硼替佐米对小鼠急性移植物抗宿主病的抑制作用  

Prevention and treatment of acute graft-versus-host disease in mice by bortezomib

作　　者：孙海英[1] 耿华云[1] 曾令宇[1] 李振宇[1] 徐开林[1] 

机构地区：[1]徐州医学院附属医院血液科徐州医学院移植免疫实验室,江苏省徐州市221002

出　　处：《中华器官移植杂志》2011年第1期11-15,共5页Chinese Journal of Organ Transplantation

摘　　要：目的 探讨硼替佐米对小鼠急性移植物抗宿主病（aGVHD）的抑制作用及其可能机制.方法 以C57BL/6小鼠为供鼠,获取骨髓细胞及脾细胞.以Balb/c小鼠为受鼠,共分为5组：空白对照组（n=17）小鼠不予任何处理;单纯照射组（n=17）小鼠仅接受7.0 Gy X射线全身照射（TBI）;药物对照组（n=17）小鼠也接受TBI,并且由尾静脉注射硼替佐米;aGVHD组（n=8）小鼠TBI后注射供鼠骨髓细胞及脾细胞;实验组（n=8）小鼠TBI后输注供鼠骨髓细胞及脾细胞,并予以硼替佐米.观察各组小鼠aGVHD的发生情况、存活时间及嵌合状态,蛋白印迹法测定空白对照组、单纯照射组和药物对照组小鼠肝脏及小肠组织细胞核中核因子κB（NF-κB）p65的表达.结果 aGVHD组和实验组的临床aGVHD评分分别为7.37±0.32和5.85±0.40,实验组明显低于aGVHD组（P＜0.05）.aGVHD组受鼠肝脏、小肠及皮肤组织为Thomas GVHD病理分级Ⅲ～Ⅳ级改变.实验组受鼠肝脏、小肠及皮肤组织为Ⅰ～Ⅲ级GVHD改变,较aGVHD组有所减轻.实验组存活时间长于aGVHD组（P＜0.05）.aGVHD组和实验组小鼠移植后12 d时外周血细胞中H-2Kb分子阳性细胞的百分率均＞90%.药物对照组肝脏及小肠组织细胞核内NF-κB p65表达均高于单纯照射组（P＜0.05）.结论 硼替佐米可能通过在一定程度上抑制照射预处理损伤所致肝脏及小肠组织中NF-κB的激活起到减轻aGVHD的作用.Objective To observe the effect of bortezomib on acute graft-versus-host disease （aGVHD） in an aGVHD model of mice and investigate the related mechanism. Methods Male C57BL/6（ H-2Kb）mice were used as donors and female Balb/c （H-2Kd） mice used as recipients. Balb/c mice received total body irradiation （TBI） by 7.0 Gy X-radiation, and randomly divided into five groups. normal （group A）, TBI （group B）, TBI ＋ bortezomib （group C）, TBI ＋ bone marrow cells （BMC） ＋ spleen cells （SC） （group D） and TBI ＋ bortezomib ＋ BMC ＋ SC （group E）. The physical signs and the pathological damage of aGVHD, mean survival time, and chimerism were observed in recipients. The NF-κB p65 levels in nuclei of the liver and small intestine tissues of groups A,B and C were analyzed by Western blot. Results （ 1 ） The clinical aGVHD score in group D was （7.37±0. 32）, significantly higher than in group E （5.85 ± 0.40） （P〈0. 05）. Histopathology of the gut, liver and skin illuminated that the Ⅲ-Ⅳ degree GVHD occurred in group D. The occurrence of aGVHD in group E was later than in group D. The symptoms and the pathological damage of aGVHD in group E were milder than in group D. The average survival time in group E was significantly longer than that in group D （P〈0.05）. The percentage of donor-derived cells in recipient mice was above 90% at day 12 after transplantation; （2） NF-κB p65 levels in nuclei of the liver and small intestine tissues in group B was significantly higher than in group C on the day 1,3 and 5 （P〈0. 05）. Conclusion Bortezomib can inhibit the activation and expression of NF-κB,which may be the underlying mechanism for it to relieve aGVHD.

关 键 词：硼替佐米 移植物抗宿主病 核因子ΚB 小鼠 

分 类 号：R965[医药卫生—药理学]