KIR受配体模式在治疗急性淋巴细胞白血病中的研究  

Study on the KIR receptor-ligand model in treatment of acute lymphoblastic leukemia

作　　者：何军[1] 鲍晓晶[1] 孙爱宁[1] 陈子兴[1] 吴德沛[1] 袁晓妮[1] 邱桥成[1] 岑建农[1] 阮长耿[1] 

机构地区：[1]苏州大学附属第一医院,江苏省血液研究所,卫生部血栓与止血重点实验室,215006

出　　处：《中华微生物学和免疫学杂志》2009年第2期160-164,共5页Chinese Journal of Microbiology and Immunology

基　　金：卫生部科研基金资助项目（wkj2006-2-023）;江苏省六大高峰人才资助项目（07-B-021）;江苏省卫生厅135开放资助项目（K0611）;江苏省高校自然科学基金资助项目（07kj320106）;苏州市中外国际合作资助项目（SWH0716）;苏州市基础设施资助项目（SZS0702）

摘　　要：目的研究在无关供体造血干细胞移植中急性淋巴细胞白血病（ALL）的杀伤细胞免疫球蛋白样受体（KIR）受配体模式对自然杀伤（NK）细胞的异源反应性活性预示造血干细胞移植的影响。方法采用基因测序和序列特异性引物聚合酶链反应（PCR-SSP）的方法，对中国造血干细胞捐献者资料库中提供的23对HLA全相合供受者进行KIR及HLA高分辨基因分型；流式细胞术动态随访CD158分子表达水平；患者均为ALL。结果23对供受者中17例供者KIR2DL2／L3有相应的患者配体HLA-Cw1、3、7、8、12、14；6例供者KIR2DL1有相应的患者配体HLA—Cw6、15；16例供者KIR3DL1有相应的患者配体HLA—Bw4；12例供者3DL2有相应的患者配体HLA—A11。23对供受者中有19对接受了造血干细胞移植，供受者KIR基因完全相同或宿主抗移植物（HVG）方向移植相关死亡率高，分别为33．3％和40．0％；移植物抗宿主（GVH）方向移植相关死亡率低，为12．5％。供受者在GVH方向时，移植物抗宿主病（GVHD）发生率高（50．0％）且有多种激活性（aKIR）的组合；而HVG方向GVHD发生率低（20．0％）。19对供受者有5对均为KIR基因A单体型，其中2对供受者为KIR2DS4$00I／002亚型，移植后死亡；3对供受者KIR2DS4为KIR2DS4＊003-007亚型，1年后无病生存。移植后随访无GVHD发生时，CD158a的表达逐渐下降；有GVHD发生时，CD158a的表达逐渐增高；移植后早期受者NK细胞百分比为（23．4±3．8）％，高于正常人水平[（2．04±0．58）％，P〈0．05]，差异有统计学意义。结论供者的KIR2DL1、KIR3DL1是引起NK细胞异源反应活性的重要抑制性KIR。KIR受配体模式不仅能预示无关供体异基因造血干细胞移植的预后，更能帮助临床提高ALL异基因造血干细胞移植的总生存率及无病生存率，降低移植后相关死亡率和防止白血病复发。Objective To investigate the effect of KIR-HLA receptor-ligand model on the unrelated allo-hematopoietic stem cell transplantation （Allo-HSCT） of acute lymphoblastic leukemia （ALL）. Methods The KIR genotype of 23 pairs of ALL patients and their HLA-matched unrelated donors obtained from the Database of China Marrow Donor Program. KIR genotype was determined using PCR-SSP. The expression of inhibitory KIR（iKIR） was determined by flow cytometry analysis on recipients after HSCT. Results Among all 23 donor/recipient pairs, 17 donors with KIR2DL2/L3 could find corresponding HLA-Cw1, 3, 7, 8, 12, 14 ligands in their recipients. Six donors with KIR2DL1 could match with HLA-Cw6, 15 in recipients. Sixteen donors with KIR3DL1 could recognize HLA-Bw4 and 12 donors with 3DL2 could find HLA-All in their corresponding recipients, respectively. Ninteen patients were successfully transplanted, and the death rate of transplantation were 33.3% （2/6） and 40.0% （2/5） in KIR receptor-ligand matched model and the graft versus leukemia（HVG） KIR ligand-mismatching pattern. The frequency of acute graft versus host disease（GVHD） was 50.0% and death rate was 12.5% （ 1/8 ） in GVH KIR ligand-mismatching. The incidence rate of activated GVHD（aGVHD） was 20.0% in the HVG KIR ligand-mismatching. Five donor/recipient pairs of KIR gene typing were the KIR-haplotype A, 2 donor/recipient pairs with KIR2DS4 ＊ 001/002 were died, 3 donor/recipient pairs with KIR2DS4 ＊ 003-007 were obtained the disease free survival. The expression of CD158a/2DL1 was low when the patient had no aGVHD, but became much higher when aGVHD occurred. The percentage of NK cell of the patients was decreasing since transplantation, but still higher than normal after HSCT [（23.4±3.8 ）% vs （2.04 ± 0.58）%, P 〈 0.05 ]. Condusion Analysis on KIR-HLA gene loci pattern may provide a useful parameter in predicting the clinical outcome of HLA-matched unrelated allogeneic hematopoietic stem cell transplantation for leukemia patients. Mo

关 键 词：杀伤细胞免疫球蛋白样受体 受配体模式 急性淋巴细胞白血病 移植 无关供体 

分 类 号：R733.71[医药卫生—肿瘤] R373.9[医药卫生—临床医学]