The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation
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DOI：
10.3324/haematol.2011.058677
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发表时间：
2012-09-01
期刊：
影响因子：
--
通讯作者：
Perez-Simon, Jose A.
中科院分区：
文献类型：
--
作者：
Caballero-Velazquez, Teresa;Sanchez-Abarca, Luis Ignacio;Perez-Simon, Jose A.
背景我们先前已经证明硼替佐米诱导同种异体反应性T细胞的耗竭，并允许具有抑制特性的T细胞扩增。在目前的研究中，我们分析了潜在的协同作用硼替佐米与西罗莫司，以减少移植物抗宿主病，而不妨碍移植物抗白血病的效果在同种异体transplantationsetting.Design和MethodsWe评估西罗莫司，硼替佐米或两者的组合在体外刺激的T淋巴细胞的增殖和活化的效果。还使用蛋白质印迹测定分析了参与这种协同作用的途径。最后，BALB/c小鼠接受C57 BL/6异基因供体骨髓与脾细胞被用来测量在体内的影响，这种新的组合对移植物抗宿主病的风险。ResultsThe组合的两种药物协同抑制激活和增殖的刺激T细胞。此外，Th 1细胞因子（IFN γ、IL-2和TNF）的产生也受到显著抑制。这种作用至少部分是由于抑制了Erk和Akt磷酸化。在体内，该组合降低了移植物抗宿主病的风险，而不妨碍移植物抗白血病效应，如接受用肿瘤WEHI细胞加C57 BL/6供体BM和脾细胞输注西罗莫司加硼替佐米预防移植物抗宿主病的小鼠中所示。抗白血病效应
BackgroundWe 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 MethodsWe 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.ResultsThe combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN gamma, 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.ConclusionsThe 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.