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 reduce-graft-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.
journal_name
Haematologicajournal_title
Haematologicaauthors
Caballero-Velázquez T,Sánchez-Abarca LI,Gutierrez-Cosio S,Blanco B,Calderon C,Herrero C,Carrancio S,Serrano C,del Cañizo C,San Miguel JF,Pérez-Simón JAdoi
10.3324/haematol.2011.058677subject
Has Abstractpub_date
2012-09-01 00:00:00pages
1329-37issue
9eissn
0390-6078issn
1592-8721pii
haematol.2011.058677journal_volume
97pub_type
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