血漿Programmed Death-1及Interleukin-12之表現在B型肝炎自然史所扮演的角色

Abstract

背景與目的：慢性B型肝炎病毒（HBV）感染者疾病結果差異大。Programmed death-1 (PD-1)是免疫系統的負向調控因子，其表現與Interleukin-12 (IL-12)的製造有負相關，而IL-12活化CD8+ T細胞並促進Th1細胞激素的分泌，有助於清除HBV。本研究前瞻性地探討血漿PD-1與HBV相關疾病的關係，並評估血漿PD-1或IL-12濃度是否可作為肝細胞癌病人的預後指標。 材料與方法：我們進行病例世代研究，研究個案自1989至1992年收集，至多追蹤十七年，含1177位HBV帶原、抗C型肝炎病毒抗體陰性的健康男性。我們亦比較HBV單一感染者與151位HBV/HCV雙重病毒感染者之血漿PD-1濃度。在肝細胞癌病人存活分析部分，進行多中心合作研究，收集614位肝細胞癌病人。 結果：HBV單一感染族群與HBV/HCV雙重病毒感染族群之血漿PD-1無顯著差異。血漿PD-1濃度與基線病毒量（Ptrend=0.0003）以及病毒量長期趨勢（Ptrend=0.0115）有正相關，此正相關在基因型為C者及抽煙者當中尤其明顯。血漿PD-1濃度增加，提高罹患HCC的危險性（最高三分位與最低三分位比較之調整勝算比 = 1.83，95%信賴區間 = 1.16-2.90，Ptrend = 0.0086）。我們也在血漿PD-1濃度與丙胺酸轉胺酶升高或慢性肝臟疾病史之間發現類似關係。血漿PD-1及IL-12皆與肝細胞癌病人生存率無顯著相關。 結論：血漿PD-1與HBV感染者的疾病進展有關，其原因有一部分是源於血漿PD-1與宿主較差病毒量控制能力的相關。

Background and Aims: The outcomes of chronic hepatitis B virus infection (HBV) vary widely. Programmed death-1 (PD-1) is a negative regulator of the immune system, and its expression is inversely correlated with the production of interleukin-12 (IL-12), a key cytokine involved in activating CD8+ T cells secreting Th1 cytokines, which in turn facilitate HBV clearance. This study aimed to prospectively evaluate the association between expression of plasma PD-1 and HBV disease progression, and examine whether plasma concentration of PD-1 or IL-12 is a prognostic marker of survival in patients with HCC. Materials and Methods: We conducted a case-cohort study of 1177 male HBV carriers who were healthy and tested negative for antibodies against hepatitis C virus (HCV) at recruitment in 1989-1992 after a maximum of 17 years of follow-up. The plasma PD-1 concentrations in the individuals with HBV monoinfection were compared with 151 men with dual HBV/HCV infection. For survival analysis of HCC, a total of 614 HCC patients were recruited from a multicenter collaboration study. Results: No significant difference was detected in the plasma PD-1 concentrations between individuals with HBV monoinfection and those with dual HBV/HCV infection. Plasma PD-1 concentration was positively correlated with baseline (Ptrend=0.0003) and time trend of viral load (Ptrend=0.0115). This association varied by HBV genotype and smoking status, with a stronger association among smokers and those with genotype C HBV infection. The risk of HCC increased with increasing plasma concentrations of PD-1 (adjusted odds ratio for highest vs lowest tertile=1.83, 95% confidence interval= 1.16 to 2.90, Ptrend=0.0086). We also found a similar association between plasma PD-1 concentration and elevated alanine aminotransferase and a history of chronic liver disease. Neither plasma PD-1 or IL-12 was significantly associated with HCC survival. Conclusions: An elevated plasma concentration of PD-1 was associated with hepatitis B progression due at least in part to a positive correlation between PD-1 upregulation and poor immune control of viral load.