利巴韦林可改善 HCV 感染肝移植受者基于索非布韦的 DAA 治疗期间 NK 细胞 IFNγ 应答。

Ribavirin Improves NK Cell IFNγ Response During Sofosbuvir-based DAA Therapy in HCV-infected Liver Transplant Recipients.

机构信息

Department of Surgery, University Hospital Regensburg, Regensburg, Germany.

Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.

出版信息

Transplantation. 2021 Oct 1;105(10):2226-2238. doi: 10.1097/TP.0000000000003612.

DOI:10.1097/TP.0000000000003612

PMID:33587435

Abstract

BACKGROUND

Chronic hepatitis C virus (HCV) infection is characterized by activation of natural killer (NK) cells. Here, we asked whether HCV elimination by sofosbuvir-based direct-acting antivirals (DAAs) and the addition of ribavirin (RBV) improve NK cell function in liver transplant (LTx) recipients.

METHODS

We analyzed NK cell degranulation and interferon (IFN)γ-response along with STAT1 and STAT4 phosphorylation in 29 HCV-infected LTx recipients and 17 HCV-infected patients during DAA treatment.

RESULTS

Compared with uninfected LTx recipients, NK cells from HCV-infected LTx recipients were polarized toward cytotoxicity with increased CD107a-degranulation (10.1% versus 14.6%; P = 0.0263) and reduced capacity to produce IFNγ (43.0% versus 26.7%; P = 0.0002). The altered phenotype of NK cells in HCV-infected LTx recipients was accompanied by increased STAT1 (44.6% versus 87.4%; P < 0.0001) and STAT1 phosphorylation (0.7% versus 8.9%; P = 0.0005) compared with pSTAT4 IFNα-induction (29.9% versus 17.6%; P = 0.0014). Successful DAA therapy did not affect CD107a-degranulation but decreased STAT1. RBV cotreatment with DAA therapy for HCV increased CD56Bright NK cell IFNγ-responses in LTx recipients (70.9% versus 89.2%; P = 0.002), and this correlated to an increase in the inducibility of pSTAT4 (MFI 157 versus 173; P = 0.0002).

CONCLUSIONS

RBV cotreatment of HCV infection improved pSTAT4-dependent IFNγ-production in NK cells. This is relevant especially for immunocompromised patients such as LTx recipients or patients with end-stage liver disease.

摘要

背景

慢性丙型肝炎病毒（HCV）感染的特征是自然杀伤（NK）细胞的激活。在这里，我们想知道基于索非布韦的直接作用抗病毒药物（DAA）联合利巴韦林（RBV）清除 HCV 是否能改善肝移植（LTx）受者的 NK 细胞功能。

方法

我们分析了 29 例 HCV 感染的 LTx 受者和 17 例 HCV 感染患者在 DAA 治疗期间 NK 细胞脱颗粒和干扰素（IFN）γ反应，以及 STAT1 和 STAT4 磷酸化。

结果

与未感染的 LTx 受者相比，HCV 感染的 LTx 受者的 NK 细胞向细胞毒性极化，CD107a 脱颗粒增加（10.1%对 14.6%；P=0.0263），产生 IFNγ的能力降低（43.0%对 26.7%；P=0.0002）。在 HCV 感染的 LTx 受者中，NK 细胞的表型改变伴随着 STAT1 的增加（44.6%对 87.4%；P<0.0001）和 STAT1 磷酸化（0.7%对 8.9%；P=0.0005），而 pSTAT4 IFNα诱导则减少（29.9%对 17.6%；P=0.0014）。成功的 DAA 治疗并不影响 CD107a 脱颗粒，但降低了 STAT1。DAA 联合 RBV 治疗 HCV 可增加 LTx 受者 NK 细胞 IFNγ反应（70.9%对 89.2%；P=0.002），这与 pSTAT4 诱导的增加相关（MFI 157 对 173；P=0.0002）。