Controlled infection with a therapeutic virus defines the activation kinetics of human natural killer cells in vivo
Controlled infection with a therapeutic virus defines the activation kinetics of human natural killer cells in vivo
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DOI：
10.1111/cei.12562
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发表时间：
2015-04-01
影响因子：
4.6
通讯作者：
Cook, G. P.
中科院分区：
文献类型：
--
作者：
El-Sherbiny, Y. M.;Holmes, T. D.;Cook, G. P.
人体自然杀伤细胞（NK）在抗病毒免疫中起着重要作用。然而，研究它们在感染过程中的激活动力学是非常有问题的。一种治疗性病毒的临床试验提供了一个机会，以受控的方式在体内研究人类NK细胞的活化。10例肝转移的结直肠癌患者在手术切除肿瘤前接受了1至5剂溶瘤呼肠孤病毒治疗。干扰素诱导分子CD69和tetherin在感染后24-48h的NK细胞表面表达达到峰值，与干扰素诱导基因表达高峰一致。干扰素应答和NK细胞活化是短暂的，在感染后96h下降。此外，在接受多轮病毒治疗的患者中，NK细胞活化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细胞的活性，并提示这可能有助于这种溶瘤病毒的任何治疗效果。尽管进行了多次治疗，但检测到一个短暂的激活峰，对设计基于呼肠孤病毒的治疗具有重要意义。此外，我们的结果表明存在感染后不应期，此时干扰素反应和NK细胞激活减弱。先前在动物模型中观察到这种不应期，可能是病毒感染后对继发性感染的易感性增强的基础。
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 24-48h post-infection, coincident with a peak of interferon-induced gene expression. The interferon response and NK cell activation were transient, declining by 96h 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.