Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity
Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity
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DOI：
10.1182/blood-2004-11-4526
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发表时间：
2005-11-01
期刊：
影响因子：
20.3
通讯作者：
Murphy, WJ
中科院分区：
文献类型：
--
作者：
Sun, K;Wilkins, DEC;Murphy, WJ
我们最近证明，蛋白酶体抑制剂硼替佐米，小鼠异基因骨髓移植（BMT）后立即给药，导致急性移植物抗宿主病（GVHD）的显着抑制与保留移植物抗肿瘤效应。我们现在评估延迟硼替佐米给药（BMT后5天或更长时间）对GVHD的影响。对BALB/c C57 BL/6（H2（B））小鼠进行致死性照射，并给予来自主要组织相容性复合体（MHC）-不同BALB/c（H2（d））供体的骨髓细胞和脾细胞移植物。与BMT后立即给予硼替佐米对GVHD预防的作用形成鲜明对比，延迟给予硼替佐米导致GVHD依赖性发病率显著加速。在供体T细胞未共同给药的模型中，延迟硼替佐米给药后未观察到毒性，表明这些有害作用严重依赖于GVHD诱导。GVHD易感性的增加甚至在硼替佐米的晚期施用之前早期施用时发生。病理学评估显示，在GVHD期间延迟硼替佐米给药后胃肠道病变显著增加。这种病理学与胃肠道细胞中1型肿瘤坏死因子α（TNF-α）受体转录的显著增加以及血清中TNF-α、白细胞介素1 β（IL-1 β）和IL-6水平的显著增加相关。这些结果表明，硼替佐米对GVHD的蛋白酶体抑制作用的差异严重依赖于硼替佐米给药的时机。
We have recently demonstrated that the proteasome inhibitor, bortezomib, administered immediately following murine allogeneic bone marrow transplantation (BMT) resulted in marked inhibition of acute graft-versus-host disease (GVHD) with retention of graft-versus-tumor effects. We now assessed the effects of delayed bortezomib administration (5 or more days after BMT) on GVHD. Recipient C57BL/6 (H2(b)) mice were lethally irradiated and given transplants of bone marrow cells and splenocytes from major histocompatibility complex (MHC)-disparate BALB/c (H2(d)) donors. In marked contrast to the effects of bortezomib on GVHD prevention when administered immediately after BMT, delayed bortezomib administration resulted in significant acceleration of GVHD-dependent morbidity. No toxicity was observed following delayed bortezomib administration in models where donor T cells were not coadministered, indicating that these deleterious effects were critically dependent on GVHD induction. The increase in GVHD susceptibility even occurred when late administration of bortezomlb was preceded by early administration. Pathologic assessment revealed that significant increases in gastrointestinal lesions occurred following delayed bortezomib administration during GVHD. This pathology correlated with significant increases of type 1 tumor necrosis factor alpha (TNF-alpha) receptor transcription in gastrointestinal cells and with significant increases of TNF-alpha, interleukin 1 beta (IL-1 beta), and IL-6 levels in the serum. These results indicate that the differential effects of proteasome inhibition with bortezomib on GVHD are critically dependent on the timing of bortezomib administration.