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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib.
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Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib.

机译：蛋白酶体抑制剂硼替佐米可抑制急性移植物抗宿主病并保留移植物抗肿瘤作用。

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摘要

Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer.
机译：移植物抗宿主病（GVHD）是阻碍同种异体骨髓移植（BMT）功效的主要障碍。硼替佐米是一种蛋白酶体抑制剂，最近被批准用于治疗骨髓瘤。我们发现硼替佐米有效抑制体外混合淋巴细胞反应，并促进同种反应性T细胞的凋亡。在小鼠接受同种异体BMT时给予的硼替佐米对急性GVHD有明显的保护作用。使用该方案可观察到GVHD相关参数的降低和蛋白酶体抑制的生物学证据，但对长期供体重构没有不利影响。评估晚期白血病小鼠的移植物抗肿瘤反应表明，只有异基因BMT和T细胞与硼替佐米的组合才能显着提高生存率。还观察到肿瘤的细胞毒性T细胞杀伤力增加。因此，蛋白酶体抑制与选择性免疫攻击的结合可以显着提高BMT在癌症中的疗效。

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