免疫抑制剂联合脐血治疗重型再生障碍性贫血的机制及临床研究

Mechanism and clinical study of immunosuppressants combined with cord blood for treating severe aplastic anemia

目的:本研究通过监测细胞因子在治疗前后的变化及脐带血干细胞的植入,探讨免疫抑制剂联合脐血输注(IS+CBI)治疗重型再生障碍性贫血(SAA)的作用机制。方法:选择SAA患者30例(初诊组),均采用IS+CBI治疗。其中23例患者有效(有效组),7例患者无效(无效组)。以20名健康体检者作为对照组。采用ELISA法检测各组外周血中白细胞介素(IL)-22、IL-17、IL-21、干扰素(IFN)-γ、肿瘤坏死因子(TNF)-α的表达水平。使用DNA可变短串联重复序列多态性分析(STR-PCR)检测脐血干细胞的植入情况。结果:1SAA初诊组IL-22、IL-17、IL-21、IFN-γ、TNF-α的表达水平均明显高于对照组(均P<0.05);有效组治疗3个月后细胞因子水平较治疗前无明显变化,治疗6、12个月后细胞因子水平明显低于治疗前(P<0.05);无效组在治疗前后各细胞因子水平无明显差异。2STR-PCR检测发现治疗后有效组1、3个月脐带血干细胞有嵌合性植入,治疗6个月后均排斥;治疗无效组未观察到有效植入。3与外周血造血干细胞移植(PBSCT)相比,IS+CBI的白细胞、血小板和血红蛋白恢复时间均明显延长(均P<0.05),但总有效率为76.67%,与PBSCT的77.08%相比差异无统计学意义。4供患者的人类白细胞抗原(HLA)配型相合性在有效组和无效组间差异无统计学意义。结论:1SAA患者体内IL-22、IL-17水平升高,可能与SAA的发生发展呈正相关;2在治疗过程中存在早期脐带血造血干细胞植入和中晚期免疫抑制剂调节的桥接机制,治疗后前3个月依靠脐血干细胞植入来促进造血恢复,治疗3个月后依靠免疫抑制剂来维持正常造血;3IS+CBI是无合适HLA配型SAA患者有效的治疗方案,供患者的HLA配型相合性与疗效之间无相关性。

Objective：To explore the mechanism of immunosuppressants combined with cord blood （IS＋CBI） for treating severe aplastic anemia （SAA）. Method： A total of 30 patients with SAA were treated with IS＋ CBI （newly diagnosed group）. Twenty-three patients were treated effectively （effective group） while 7 cases were trea ted invalidly （invalid group）. Twenty healthy individuals were selected as control group. The expression levels of IL-17,IL-22 and other cytokines in each group were detected by ELISA method. The engraftment of cord blood stem cells was detected by using short tandem repeat-polymerase chain reaction （STR-PCR） method. Result：①IL- 17 ,IL-22 and other cytokines expressions in newly diagnosed group were significantly higher than those in control group （P〈 0. 05）. After 6 months, the level in effective group was significantly lower than pre-therapy （P〈 0.05）. But the level in invalid group had no change compared with before. ②After 1 month and 3 months treatment,a small amount of engraftment was found in effective group. After 6 months,implant rejection was found. No effective engraftment was observed in invalid group.③The recovery time of WBC, PLT and Hb in PBSCT group was significantly faster than those in the IS＋CBI group （P〈0.05）. But the total efficiency of two kinds of treatment was not significantly different （76.67% vs 77.08% ,P〉0.05）.④HLA typing in the effective group and invalid group had no significant difference. Coneluslon： ①IL-17,IL-22 cells in SAA patients increase which may positively correlate with the progression of SAA. ②During the treatment of IS＋CBI, there is a bridging mechanism between early stage engraftment and immunosuppressant adjustment at advanced stage. ③IS＋ CB1 is an effective treatment for SAA patients without appropriate HLA matched donor. HLA match between the donor and the patients is not related with the treatment efficiency.