Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection

Cytomegalovirus (CMV) reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early natural killer (NK) cell reconstitution may protect against the development of human CMV (HCMV) infection post-HSCT. Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells. Nevertheless, whether expanded NK cells have stronger anti-HCMV function is unknown. Herein, we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells. Expanded NK cells showed higher expression of activating receptors, chemokine receptors and adhesion molecules;stronger cytotoxicity against HCMV-infected fibroblasts;and better inhibition of HCMV propagation in vitro than primary NK cells. In HCMV-infected humanized mice, expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion. A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection (HR = 0.54, 95% CI = 0.32–0.93, p = 0.042) and refractory HCMV infection (HR = 0.34, 95% CI = 0.18–0.65, p = 0.009) than controls and better NK cell reconstitution on day 30 post NK cell infusion. In conclusion, expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.

Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease

Although glucorticosteroids(GCs)are the standard first-line therapy for acute graft-versus-host disease(a Gv HD),nearly 50%of a Gv HD patients have no response to GCs.The role of T cell metabolism in murine a Gv HD was recently reported.However,whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate a Gv HD remains to be elucidated.Increased glycolysis,characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(PFKFB3),and higher rates of glucose consumption and lactate production were found in Tcells from a Gv HD patients.Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells.In a humanized mouse model,PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented a Gv HD,respectively.Importantly,our integrated data from patient samples in vitro,in a humanized xenogeneic murine model of a Gv HD and graft-versus-leukaemia(GVL)demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate a Gv HD without loss of GVL effects.Together,the current study indicated that glycolysis is critical for T cell activation and induction of human a Gv HD.Therefore,the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for a Gv HD patients.GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for a Gv HD patients.

单倍型相合移植治疗重型再生障碍性贫血长期随访:一项多中心前瞻性研究

近年来,单倍型相合移植治疗重型再生障碍性贫血(再障)取得了很大的进展,但尚缺乏长期随访的数据.本文报道了一项前瞻性、多中心临床研究,聚焦单倍型相合移植作为二线方案治疗重型再障的长期疗效及生活质量,纵向、前瞻性评估了移植前、移植后3年和移植后5年的生活质量(成人应用SF-36量表,儿童应用PedsQL4.0量表).该项研究总共纳入287例病人,存活病人的中位随访时间4.56(3.01~9.05)年.在长期随访中,97.5%病人获得稳定的完全供者嵌合,93.4%病人获得完全造血重建.预计9年总生存率和无失败生存率85.4%±2.1%和84.0%±2.2%.移植时年龄(≥18岁)和体能状态评估(ECOG≥2分)是影响生存的预后因素.再障病人在单倍型移植后3年的生活质量较移植前有明显改善,且在移植后5年时有进一步改善.无论是儿童还是成人,中重度慢性移植物抗宿主病是影响生活质量的不良因素.末次随访时74.0%儿童和72.9%成人已恢复正常学习或工作.该研究提示在没有同胞全合供者的情况下,移植作为治疗重型再障患者的二线方案,单倍型供者可成为常规推荐.