Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Gastroenterology. 2011 Oct;141(4):1231-9, 1239.e1-2. doi: 10.1053/j.gastro.2011.06.069. Epub 2011 Jul 7.
BACKGROUND & AIMS: Mathematical modeling of hepatitis C virus (HCV) kinetics indicated that cellular immune responses contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process.
Phenotype and function of blood and liver NK cells were studied during the first 12 weeks of treatment with pegylated IFN-alfa and ribavirin, the time period used to define the early virological response.
Within hours of treatment initiation, NK cells of patients that had an early virological response increased expression of activating receptors NKG2D, NKp30, and CD16 and decreased expression of NKG2C and 2B4, along with inhibitory receptors SIGLEC7 and NKG2A, resulting in NK cell activation. NK cell cytotoxicity, measured by degranulation and tumor necrosis factor-related apoptosis-inducing ligand production, peaked after 24 hours (P<.01), concomitant with an increase in alanine aminotransferase levels (P<.05), whereas IFN-γ production decreased within 6 hours and did not recover for more than 4 weeks (P<.05). NK cells from liver biopsies taken 6 hours after treatment initiation had increased numbers of cytotoxic CD16+NK cells (P<.05) and a trend toward increased production of tumor necrosis factor-related apoptosis-inducing ligand. Degranulation of peripheral blood NK cells correlated with treatment-induced, first-phase decreases in viral load (P<.05) and remained higher in early virological responders than in nonresponders for weeks.
IFN activates NK cells early after treatment is initiated. Their cytotoxic function, in particular, is strongly induced, which correlates to virologic response. Therefore, NK cell activation indicates responsiveness to IFN-α-based treatment and suggests the involvement of the innate immune cells in viral clearance.
丙型肝炎病毒（HCV）动力学的数学模型表明，细胞免疫反应有助于干扰素（IFN）诱导清除 HCV。我们研究了自然杀伤（NK）细胞在这一过程中的潜在作用。
在聚乙二醇化 IFN-α和利巴韦林治疗的前 12 周内，即定义早期病毒学应答的时间段内，研究了血液和肝脏 NK 细胞的表型和功能。
在治疗开始后的数小时内，早期病毒学应答患者的 NK 细胞增加了激活受体 NKG2D、NKp30 和 CD16 的表达，减少了 NKG2C 和 2B4 的表达，同时还减少了抑制性受体 SIGLEC7 和 NKG2A 的表达，导致 NK 细胞活化。NK 细胞的细胞毒性，通过脱颗粒和肿瘤坏死因子相关凋亡诱导配体的产生来测量，在 24 小时后达到峰值（P<.01），同时伴随着丙氨酸氨基转移酶水平的升高（P<.05），而 IFN-γ的产生在 6 小时内下降，超过 4 周都没有恢复（P<.05）。在治疗开始后 6 小时从肝活检中取出的 NK 细胞具有更多的细胞毒性 CD16+NK 细胞（P<.05），并且肿瘤坏死因子相关凋亡诱导配体的产生有增加的趋势。外周血 NK 细胞的脱颗粒与治疗诱导的第一阶段病毒载量下降相关（P<.05），并且在早期病毒学应答者中比在无应答者中持续更高数周。
IFN 在治疗开始后早期激活 NK 细胞。它们的细胞毒性功能，特别是强烈诱导，与病毒学反应相关。因此，NK 细胞的激活表明对 IFN-α为基础的治疗有反应，并提示固有免疫细胞参与病毒清除。
