Ding Fei-Xiang, Wang Fang, Lu Yi-Ming, Li Ka, Wang Kai-Hui, He Xiao-Wen, Sun Shu-Han
Department of Medical Genetics, The Second Military Medical University, Shanghai, People's Republic of China.
Hepatology. 2009 May;49(5):1492-502. doi: 10.1002/hep.22816.
To develop a hepatitis B virus (HBV) therapeutic vaccine that can induce a broad but specific immune response and significant antitumor effects both in vivo and in vitro, we inserted HBV X protein (HBx)-derived epitopes HBx(52-60), HBx(92-100), and HBx(115-123); a novel subdominant cytolytic T lymphocyte (CTL) epitope HBx(140-148); and the universal T helper epitope pan human leukocyte antigen DR-binding epitope into HBV core protein to form multiepitope peptide-loaded virus-like particles (VLPs). CTL responses against epitope-loaded VLPs were elicited by priming with VLP-pulsed dendritic cells in both HLA-A*0201 transgenic (Tg) mice and peripheral blood lymphocytes from HLA-A2(+)/HBx(+) HBV-infected hepatocellular carcinoma (HCC) patients. The multiepitope peptide-loaded VLPs demonstrated significantly higher immunogenicity in Tg mice than any single responsive epitope. Significant antitumor effects were demonstrated both with primary cultured autologous HCC cells in vitro and tumor-bearing Tg mice in vivo in an HLA-A2-restricted and epitope-specific fashion.
The significant antitumor effects both in vivo and in vitro demonstrate the potential of multiepitope peptide-loaded VLPs as a vaccine against HCC.
为研发一种能诱导广泛而特异性免疫应答并在体内和体外均产生显著抗肿瘤作用的乙型肝炎病毒（HBV）治疗性疫苗，我们将源自HBV X蛋白（HBx）的表位HBx(52 - 60)、HBx(92 - 100)和HBx(115 - 123)；一种新型的次显性细胞毒性T淋巴细胞（CTL）表位HBx(140 - 148)；以及通用T辅助表位全人类白细胞抗原DR结合表位插入HBV核心蛋白，以形成负载多表位肽的病毒样颗粒（VLP）。在HLA - A*0201转基因（Tg）小鼠以及来自HLA - A2(+)/HBx(+) HBV感染的肝细胞癌（HCC）患者的外周血淋巴细胞中，通过用VLP脉冲的树突状细胞启动，引发了针对负载表位的VLP的CTL应答。负载多表位肽的VLP在Tg小鼠中表现出比任何单个反应性表位显著更高的免疫原性。在体外对原代培养的自体HCC细胞以及在体内对荷瘤Tg小鼠均以HLA - A2限制和表位特异性方式显示出显著的抗肿瘤作用。
体内和体外的显著抗肿瘤作用证明了负载多表位肽的VLP作为抗HCC疫苗的潜力。
