Huang Y F, Zhang S Y, He J B, Zhou Y, Xue R T, Fan Z P, Huang F, Xu N, Sun J, Liu Q F, Lin R
Department of Hematology, Nanfang Hospital, Southern Medical University, Clinical Medical Research Center of Hematological Diseases of Guangdong Province, Guangzhou 510515, China.
Zhonghua Xue Ye Xue Za Zhi. 2024 Nov 14;45(11):998-1004. doi: 10.3760/cma.j.cn121090-20240825-00322.
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. 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. 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 EBV- group at 1 month post-transplantation (=0.033). The median proportion of the CD3(-)CD16(neg)CD56(bri) subset in the EBV+ group was significantly higher than that in the EBV- group at 2 months post-transplantation (=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(-)CD16(bri)CD56(dim) NK cells in the EBV+ group was significantly higher than that in the EBV- group at 1 month post-transplantation (=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 (=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 EBV- group at 2 months post-transplantation (=0.023). The expression levels of TIM-3 on CD3(+)CD4(+) T cells in the EBV+ group than those in the EBV- group at 1 and 3 months post-transplantation (=0.002, =0.043). The median positive rate of Granzyme B expression in CD3(+)CD8(+) T cells and CD3(+)CD4(+) T cells in the EBV+ group was significantly lower than that in the EBV- group at 1-month post-transplantation (=0.033, =0.016). The median positive rate of Granzyme B expression in the CD3(-)CD16(bri)CD56(neg) cell subset in the EBV+ group was higher than that in the EBV- group at 2 months post-transplantation (=0.012). The median positive rate of Granzyme B expression in CD3(+)CD4(+) T cells in the EBV+ group remained significantly lower than that in the EBV- group at 2 months post-transplantation (=0.049). The median positive rate of perforin expression in the CD3(-)CD16(bri)CD56(dim) cell subset was significantly higher in the EBV+ group than in the EBV- group at 3 months post-transplantation (=0.003). The median positive rate of IFN-γ expression in CD3(+)CD8(+) T cells in the EBV+ group was significantly lower than that in the EBV- group at 3 months post-transplantation (=0.036) . Delayed NK cell and T lymphocyte reconstitution, high exhaustion marker expression, and weakened cytotoxic functions may be related to EBV reactivation after haploidentical HSCT.
本研究旨在通过分析移植后早期外周血中自然杀伤（NK）细胞、B细胞和T细胞的变化及其功能状态，探讨早期免疫重建与爱泼斯坦-巴尔病毒（EBV）激活之间的关联。本研究纳入了23例行单倍体造血干细胞移植（HSCT）的患者。比较了移植后1、2和3个月时EBV激活患者（EBV+组）和未激活患者（EBV-组）的NK细胞、T细胞和B细胞的免疫重建情况，以及NK和T细胞耗竭标志物（PD-1、TIM-3和CTLA-4）的表达水平和细胞毒性功能。9例患者移植后发生EBV激活（EBV+组），14例患者未发生激活（EBV-组）。所有EBV激活患者均出现EBV病毒血症，未发生EBV相关疾病。两组患者的临床特征无显著差异。移植后1个月，EBV+组CD3(+)CD8(+) T细胞的中位比例显著低于EBV-组（P=0.033）。移植后2个月，EBV+组CD3(-)CD16(neg)CD56(bri)亚群的中位比例显著高于EBV-组（P=0.046）。移植后1、2和3个月，两组CD3(-)CD19(+) B细胞的中位比例无显著差异。移植后1个月，EBV+组CD۳(-)CD16(bri)CD56(dim) NK细胞上CTLA-4的表达显著高于EBV-组（P=0.033）。EBV+组CD3(+)CD8(+) T细胞上TIM-3的表达显著高于EBV-组（P=0.009）。移植后2个月，EBV+组CD3(-)CD16(neg)CD56(dim) NK细胞上TIM-3的表达水平显著低于EBV-组（P=0.023）。移植后1个月和3个月，EBV+组CD3(+)CD4(+) T细胞上TIM-3的表达水平高于EBV-组（P=0.002，P=0.043）。移植后1个月，EBV+组CD3(+)CD8(+) T细胞和CD3(+)CD4(+) T细胞中颗粒酶B表达的中位阳性率显著低于EBV-组（P=0.033，P=0.016）。移植后2个月，EBV+组CD3(-)CD16(bri)CD56(neg)细胞亚群中颗粒酶B表达的中位阳性率高于EBV-组（P=0.012）。移植后2个月，EBV+组CD3(+)CD4(+) T细胞中颗粒酶B表达的中位阳性率仍显著低于EBV-组（P=0.049）。移植后3个月，EBV+组CD3(-)CD16(bri)CD56(dim)细胞亚群中穿孔素表达的中位阳性率显著高于EBV-组（P=0.003）。移植后3个月，EBV+组CD3(+)CD8(+) T细胞中IFN-γ表达的中位阳性率显著低于EBV-组（P=0.036）。单倍体HSCT后NK细胞和T淋巴细胞重建延迟、耗竭标志物表达高以及细胞毒性功能减弱可能与EBV激活有关。
