化疗诱发异基因造血干细胞移植后急性T淋巴细胞白血病复发患者移植物抗宿主病及其Th17／Treg细胞动态观察

 【摘要】　目的　探讨化疗诱发异基因造血干细胞移植（allo-HSCT）后急性T淋巴细胞白血病（T-ALL）髓外复发患者发生移植物抗宿主病（GVHD）的临床特征及Th17／Treg细胞及相关细胞因子的动态变化。方法　以20名健康体检者为健康对照。1例诊断为T-ALL患者在2个疗程化疗后血液学完全缓解时，行同胞供者HLA配型全相合的allo-HSCT。移植后对患者进行随访，同时采用流式细胞术和酶联免疫吸附法（ELISA）检测患者在供者细胞植入状态、疾病复发、GVHD各个时期外周血Th17／Treg细胞及相关因子的动态变化。结果　患者+27天获得完全供者嵌合体（FDC），+34天造血功能完全恢复，+110天出现慢性GVHD（cGVHD），+264天在cGVHD状态下髓外复发，Hyper-CVAD方案化疗后，+347天相继出现表现为口腔溃疡的cGVHD及伴有Ⅳ度肠道GVHD的重叠综合征。患者外周血中Th17细胞占CD+4 T细胞比例在发生重叠综合征时（1.70 %）较健康对照组（0.56±0.35）%]有所增高，Treg细胞占CD+4 T细胞的比例在患者发生cGVHD时（4.66 %）较健康对照组（0.59±0.33）%]及患者复发时（0.39 %）、造血干细胞植入时（1.15 %）高，发生重叠综合征时升高更加明显（7.83 %），同时在复发时Th17／Treg比例＞1，而发生GVHD时Th17／Treg比例＜1。血清中白细胞介素-17A 在患者发生cGVHD时（6.11 pg／ml）及化疗后诱导重叠综合征时（6.81 pg／ml）均较健康对照组（5.19±0.77）pg／ml]有所增高，TGF-β1浓度在患者移植后不同时期均较健康对照（48.81±4.90）ng／ml]高。结论　化疗可诱发allo-HSCT术后复发的急性白血病患者发生GVHD；Th17／Treg细胞及相关细胞因子的失衡可能与疾病复发、GVHD的发生相关。

Dynamic observation of GVHD induced by chemotherapy and Th17/Treg in a relapse T-ALL patient after allo-HSCT

Objective To explore clinical features of chemotherapy-induced graft-versus-host disease and to observe the dynamical changes of Thl7/Treg ratio and related eytokines in one relapsed acute T- lymphohlastic leukemia after allo-HSCT. Methods Twenty health volunteers were heahhy controls. One patient achieved complete haematologie remission after two courses of chemotherapy and underwent matched HLA identical sibling allogenic peripheral blood stem cell transplantation, donor cell implanted state, disease recurrence and graft- versus -host disease were observed and Thl7/Treg cells and its related factors in the peripheral blood were detected in different periods dynamically changes by methods of flow cytometry and ELISA. Results The patient achieved complete donor chimerism （FDC） at day ＋27 after transplantation. Hernatopoietic function was fully recovered at day ＋34.Chronic GVHD （cGVHD） occurred at day ＋110. Thereafter, extramedullary relapse occurred in cGVHD state at day ＋264. After one course of Hyper-CVAD chemotherapy, patient complicated overlap syndrome with eGVHD of oral cavity ulcer and degree IV intestinal aGVHD at day ＋294 and day ＋347, respectively. Thl7 cell ratio in CD T cells （l.7 %） in the overlap syndrome slightly increased,compared with control group （0.56±0.35） %]. The ratio of Treg cells in CD T cells （4.66 %） with cGVHD increased compared with normal control group （0.59±0.33） %], recurrence （0.39 %）, and hematopoietic stem cell implantation （1.15 %）, but the ratio of Treg cells increased significantly when patient complicated overlap syndrome （7.83 %）. The ratios of Thl7/Treg were more than 1 at relapse and less than 1 at GVHD stage. The IL-17A level in serum significantly increased in cGVHD （6.114 pg/ml） and overlap syndrome （6.805 pg/m｜） stage compared with normal control group （5.19±0.77） pg/ml]. TGF-β1 levels were significantly higher at different periods after transplantation compared with control group （48.81± 4.9） ng/ml]. Conclusion Chemotherapy can induce GVHD in relapsed acute leukemia patients after hematopoietic stem cell transplantation, and the imbalance of the Thl7/Treg cells and its cytokines maybe related with disease relapse and GVHD.