单倍体造血干细胞移植后EB病毒激活患者早期细胞免疫功能耗竭的研究  

Early cellular immune exhaustion in patients with Epstein-Barr virus activation following haploidentical hematopoietic stem cell transplantation

作　　者：黄怡霏 张珊毓 何家宝 周雅 薛容涛 范志平[1] 黄芬[1] 许娜[1] 孙竞[1] 刘启发[1] 林韧[1] Huang Yifei;Zhang Shanyu;He Jiabao;Zhou Ya;Xue Rongtao;Fan Zhiping;Huang Fen;Xu Na;Sun Jing;Liu Qifa;Lin Ren(Department of Hematology,Nanfang Hospital,Southern Medical University,Clinical Medical Research Center of Hematological Diseases of Guangdong Province,Guangzhou 510515,China)

机构地区：[1]南方医科大学南方医院血液内科,广东省血液病临床研究中心,广州510515

出　　处：《中华血液学杂志》2024年第11期998-1004,共7页Chinese Journal of Hematology

基　　金：国家自然科学基金(82070190、82293634);广州市科技计划(2023A04J2325)。

摘　　要：目的本研究通过检测单倍体造血干细胞移植(HSCT)后早期外周血NK细胞、T细胞和B细胞亚群及功能变化情况,探讨移植早期免疫重建与EB病毒(EBV)激活的关联。方法纳入23例接受单倍体HSCT患者,比较移植后发生EBV激活(EBV+组)与未激活(EBV-组)患者移植后1、2、3个月的NK细胞、T细胞和B细胞免疫重建情况以及NK细胞和T细胞耗竭标志物(PD-1、TIM-3、CTLA-4)的表达水平及其杀伤功能的差异。结果EBV+组9例,均为EBV血症,未发生EBV相关终末器官疾病;EBV-组14例。两组患者基线临床特征差异均无统计学意义。移植后1个月EBV+组CD3^(+)CD8^(+)T细胞中位比例低于EBV-组(P=0.033);移植后2个月EBV+组患者CD3-CD16_(neg)CD56briNK细胞亚群中位比例高于EBV-组(P=0.046);移植后1、2、3个月两组间CD3-CD19^(+)B细胞中位比例差异均无统计学意义。移植后1个月EBV+组CD3-CD16briCD56_(dim)NK细胞亚群上CTLA-4的表达水平高于EBV-组(P=0.033),EBV+组CD3^(+)CD8^(+)T细胞上TIM-3的表达水平高于EBV-组(P=0.009);移植2个月EBV+组CD3-CD16_(neg)CD56_(dim)NK细胞亚群上TIM-3的表达水平低于EBV-组(P=0.023);移植后1、3个月EBV+组CD3^(+)CD4^(+)T细胞上TIM-3的表达水平均高于EBV-组(P=0.002、P=0.043)。移植后1个月EBV+组CD3^(+)CD8^(+)T和CD3^(+)CD4^(+)T细胞表达颗粒酶B的中位阳性率低于EBV-组(P=0.033、P=0.016);移植后2个月EBV+组CD3-CD16briCD56_(neg)细胞亚群表达颗粒酶B的中位阳性率高于EBV-组(P=0.012);EBV+组CD3^(+)CD4^(+)T细胞表达颗粒酶B中位阳性率低于EBV-组(P=0.049);移植后3个月EBV+组CD3-CD16briCD56_(dim)细胞亚群表达穿孔素的中位阳性率高于EBV-组(P=0.003);EBV+组CD3^(+)CD8^(+)T细胞表达IFN-γ中位阳性率低于EBV-组(P=0.036)。结论单倍体HSCT后NK细胞与T淋巴细胞重建延迟、耗竭分子高表达及杀伤功能减弱可能与移植后EBV激活相关。Objective This study aimed to investigate the association between early immune reconstitution and Epstein-Barr virus(EBV)reactivation by analyzing changes in natural killer(NK),B,and T cells and their functional status in the peripheral blood during the early post-transplant period.Methods This study included 23 patients who underwent haplo-hematopoietic stem cell transplantation(HSCT).The immune reconstitution of NK cells,T cells,and B cells as well as the expression levels of NK and T cell exhaustion markers(PD-1,TIM-3,and CTLA-4)and cytotoxic function at 1,2,and 3 months post-transplantation were compared between patients with EBV activation(EBV+group)and those without activation(EBV-group)post-transplantation.Results EBV activation occurred in nine patients post-transplantation(EBV+group),whereas 14 patients demonstrated no activation(EBV-group).All patients with EBV activation exhibited EBV viremia,and no EBV-associated diseases occurred.No significant differences in the clinical characteristics were found between the two groups of patients.The median proportion of CD3^(+)CD8^(+)T cells in the EBV+group was significantly lower than that in the EBVgroup at 1 month post-transplantation(P=0.033).The median proportion of the CD3-CD16_(neg)CD56bri subset in the EBV+group was significantly higher than that in the EBV-group at 2 months posttransplantation(P=0.046).No significant differences in the median proportions of CD3-CD19^(+)B cells were observed between the two groups at 1,2,and 3 months post-transplantation.The expression of CTLA-4 on CD3-CD16briCD56_(dim)NK cells in the EBV+group was significantly higher than that in the EBVgroup at 1 month post-transplantation(P=0.033).The expression of TIM-3 on CD3^(+)CD8^(+)T cells in the EBV+group was significantly higher than that in the EBV-group(P=0.009).The expression level of TIM-3 on CD3-CD16_(neg)CD56_(dim)NK cells in the EBV+group was significantly lower than that in the EBVgroup at 2 months post-transplantation(P=0.023).The expression levels of TIM-3 on CD3^(+

关 键 词：异基因造血干细胞移植 EB病毒感染 免疫重建 耗竭标志物 免疫功能 

分 类 号：R457.7[医药卫生—治疗学]