A single-center study of changes in the immune repertoire of cytomegalovirus-activated patients within six months after haploid allogeneic hematopoietic stem cell transplantation
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摘要: 目的 明确单倍体异基因造血干细胞移植(Haplo-HSCT)术后半年内巨细胞病毒(CMV)感染的发生情况，并探讨CMV激活及其转归过程中T细胞受体(TCR)组库变化的意义。方法 回顾性分析2022年1月—2024年1月在新疆医科大学第一附属医院血液中心行Haplo-HSCT的141例患者，评估其在移植后6个月内的CMV再激活情况，并监测CMV激活患者在感染急性期及转归期的TCR组库变化。结果 移植中心2年内行Haplo-HSCT患者共141例，移植后6个月内发生CMV再激活患者64例，累计再激活率45.39%，其中，57例(89.06%)出现CMV血症，7例(10.94%)发展为CMV病。清髓性预处理方案单倍体异基因造血干细胞移植(MAC Haplo-HSCT)38例与减低预处理剂量方案单倍体异基因造血干细胞移植(RIC Haplo-HSCT)26例进行组间比较，年龄差异有统计学意义(P < 0.001)。性别、CMV临床诊断、CMV发生时间、CMV持续时间、合并其他感染比较差异无统计学意义(P>0.05)。对10例首次CMV激活患者在急性期和转归期的TCR组库进行监测，结果显示3例患者出现二次激活。急性期与转归期外周血TCR指标(CDR3氨基酸序列长度均值、克隆性、多样性)之间差异无统计学意义(P>0.05)。对比一次激活患者与二次激活患者的TCR数据，发现一次激活患者在CMV感染急性期的TCR多样性差异有统计学意义(P < 0.05)，而CDR3氨基酸序列长度均值及克隆性方面差异无统计学意义(P>0.05)。然而，一次激活患者的CMV特异性TCR丰度显著高于二次激活患者，差异有统计学意义(P < 0.05)。CMV特异性TCR丰度低于1%的患者病程显著长于高丰度组，且CMV特异性TCR丰度与CMV病程时长之间可能存在线性关系(P < 0.05)。结论 ① CMV再激活主要发生在Haplo-HSCT后3个月内，免疫功能低下是CMV激活的主要原因；②预处理方案对Haplo-HSCT患者发生CMV激活的影响不显著；③组库数据显示CMV二次激活患者体内可能缺乏足够的CMV特异性T细胞，导致对CMV感染的保护效力不足，病程延长；④CMV特异性TCR丰度可作为预测CMV二次激活的重要指标，并与CMV复发难治性高度相关。
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关键词:
- 单倍体异基因造血干细胞移植 /
- 巨细胞病毒 /
- T细胞受体组库 /
- 复发难治
Abstract: Objective To determine the incidence of cytomegalovirus(CMV) infection within six months after haploid allogeneic hematopoietic stem cell transplantation(Haplo-HSCT) and to investigate the significance of changes in the T-cell receptor(TCR) repertoire during CMV activation and its resolution.Methods A retrospective analysis was conducted on 141 patients who underwent Haplo-HSCT at the Hematology Center of First Affiliated Hospital of Xinjiang Medical University between January 2022 and January 2024. The study assessed the incidence of CMV reactivation within six months post-transplantation and monitored the changes in the TCR repertoire during the infection and resolution phases in patients with CMV activation.Results Among the 141 patients who received Haplo-HSCT within the two-year period, 64(45.39%) experienced CMV reactivation within six months post-transplantation. Of these, 57 patients(89.06%) developed CMV viremia, and 7 patients(10.94%) progressed to CMV disease. A comparison between the myeloablative conditioning(MAC) Haplo-HSCT group(38 cases) and the reduced-intensity conditioning(RIC) Haplo-HSCT group(26 cases) showed a statistically significant difference in age(P < 0.001). No significant differences were observed between the two groups in terms of gender, clinical diagnosis of CMV, time to CMV onset, duration of CMV infection, or co-infections(P>0.05). TCR repertoire monitoring of 10 patients during their first episode of CMV activation revealed that 3 patients experienced a second episode of CMV reactivation. There was no significant difference in TCR indexes(mean length, clonality and diversity of CDR3 amino acid sequence) in peripheral blood between acute phase and resolution phase(P>0.05). It was found that there was a significant difference in TCR diversity between acute phase and resolution phase in peripheral blood TCR indices(P < 0.05), but no statistically significant differences were found in other peripheral blood TCR indices, including the mean CDR3 amino acid sequence length, and clonality(P>0.05). However, a comparison of TCR data between patients with a single CMV activation and those with a second activation indicated that the CMV-specific TCR abundance was significantly higher in patients with a single activation(P < 0.05). Patients with CMV-specific TCR abundance below 1% had a significantly longer disease course compared to those with higher TCR abundance, and there was a potential linear relationship between CMV-specific TCR abundance and the duration of CMV infection. (P < 0.05).Conclusion ① CMV reactivation primarily occurs within the first three months post-Haplo-HSCT, with immunosuppression being the primary cause of CMV activation. ②The conditioning regimen has a negligible impact on the incidence of CMV activation in Haplo-HSCT patients. ③The data suggest that patients with CMV reactivation may lack sufficient CMV-specific T cells, leading to inadequate protective immunity against CMV and a prolonged disease course. ④CMV-specific TCR abundance could serve as a predictive marker for CMV reactivation and is closely associated with the refractory nature of CMV relapse. -
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表 1 不同预处理方案下Haplo-HSCT患者CMV发生情况
例(%) 项目 MAC RIC P 例数 38(59.38) 26(40.63) 年龄/岁 33.8
(9.0~52.0)49.3
(7.0~66.0)＜0.001 性别 0.773 男 25(65.79) 18(69.23) 女 13(34.21) 8(30.77) CMV临床诊断 0.602 CMV血症 34(89.47) 23(88.46) CMV病 4(10.53) 3(11.54) CMV发生时间/d 50.1
(11.0~176.0)48.6
(29.0~63.0)0.797 CMV持续时间/d 20.1
(6.0~73.0)22.5
(4.0~58.0)0.443 合并其他感染 21(55.26) 13(50.00) 0.618 EB病毒感染 16(42.11) 9(34.62) 新冠病毒感染 3(7.89) 1(3.85) 真菌感染 2(5.26) 2(7.69) 细菌感染 0 1(3.85) 
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表 2 CMV激活急性期及转归期患者TCR变化及疾病转归
患者编号 感染急性期 转归期 CMV首次激活病程/d 二次激活 总克隆数 多样性 克隆性 总克隆数 多样性 克隆性 1 668 5.987 0.362 3 290 10.173 0.129 18 1 2 536 7.423 0.181 821 7.460 0.229 28 1 3 1 006 8.356 0.162 783 6.153 0.360 28 1 4 1 145 7.448 0.267 1 436 7.822 0.254 12 1 5 871 6.347 0.350 1 454 7.994 0.144 7 1 6 244 5.315 0.330 695 5.299 0.439 18 1 7 855 7.382 0.242 1 094 6.548 0.351 21 1 8 450 5.491 0.377 1 084 7.615 0.255 36 2 9 478 6.158 0.308 106 3.377 0.498 78 2 10 16 3.401 0.150 96 2.846 0.248 31 2
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