Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Institute of Liver Disease, Shanghai, China.
J Viral Hepat. 2021 May;28(5):795-808. doi: 10.1111/jvh.13476. Epub 2021 Feb 2.
The immunomodulatory effects of entecavir (ETV) in anti-hepatitis B virus (HBV) therapy have long been recognized. This study aimed to determine the effects of ETV on non-natural killer innate lymphoid cells (non-NK ILCs) in HBV-related liver disease progression. We enrolled treatment-naïve chronic hepatitis B (CHB) and HBV-related liver cirrhosis (LC) patients treated with ETV for 24 months. Before and after therapy, the frequency and cytokine profiles of ILC2s and non-NK ILCs subset homeostasis and their clinical significance were determined, and serial serum interferon (IFN)-λ levels were analysed. Peripheral blood mononuclear cells (PBMCs) of untreated LC patients were cultured with serum from untreated and ETV-treated LC patients in addition to being subject to IFN-λ1 neutralization and stimulation, and the frequency and cytokine production of ILC2s as well as non-NK ILCs subset ratios were calculated. Furthermore, IFN-λ receptor expression on non-NK ILCs and dendritic cells (DCs) was measured. After 24 months of ETV treatment, the frequency and cytokine production of ILC2s (IL-4, IL-13, IFN-γ, TNF-α) decreased with increased ILC1/ILC2 and decreased ILC2/ILC3 ratios, revealing a close association with disease status in LC patients. Long-term ETV administration-induced serum IFN-λ1 levels were negatively correlated with ILC2s. ETV-treated LC serum culture and IFN-λ1 stimulation yielded similar effects on suppression of ILC2s, and IFN-λ1 neutralization in serum culture partly inhibited this effect. The IFN-λ receptor was detected on DCs but not on non-NK ILCs. In conclusion, ETV suppresses the frequency and cytokine profiles of ILC2s by increasing IFN-λ1 in LC patients.
恩替卡韦（ETV）在抗乙型肝炎病毒（HBV）治疗中的免疫调节作用早已被认识。本研究旨在确定 ETV 对 HBV 相关肝病进展中非自然杀伤先天淋巴样细胞（non-NK ILCs）的影响。我们招募了未经治疗的慢性乙型肝炎（CHB）和 HBV 相关肝硬化（LC）患者，这些患者接受 ETV 治疗 24 个月。在治疗前后，测定了 ILC2s 和非 NK ILCs 亚群的频率和细胞因子谱及其与临床的相关性，并分析了干扰素（IFN）-λ的血清水平。此外，还分析了未经治疗的 LC 患者 PBMC 与未经治疗和 ETV 治疗的 LC 患者血清共培养后的 ILC2 和非 NK ILCs 亚群比例的频率和细胞因子产生情况，以及对 IFN-λ1 进行中和和刺激。还测量了非 NK ILCs 和树突状细胞（DCs）上的 IFN-λ 受体表达。在 ETV 治疗 24 个月后，ILC2s（IL-4、IL-13、IFN-γ、TNF-α）的频率和细胞因子产生减少，而 ILC1/ILC2 增加，ILC2/ILC3 减少，这与 LC 患者的疾病状态密切相关。长期 ETV 给药诱导的血清 IFN-λ1 水平与 ILC2s 呈负相关。ETV 治疗的 LC 血清培养和 IFN-λ1 刺激对 ILC2s 的抑制作用相似，而在血清培养中进行 IFN-λ1 中和部分抑制了这种作用。IFN-λ 受体在 DC 上检测到，但在非 NK ILCs 上未检测到。总之，ETV 通过增加 LC 患者的 IFN-λ1 来抑制 ILC2s 的频率和细胞因子谱。
