.org/10.3324/haematol.2011.058677. |
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