Luo H, Wu Y, Qi S, Wan X, Chen H, Wu J
The Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Canada.
Transplantation. 2001 Jul 27;72(2):196-202. doi: 10.1097/00007890-200107270-00005.
We have previously demonstrated in vitro that proteasome inhibitors could suppress proliferation and induce apoptosis of activated T cells. This finding suggests that such inhibitors could be used as a novel category of immunosuppressants in blocking allograft rejection.
The proteasome inhibitor dipeptide boronic acid (DPBA) was tested in vitro for its inhibitory effect on mouse T-cell proliferation and lymphokine secretion. DPBA was also used in vivo to treat mouse heterotopic heart allograft rejection. Possible side effects of this compound were examined according to blood chemistry of mice treated with DPBA.
DPBA suppressed the T-cell proliferation and potently inhibited interleukin (IL)-2, IL-6, IL-10, IL-13, and IFN-gamma produced by anti-CD3-activated T cells. Given i.p. starting 1 day after transplantation at 0.66 mg/kg per day for 16 days, or at 1 mg/kg per day for 4 days followed by 0.5 mg/kg per day for 12 days, DPBA could prolong heart allograft survival to 35.5 days (mean survival time, MST) and to 36.2 days, respectively. The control group had MST of 7.3 days. When administrated 72 hr post operation at 1 mg/kg per day for 4 days, DPBA could prolong the graft survival to 19.8 days. During the course of these effective dosages, DPBA had no apparent toxicity in the liver, kidney, pancreas, or heart, according to analysis of blood chemistry.
The proteasome inhibitor could repress allograft rejection in mice without apparent side-effects at the effective dosages. This finding has opened a new dimension in development of novel immunosuppressants for organ transplantation.
我们之前在体外已证明蛋白酶体抑制剂可抑制活化T细胞的增殖并诱导其凋亡。这一发现表明此类抑制剂可作为一类新型免疫抑制剂用于阻断同种异体移植排斥反应。
在体外测试蛋白酶体抑制剂二肽硼酸（DPBA）对小鼠T细胞增殖和淋巴因子分泌的抑制作用。DPBA也用于体内治疗小鼠异位心脏同种异体移植排斥反应。根据用DPBA处理的小鼠的血液化学检查该化合物可能的副作用。
DPBA抑制T细胞增殖，并有效抑制抗CD3活化的T细胞产生的白细胞介素（IL）-2、IL-6、IL-10、IL-13和干扰素-γ。在移植后第1天开始腹腔注射，每天0.66mg/kg，共16天，或每天1mg/kg，共4天，随后每天0.5mg/kg，共12天，DPBA可将心脏同种异体移植存活时间分别延长至35.5天（平均存活时间，MST）和36.2天。对照组的MST为7.3天。在术后72小时开始每天1mg/kg，共4天给药时，DPBA可将移植物存活时间延长至19.8天。根据血液化学分析，在这些有效剂量的给药过程中，DPBA在肝脏、肾脏、胰腺或心脏方面没有明显毒性。
蛋白酶体抑制剂可在有效剂量下抑制小鼠同种异体移植排斥反应且无明显副作用。这一发现为开发用于器官移植的新型免疫抑制剂开辟了新的方向。
