PDF(Sci-hub)
Abstract：
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.
摘要：
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得到认可。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细胞（非NKILC）的影响。我们招募了接受ETV治疗的初治慢性乙型肝炎（CHB）和HBV相关肝硬化（LC）患者24个月。治疗前后,确定了ILC2s和非NKILC亚群稳态的频率和细胞因子谱及其临床意义，和系列血清干扰素（IFN）-λ水平进行分析。未经治疗的LC患者的外周血单核细胞（PBMC）除了接受IFN-λ1中和和刺激外，还与未经治疗和ETV治疗的LC患者的血清一起培养，并计算ILC2s的频率和细胞因子产生以及非NKILC亚群比率。此外，测量非NKILC和树突细胞(DC)上的IFN-λ受体表达。经过24个月的ETV治疗，ILC2s的频率和细胞因子产生(IL-4，IL-13，IFN-γ，TNF-α)随着ILC1/ILC2和ILC2/ILC3比率的增加而降低，揭示与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处理的LC血清培养和IFN-λ1刺激对抑制ILC2s产生类似的作用，和血清培养物中的IFN-λ1中和部分抑制了这种作用。在DC上检测到IFN-λ受体，但在非NKILC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。
