title: The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation.
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.
  
  
  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.
authors.affiliation: Servicio de Hematología, Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Instituto de Biomedicina de Sevilla (IBIS), Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Caballero-Velázquez
authors.forename: Luis Ignacio
authors.initials: LI
authors.lastname: Sánchez-Abarca
authors.forename: Silvia
authors.initials: S
authors.lastname: Gutierrez-Cosio
authors.forename: Belén
authors.initials: B
authors.lastname: Blanco
authors.forename: Cristina
authors.initials: C
authors.lastname: Calderon
authors.forename: Carmen
authors.initials: C
authors.lastname: Herrero
authors.forename: Soraya
authors.initials: S
authors.lastname: Carrancio
authors.forename: Concepción
authors.initials: C
authors.lastname: Serrano
authors.forename: Consuelo
authors.initials: C
authors.lastname: del Cañizo
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
authors.forename: José A
authors.initials: JA
authors.lastname: Pérez-Simón
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D020350:Graft vs Tumor Effect; D007942:Leukemia, Experimental / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011719:Pyrazines / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D001897:Boronic Acids; D016207:Cytokines; D011719:Pyrazines; D000069286:Bortezomib; D020123:Sirolimus