Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No 1095, Jiefang Avenue, Wuhan, 430030, China.
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 10050, China.
Hepatol Int. 2017 Sep;11(5):419-428. doi: 10.1007/s12072-017-9803-4. Epub 2017 Jun 20.
Hepatitis B virus (HBV) is intrinsically immunogenic, with long-lasting immune control in many patients. However, the mechanisms and key cell types underlying effective immune control are incompletely understood.
We studied the restoration of natural killer (NK) cell numbers and function post antiviral treatment in 52 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients who received telbivudine (LdT) for 48 weeks. Blood samples were collected at week 0, 12, 24, 36, and 48 and tested for HBV DNA, hepatitis B surface antigen (HBsAg), HBeAg, liver enzymes, and NK cell parameters.
Compared with baseline, the number of peripheral CD3CD56 NK cells increased significantly from week 24 to 48, especially in patients with baseline alanine transaminase (ALT) two- to fivefold the upper line of normal (ULN) or HBV DNA <9 log copies/ml. Expression (number and density) of activating receptors NKG2D and NKp46 on CD3CD56 NK cells was enhanced, while inhibitory receptor NKG2A decreased. Notably, numbers of CD3CD56 or NKG2DCD3CD56 NK cells were significantly better restored in patients with HBeAg seroconversion. NK cell activating serum interleukin 15 (IL-15) was significantly increased during LdT treatment, especially in HBeAg seroconverters. LdT significantly enhanced expression of NKG2D and IL-15 in cultures of purified peripheral NK cells from treatment-naïve HBeAg-positive CHB patients.
Functional restoration of CD56 NK cells via upregulation of IL-15 and NKG2D is a novel activity of LdT and likely other antivirals, independent of its effect on HBV replication. This also demonstrates the importance of host immune restoration in controlling chronic HBV infection.
乙型肝炎病毒（HBV）具有固有免疫原性，在许多患者中能产生持久的免疫控制。然而，有效的免疫控制背后的机制和关键细胞类型仍不完全清楚。
我们研究了 52 例接受替比夫定（LdT）治疗 48 周的 HBeAg 阳性慢性乙型肝炎（CHB）患者在抗病毒治疗后自然杀伤（NK）细胞数量和功能的恢复情况。在第 0、12、24、36 和 48 周采集血样，检测 HBV DNA、乙型肝炎表面抗原（HBsAg）、HBeAg、肝酶和 NK 细胞参数。
与基线相比，外周血 CD3CD56 NK 细胞数量从第 24 周开始至第 48 周显著增加，尤其是基线丙氨酸氨基转移酶（ALT）为正常值上限（ULN）的 2 至 5 倍或 HBV DNA<9 log 拷贝/ml 的患者。CD3CD56 NK 细胞上激活受体 NKG2D 和 NKp46 的表达（数量和密度）增强，而抑制性受体 NKG2A 减少。值得注意的是，在 HBeAg 血清学转换患者中，CD3CD56 或 NKG2DCD3CD56 NK 细胞数量的恢复明显更好。替比夫定治疗期间，NK 细胞激活的血清白细胞介素 15（IL-15）明显增加，尤其是在 HBeAg 血清学转换患者中。替比夫定显著增强了来自未经治疗的 HBeAg 阳性 CHB 患者外周 NK 细胞培养物中 NKG2D 和 IL-15 的表达。
通过上调 IL-15 和 NKG2D 来恢复 CD56 NK 细胞的功能是替比夫定及其他抗病毒药物的一种新的作用机制，独立于其对 HBV 复制的作用。这也证明了宿主免疫恢复在控制慢性 HBV 感染中的重要性。
