Rigopoulou Eirini I, Suri Deepak, Chokshi Shilpa, Mullerova Ivana, Rice Steven, Tedder Richard S, Williams Roger, Naoumov Nikolai V
Institute of Hepatology, Division of Medicine, University College London, London, UK.
Hepatology. 2005 Nov;42(5):1028-36. doi: 10.1002/hep.20888.
Interleukin-12 (IL-12) is an immunomodulatory cytokine that promotes cellular immunity. Pre-clinical data suggest that IL-12 inhibits hepatitis B virus (HBV) replication by stimulating interferon-gamma (IFN-gamma) production. We investigated whether a combination treatment with lamivudine plus recombinant human interleukin-12 (rhIL-12) will result in a greater and prolonged suppression of HBV replication in comparison with lamivudine monotherapy. Fifteen patients with HBeAg-positive chronic hepatitis B were randomized to receive either lamivudine alone for 24 weeks (group 1); combination of lamivudine for 16 weeks and rhIL-12 (200 ng/kg twice weekly), starting 4 weeks after initiation of lamivudine, for 20 weeks (group 2), or the same schedule as for group 2, with lamivudine and a higher dose of rhIL-12 (500 ng/kg, group 3). Serum HBV DNA levels, T-cell proliferation, frequency of virus-specific T-cells, and IFN-gamma production were evaluated serially during and 24 weeks posttreatment. Lamivudine plus rhIL-12/500 showed greater antiviral activity than lamivudine monotherapy. However, after stopping lamivudine in groups 2 and 3, serum HBV DNA increased significantly despite continuing rhIL-12 administration. Lamivudine plus rhIL-12 treatment was associated with a greater increase in virus-specific T-cell reactivity, IFN-gamma production, and an inverse correlation between the frequency of IFN-gamma-producing CD4+ T-cells and viremia. The T-cell proliferative response to HBcAg did not differ between the three groups. In conclusion, the addition of IL-12 to lamivudine enhances T-cell reactivity to HBV and IFN-gamma production. However, IL-12 does not abolish HBV replication in HBeAg-positive patients and does not maintain inhibition of HBV replication after lamivudine withdrawal.
白细胞介素-12（IL-12）是一种促进细胞免疫的免疫调节细胞因子。临床前数据表明，IL-12通过刺激γ干扰素（IFN-γ）的产生来抑制乙型肝炎病毒（HBV）复制。我们研究了与单用拉米夫定相比，拉米夫定联合重组人白细胞介素-12（rhIL-12）治疗是否能更有效且持久地抑制HBV复制。15例HBeAg阳性慢性乙型肝炎患者被随机分为三组：单独接受拉米夫定治疗24周（第1组）；拉米夫定治疗16周，从拉米夫定开始治疗4周后加用rhIL-12（200 ng/kg，每周两次），共治疗20周（第2组）；或与第2组治疗方案相同，但rhIL-12剂量更高（500 ng/kg，第3组）。在治疗期间及治疗后24周连续评估血清HBV DNA水平、T细胞增殖、病毒特异性T细胞频率和IFN-γ产生情况。拉米夫定联合rhIL-12/500显示出比单用拉米夫定更强的抗病毒活性。然而，在第2组和第3组停用拉米夫定后，尽管继续给予rhIL-12，血清HBV DNA仍显著升高。拉米夫定联合rhIL-12治疗与病毒特异性T细胞反应性、IFN-γ产生的更大增加以及产生IFN-γ的CD4+T细胞频率与病毒血症之间的负相关有关。三组对HBcAg的T细胞增殖反应无差异。总之，拉米夫定加用IL-12可增强T细胞对HBV的反应性和IFN-γ产生。然而，IL-12并不能消除HBeAg阳性患者的HBV复制，且在停用拉米夫定后不能维持对HBV复制的抑制作用。
