Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide
Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide
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DOI：
10.1182/bloodadvances.2020003005
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发表时间：
2021-01-15
期刊：
影响因子：
7.5
通讯作者：
Romee, Rizwan
中科院分区：
文献类型：
--
作者：
Rambaldi, Benedetta;Kim, Haesook T.;Romee, Rizwan
移植后使用cydophosphamide （PTCy）显著增加了接受hla -单倍相同造血细胞移植（haploi - hct）的患者数量。为了检查这些患者的免疫重建，我们监测了60例接受骨髓或外周血干细胞（PBSC）移植的患者在PTCy单倍hct后的T和自然杀伤（NK）细胞恢复情况，以及35例接受hla匹配供体PBSC移植的患者在标准移植物抗宿主病（GVHD）预防后的T和自然杀伤（NK）细胞恢复情况。与hla匹配的受体相比，单倍hct患者的早期T细胞恢复延迟，并倾向于效应记忆T细胞，幼稚T细胞明显减少。我们发现，HCT后早期调节性T （Treg）细胞/常规T （Tcon）细胞比例较高，记忆T细胞中PD-1表达增加。在单倍hct中，未发生慢性GVHD （cGVHD）的患者在移植后1个月中枢和效应记忆CD4(+) Treg细胞上的PD-1表达较高。这些发现表明，免疫环境促进了单倍体hct患者的免疫耐受。与匹配供体移植相比，单倍体hct后NK细胞早期减少，未成熟CD56（亮）CD16(-) NK细胞优先扩增。移植1个月后，流式细胞术显示，单倍体hct后，未成熟的nk细胞转移细胞富集，具有高NKG2A、低CDS7和低杀伤细胞免疫球蛋白样受体表达，hct后3个月部分恢复。2个月时，两组未成熟NK细胞功能受损，但白细胞介素-15在体外修复了这些缺陷。单倍体hct后，未成熟/成熟nk细胞比例的增加与巨细胞病毒再激活和cGVHD发病率的增加有关。单倍体hct后T细胞和nk细胞重建的这些稳态失衡揭示了早期免疫干预以优化临床结果的机会。
Administration of posttransplant cydophosphamide (PTCy) has significantly expanded the number of patients undergoing HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). To examine immune reconstitution in these patients, we monitored T- and natural killer (NK)-cell recovery in 60 patients receiving bone marrow or peripheral blood stem cell (PBSC) grafts after haplo-HCT with PTCy and 35 patients receiving HLA-matched donor PBSC grafts with standard graft-versus-host disease (GVHD) prophylaxis. Compared with HLA-matched recipients, early T-cell recovery was delayed in haplo-HCT patients and skewed toward effector memory T cells with markedly reduced naive T cells. We found higher regulatory T (Treg)-cell/conventional T (Tcon)-cell ratios early after HCT and increased PD-1 expression on memory T cells. Within the haplo-HCT, patients who did not develop chronic GVHD (cGVHD) had higher PD-1 expression on central and effector memory CD4(+) Treg cells at 1 month after transplant. These findings suggest an immunologic milieu that promotes immune tolerance in haplo-HCT patients. NK cells were decreased early after haplo-HCT with preferential expansion of immature CD56(bright) CD16(-) NK cells compared with matched donor transplants. One month after transplant, mass cytometry revealed enrichment of immature NK-cell metadusters with high NKG2A, low CDS7, and low killer-cell immunoglobulin-like receptor expression after haplo-HCT, which partially recovered 3 months post-HCT. At 2 months, immature NK cells from both groups were functionally impaired, but interleukin-15 priming corrected these defects in vitro. Increased immature/mature NK-cell ratios were associated with cytomegalovirus reactivation and increased incidence of cGVHD after haplo-HCT. These homeostatic imbalances in T- and NK-cell reconstitution after haplo-HCT reveal opportunities for early immune-based interventions to optimize clinical outcomes.