Document Detail

The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation.
MedLine Citation:
PMID:  22532520     Owner:  NLM     Status:  Publisher    
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 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-cell. Also the production of Th1 cytokines (IFNγ, IL-2 and TNF) was significantly inhibited. This effect was at least in part due to the inhibition of Erk and Akt phosphorilation. In vivo, the combination decreased 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.
Teresa Caballero-Velazquez; Luis-Ignacio Sanchez-Abarca; Silvia Gutierrez-Cosio; Belen Blanco; Cristina Calderon; Carmen Herrero; Soraya Carrancio; Concepcion Rodriguez-Serrano; Maria Consuelo Del Cañizo; Jesus San Miguel; Jose-Antonio Perez-Simon
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-24
Journal Detail:
Title:  Haematologica     Volume:  -     ISSN:  1592-8721     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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