Stabile Helena, Nisti Paolo, Fionda Cinzia, Pagliara Daria, Gaspari Stefania, Locatelli Franco, Santoni Angela, Gismondi Angela
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
Department of Pediatric Hematology/Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy.
J Clin Med. 2019 Nov 7;8(11):1904. doi: 10.3390/jcm8111904.
T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reconstitute following transplantation, and play a pivotal role in mediating graft-versus-leukaemia (GvL). We recently described a CD56CD16 NK cell subset that mediates both cytotoxic activity and cytokine production. Given the multifunctional properties of this subset, we studied its functional recovery in a cohort of children given α/βT-cell-depleted haplo-HSCT followed by the infusion of a titrated number of iCasp-9-modified T cells (iCasp-9 HSCT). The data obtained indicate that multifunctional CD56CD16 NK cell frequency is similar to that of healthy donors (HD) at all time points analysed, showing enrichment in the bone marrow (BM). Interestingly, with regard to functional acquisition, we identified two groups of patients, namely those whose NK cells did (responder) or did not (non responder) degranulate or produce cytokines. Moreover, in patients analysed for both functions, we observed that the acquisition of degranulation capacity was not associated with the ability to produce interferon-gamma (IFN-γ Intriguingly, we found a higher BM and peripheral blood (PB) frequency of iCas9 donor T cells only in patients characterized by the ability of CD56CD16 NK cells to degranulate. Collectively, these findings suggest that donor iCasp9-T lymphocytes do not have a significant influence on NK cell reconstitution, even if they may positively affect the acquisition of target-induced degranulation of CD56CD16 NK cells in the T-cell-depleted haplo-HSC transplanted patients.
去除T细胞（TCD）的人类白细胞抗原（HLA）单倍型相合造血干细胞移植（HSCT）（TCD-单倍型-HSCT）对许多血液系统疾病的治疗产生了巨大影响。采用基因自杀法进行基因改造的一定数量T细胞的过继转移可以改善免疫重建，是提高单倍型HSCT成功率的一个有趣策略。自然杀伤（NK）细胞是移植后首先重建的供体来源淋巴细胞群体，在介导移植物抗白血病（GvL）中起关键作用。我们最近描述了一个CD56CD16 NK细胞亚群，它既能介导细胞毒性活性，又能产生细胞因子。鉴于该亚群的多功能特性，我们在一组接受α/βT细胞去除的单倍型HSCT，随后输注一定数量经iCasp-9修饰的T细胞（iCasp-9 HSCT）的儿童队列中研究了其功能恢复情况。获得的数据表明，在所有分析的时间点，多功能CD56CD16 NK细胞频率与健康供体（HD）相似，在骨髓（BM）中表现出富集。有趣的是，关于功能获得，我们确定了两组患者，即NK细胞发生（反应者）或未发生（无反应者）脱颗粒或产生细胞因子的患者。此外，在对两种功能都进行分析的患者中，我们观察到脱颗粒能力的获得与产生干扰素-γ（IFN-γ）的能力无关。有趣的是，我们发现仅在具有CD56CD16 NK细胞脱颗粒能力的患者中，iCas9供体T细胞在骨髓和外周血（PB）中的频率更高。总的来说，这些发现表明，供体iCasp9-T淋巴细胞对NK细胞重建没有显著影响，即使它们可能对T细胞去除的单倍型造血干细胞移植患者中CD56CD16 NK细胞靶诱导脱颗粒的获得有积极影响。
