Nelson D R, Marousis C G, Ohno T, Davis G L, Lau J Y
Department of Medicine, University of Florida, Gainesville 32610, USA.
Hepatology. 1998 Jul;28(1):225-30. doi: 10.1002/hep.510280129.
Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) have been shown to play a role in host defense and pathogenesis of chronic HCV infection. Our aim was to test the hypothesis that intrahepatic HCV-specific CTL activity may impact subsequent response to interferon alfa (IFN-alpha) therapy. Of the 37 patients that we have prospectively evaluated for HCV-specific CTL activity in liver, 21 received IFN therapy, and 19 completed a 6-month course and attended 6 to 18 months of follow-up. Intrahepatic CD8+ cells were isolated from liver biopsy tissue and tested against target cells expressing HCV antigens to determine intrahepatic CTL activity. The relationship between treatment response and HCV-specific CTL activity and other factors known to associate with response (genotype, viremia, histology) was analyzed. HCV-specific CTL activity was detected in 9 of 21 patients (and 9 of 19 who completed therapy). After 6 months of IFN therapy, 8 of 19 (42%) patients had normal serum alanine transaminase (ALT) (complete responders). After 18 months of follow-up, only 3 patients (16%) had a sustained biochemical response. Of the 9 patients with detectable HCV-specific CTL activity in their liver before treatment, 7 (78%) developed a complete response. In contrast, only 1 of the 10 patients with no detectable HCV-specific CTL activity developed a complete response to IFN (P < .01). In 6 of 8 patients with a complete response, including the 3 sustained responders, the CTL response appeared to be directed predominately to the HCV core region. These data suggest that the host immune response, particularly that mediated by CD8+ CTL, may be important in determining the outcome of IFN therapy for chronic HCV infection. Further understanding of the mechanism of action of IFN should impact the design of better therapeutic strategies against chronic HCV infection.
丙型肝炎病毒（HCV）特异性细胞毒性T淋巴细胞（CTL）已被证明在慢性HCV感染的宿主防御和发病机制中发挥作用。我们的目的是检验以下假设：肝内HCV特异性CTL活性可能影响随后对干扰素α（IFN-α）治疗的反应。在我们前瞻性评估肝脏中HCV特异性CTL活性的37例患者中，21例接受了IFN治疗，19例完成了6个月疗程并进行了6至18个月的随访。从肝活检组织中分离肝内CD8 +细胞，并针对表达HCV抗原的靶细胞进行检测，以确定肝内CTL活性。分析了治疗反应与HCV特异性CTL活性以及其他已知与反应相关的因素（基因型、病毒血症、组织学）之间的关系。21例患者中有9例（完成治疗的19例患者中有9例）检测到HCV特异性CTL活性。IFN治疗6个月后，19例患者中有8例（42%）血清丙氨酸转氨酶（ALT）正常（完全缓解者）。随访18个月后，只有3例患者（16%）有持续的生化反应。在治疗前肝脏中可检测到HCV特异性CTL活性的9例患者中，7例（78%）出现完全缓解。相比之下，10例未检测到HCV特异性CTL活性的患者中只有1例对IFN出现完全缓解（P <.01）。在8例完全缓解的患者中，包括3例持续缓解者，CTL反应似乎主要针对HCV核心区域。这些数据表明，宿主免疫反应，尤其是由CD8 + CTL介导的免疫反应，可能在决定慢性HCV感染IFN治疗的结果中起重要作用。对IFN作用机制的进一步了解应会影响针对慢性HCV感染的更好治疗策略的设计。
