El-Sherbiny Y M, Holmes T D, Wetherill L F, Black E V I, Wilson E B, Phillips S L, Scott G B, Adair R A, Dave R, Scott K J, Morgan R S M, Coffey M, Toogood G J, Melcher A A, Cook G P
Leeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St James's University Hospital, Leeds, UK; Affiliated with the Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Clin Exp Immunol. 2015 Apr;180(1):98-107. doi: 10.1111/cei.12562.
Human natural killer (NK) cells play an important role in anti-viral immunity. However, studying their activation kinetics during infection is highly problematic. A clinical trial of a therapeutic virus provided an opportunity to study human NK cell activation in vivo in a controlled manner. Ten colorectal cancer patients with liver metastases received between one and five doses of oncolytic reovirus prior to surgical resection of their tumour. NK cell surface expression of the interferon-inducible molecules CD69 and tetherin peaked 24-48 h post-infection, coincident with a peak of interferon-induced gene expression. The interferon response and NK cell activation were transient, declining by 96 h post-infection. Furthermore, neither NK cell activation nor the interferon response were sustained in patients undergoing multiple rounds of virus treatment. These results show that reovirus modulates human NK cell activity in vivo and suggest that this may contribute to any therapeutic effect of this oncolytic virus. Detection of a single, transient peak of activation, despite multiple treatment rounds, has implications for the design of reovirus-based therapy. Furthermore, our results suggest the existence of a post-infection refractory period when the interferon response and NK cell activation are blunted. This refractory period has been observed previously in animal models and may underlie the enhanced susceptibility to secondary infections that is seen following viral infection.
人类自然杀伤（NK）细胞在抗病毒免疫中发挥着重要作用。然而，研究它们在感染期间的激活动力学存在很大问题。一项治疗性病毒的临床试验提供了一个以可控方式研究人类NK细胞在体内激活的机会。十名患有肝转移的结直肠癌患者在肿瘤手术切除前接受了一至五剂溶瘤呼肠孤病毒。干扰素诱导分子CD69和束缚素在NK细胞表面的表达在感染后24 - 48小时达到峰值，这与干扰素诱导基因表达的峰值一致。干扰素反应和NK细胞激活是短暂的，在感染后96小时下降。此外，在接受多轮病毒治疗的患者中，NK细胞激活和干扰素反应均未持续。这些结果表明呼肠孤病毒在体内调节人类NK细胞活性，并表明这可能有助于这种溶瘤病毒的任何治疗效果。尽管进行了多轮治疗，但检测到单一的、短暂的激活峰值，这对基于呼肠孤病毒的治疗设计具有启示意义。此外，我们的结果表明在感染后存在一个不应期，此时干扰素反应和NK细胞激活减弱。这种不应期先前在动物模型中已被观察到，可能是病毒感染后对继发感染易感性增强的基础。
