泛素-蛋白酶体制剂在胰岛移植排斥反应中的作用

Effect of proteasome inhibitor on islet-allograft rejection

目的在小鼠胰岛移植模型上,研究泛察-蛋白酶体抑制剂在控制同种异基因移植排斥反应中的作用。方法泛素-蛋白酶体抑制剂用二肽硼酸类似物(DPBA)作代表。测定小鼠被注射DPBA后的血生化变化观察其可能的副作用。建立小鼠胰岛移植模型。受体糖尿病鼠随机分为 3组:实验组,同种异基因移植24 h时后,每天静脉注射处理DPBA持续17 d。对照1组同基因移植;对照2组,同种异基因移植。两对照组移植后不作任何药物处理。结果DPBA对肝脏胰腺轻度毒性,有一过性的肾毒性和较明显的心脏毒性,停药后毒性明显下降。实验组同种异基因移植的移植物平均存活(33．88±24．54)d;对照2组同种异基因移植的移植物平均存活(4．33±2．42)d。两组比较差异有统计学意义(P<0．05)。结论泛素-蛋白酶体抑制剂可以有效地抑制移植排斥反应,可以使用作为新的免疫抑制剂。

Objective To evaluate the effect of proteasome inhibitor on allograft rejection by setting up the mouse islet-allograft model. Methods Possible side effects of proteasome inhibitor were ex- amined according to blood chemistry of the mice treated with proteasome inhibitor （i. e. dipeptide boronic acid, DPBA）. The diabetic models in mice were made with streptozotocin. Islets were isolated by collagenase digestion and purified by discontinuous density gradient method. Then the islets were injected into the diabetic mice. The recipients were divided into 3 groups randomly：isograft control group without proteasome inhibitor, allograft control group without proteasome inhibitor and allograft test group treated with proteasome inhibitor （DPBA）. In the allograft test group, DPBA was given to the recipients intraperitoneally for 17 days. Results During the course of these effective dosages, proteasome inhibitor had mild toxicity to the liver, kidney, or pancreas, according to analysis of blood chemistry. The heart toxicity in mice appeared more prominent. The heart toxicity was dis-coutinued after termination of drug administration. The average duration of graft survival after the transplantation was （4.33 ±2.42） days in control group （allograft without DPBA） and （33.88 ± 24.54） days in test group （allograft with DPBA） （P 〈0.05）. Conclusion The proteasome inhibitor could inhibit allograft rejection in mice. The proteasome inhibitor might be a novel immunosuppressant for transplantation.