BMMSC治疗儿童难治性aGVHD的疗效和治疗前后患儿血清中细胞因子水平变化的相关分析  

Efficacy of BMMSCs on aGVHD and Its Correlation with Serum Inflammatory Cytokines in Pediatric Patients with Severe Refractory Acute Graft-Versus-Host Disease

作　　者：郭淑仪 邱坤银 汤昔康[1] 黄科[1] 徐宏贵[1] 黎阳[1] 翁文骏[1] 许吕宏[1] 方建培[1] 周敦华[1] GUO SHU-Yi;QIU Kun-Yin;TANG Xi-Kang;HUANG Ke;XU Hong-Gui;LI Yang;WENG Wen-Jun;XU Lv-Hong;FANG Jian-Pei;ZHOU Dun-Hua(Department of Pediatrics,SUN Yat-Sen Memorial Hospital of SUN Yat-Sen University,Guangzhou 510120,Guangdong Province,China)

机构地区：[1]中山大学孙逸仙纪念医院儿科,广东广州510120

出　　处：《中国实验血液学杂志》2020年第1期255-261,共7页Journal of Experimental Hematology

基　　金：广东省科技发展专项资金项目(2017A020215086).

摘　　要：目的:探讨骨髓间充质干细胞(bone marrow mesenchymal stem cell,BMMSC)治疗儿童异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,allo-HSCT)后难治性移植物抗宿主病(graft versus host disease,GVHD)疗效,通过动态监测输注BMMSC前后患儿体内细胞因子的变化,判断BMMSC的疗效并为BMMSC治疗GVHD的机制提供理论依据。方法:选取allo-HSCT后难治性aGVHD患儿17例(II级GVHD 7例,Ⅲ级GVHD 6例,Ⅳ级GVHD 4例)。所有患儿经常规免疫抑制剂治疗无效,在原有免疫抑制剂基础上联合静脉滴注BMMSC,观察GVHD的缓解情况及BMMSC治疗相关不良反应。通过化学发光法检测GVHD患儿输注BMMSC前及输注后d 7和d 14,血清细胞因子IL-2α、IL-6、IL-10、IL-8及TNF-α的水平。结果:BMMSC的累计中位使用剂量为5.5(3.4-11.1)×10^6/kg,平均使用次数3.7(1-13)次,距离确诊GVHD首次输注MSC中位时间为16.5(4-95)d。17例难治性GVHD中,14例治疗有效,3例无效,总有效率为82.4%,均未出现不良反应。存活的14例患儿,距首次输注到BMMSC中位随访时间为944(559-1245)d。治疗前Ⅱ、Ⅲ、Ⅳ级GVHD患儿血清TNF-α浓度分别为9.5±4.3、16.3±10.9和35.8±21.2 pg/ml,Ⅱ级与Ⅳ级、Ⅲ级与Ⅳ级组间差异具有统计学意义(P<0.05)。BMMSC治疗有效与无效组间比较,治疗前血清TNF-α为10.8±5.6和40.6±14.8 pg/ml(t=-3.901,P<0.05)。BMMSC治疗有效组中,d 14 IL-10(20.0±17.4)pg/ml较治疗前(7.3±3.1)pg/ml明显升高(t=-2.850,P<0.05),而IL-2α,IL-6,IL-8和TNF-α浓度在治疗前后差异不具有统计学意义(P>0.05)。结论:BMMSC治疗儿童难治性GVHD安全有效。TNF-α与GVHD的严重程度相关,可用于GVHD的病情监测。BMMSC可能通过上调体内细胞因子IL-10水平发挥抗GVHD的作用。Objective:To investigate the efficacy of bone marrow mesenchymal stem cells(BMMSC)on children with refractory graft-versus-host disease(GVHD)and to judge the efficacy of BMMSC by dynamically monitoring the changes of cytokines in children with GVHD before and after infusion of BMMSC,so as to provide a theoretical basis for clarifying the mechanism of BMMSC.Methods:17 children with refractory aGVHD including 7 of grade II,6 cases of grade III and 4 cases of grade IV after allo-HSCT were enrolled.All the children with aGVHD,who received routine immunosuppressive therapy,but the state of disease not improved,were treated with immunosuppressive drugs combined with BMMSC infusion.Study endpoints included safety of BMMSC infusion,response to BMMSC,and overall response of aGVHD.The serum levels of IL-2α,IL-6,IL-10,IL-8 and TNF-αin aGVHD patients were measured by chemiluminescence before infusion of BMMSCs and Day 7,Day 14 after infusion of BMMSCs.Results:The cumulative median dose of BMMSCs was 5.5(3.4-11.1)×10^6/kg for average of 3.7 times,and the median time of 16.5(4-95)days for the first infusion of MSCs.In 17 cases of refractory GVHD,14 responded to treatment,whereas 3 patients failed.The total effective rate was 82.4%and no adverse reactions occurred.Of the 14 survived cases(82.4%),the median follow-up time was 944(559-1245)days from the first infusion of MSCs.The levels of TNF-αin children with grade II,III and IV GVHD before treatment were 9.5±4.3 pg/ml,16.3±10.9 pg/ml and 35.8±21.2 pg/ml respectively.The difference between grade II and IV,III and IV was statistically significant(P<0.05).Compared with the ineffective group of BMMSC infusion,the serum TNF-αlevel in the BMMSCs treatment effective group was 10.8±5.6 pg/ml vs 40.6±14.8 pg/ml(t=-3.901,P<0.05)before treatment.In the effective group of BMMSCs infusion,IL-1020±17.4 pg/ml of day 14 was significantly higher than that 7.3±3.1 pg/ml before the treatment(t=-2.850,P<0.05),while,the serum levels of IL-2α,IL-6,IL-8,TNF-αwere not statistically sign

关 键 词：骨髓间充质干细胞 移植物抗宿主病 儿童 疗效 安全性 

分 类 号：R457.7[医药卫生—治疗学] R733[医药卫生—临床医学]