HBcAg可成为乙肝治疗性疫苗的候选靶标

肝胆速递

http://www.sciencedirect.com/science/article/pii/S0166354212001726
Antiviral Research
Volume 96, Issue 1, October 2012, Pages 59–64

Strong and multi-antigen specific immunity by hepatitis B core antigen (HBcAg)-based vaccines in a murine model of chronic hepatitis B: HBcAg is a candidate for a therapeutic vaccine against hepatitis B virus

    Sheikh Mohammad Fazle Akbar a, Corresponding author contact information, E-mail the corresponding author,
    Shiyi Chen b, E-mail the corresponding author,
    Mamun Al-Mahtab c, E-mail the corresponding author,
    Masanori Abe b, E-mail the corresponding author,
    Yoichi Hiasa b, E-mail the corresponding author,
    Morikazu Onji b, E-mail the corresponding author

    a Department of Medical Sciences, Toshiba General Hospital, Higashi Oi 6-3-22, Shinagawa, Tokyo 140-8522, Japan
    b Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Toon City, Ehime 791-0295, Japan
    c Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbagh, Dhaka 1000, Bangladesh

Abstract

Experimental evidence suggests that hepatitis B core antigen (HBcAg)-specific cytotoxic T lymphocytes (CTL) are essential for the control of hepatitis B virus (HBV) replication and prevention of liver damage in patients with chronic hepatitis B (CHB). However, most immune therapeutic approaches in CHB patients have been accomplished with hepatitis B surface antigen (HBsAg)-based prophylactic vaccines with unsatisfactory clinical outcomes. In this study, we prepared HBsAg-pulsed dendritic cells (DC) and HBcAg-pulsed DC by culturing spleen DC from HBV transgenic mice (HBV TM) and evaluated the immunomodulatory capabilities of these antigens, which may serve as a better therapy for CHB. The kinetics of HBsAg, antibody levels against HBsAg (anti-HBs), proliferation of HBsAg- and HBcAg-specific lymphocytes, production of antigen-specific CTL, and activation of endogenous DC were compared between HBV TM vaccinated with either HBsAg- or HBcAg-pulsed DC. Vaccination with HBsAg-pulsed DC induced HBsAg-specific immunity, but failed to induce HBcAg-specific immunity in HBV TM. However, immunization of HBV TM with HBcAg-pulsed DC resulted in: (1) HBsAg negativity, (2) production of anti-HBs, and (3) development of HBsAg- and HBcAg-specific T cells and CTL in the spleen and the liver. Additionally, significantly higher levels of activated endogenous DC were detected in HBV TM immunized with HBcAg-pulsed DC compared to HBsAg-pulsed DC (p < 0.05). The capacity of HBcAg to modulate both HBsAg- and HBcAg-specific immunity in HBV TM, and activation of endogenous DC in HBV TM without inducing liver damage suggests that HBcAg should be an integral component of the therapeutic vaccine against CHB.
Highlights

► HBsAg and HBcAg-pulsed dendritic cells (DC) were prepared as therapeutic vaccine.
► HBsAg induced HBsAg-specific, but not HBcAg-specific, immune responses in HBV TM.
► HBcAg induced strong HBcAg and HBsAg-specific humoral and cellular immunity in HBV TM.
► HBcAg-based vaccine activated endogenous dendritic cells of HBV TM.
► HBcAg should be incorporated in therapeutic vaccine for treatment of chronic HBV.

肝胆速递

抗病毒研究
96，2012年10月第1期，页59-64

强和多B型肝炎核心抗原（HBcAg）为基础的疫苗在小鼠模型的慢性B型肝炎抗原特异性免疫：乙肝病毒核心抗原是对乙肝病毒的治疗性疫苗的候选人

    谢赫·穆罕默德·Fazle Akbar a，通讯作者的联系信息，E-mail的通讯作者，
    潘石屹Chen b，E-mail的通讯作者，
    马蒙的Al-Mahtab c，E-mail的通讯作者，
    正德Abe b，E-mail的通讯作者，
    洋Hiasa b，E-mail的通讯作者，
    Morikazu Onji b，E-mail的通讯作者

    医学系，东爱22年6月3日，品川，东京140-8522，日本东芝公司总医院，
    胃肠病学和Metabology系，爱媛县，爱媛大学医学研究生院，卡通市，爱媛县791-0295，日本
    C系肝脏病学，班加班德胡谢赫·穆吉布医科大学，Shahbagh，达卡1000，孟加拉国

抽象

实验证据表明，乙肝病毒核心抗原（HBcAg）特异性细胞毒性T淋巴细胞（CTL）B型肝炎病毒（HBV）的复制和预防慢性乙型肝炎（CHB）患者肝功能损害的控制是必不可少的。然而，在慢性乙型肝炎患者的免疫治疗方法已完成与B型肝炎表面抗原（HBsAg）为基础的预防性疫苗临床结果不满意。在这项研究中，我们准备了乙肝表面抗原的树突状细胞（DC）和HBcAg的脉冲的DC培养脾DC HBV转基因小鼠（HBV TM），并评估这些抗原，这可能会成为一个更好的治疗慢性乙型肝炎的免疫调节功能。对HBsAg的动力学进行了比较，抗HBsAg的抗体水平（抗-HBs）的HBsAg和HBcAg特异性淋巴细胞的增殖，抗原特异性CTL的生产，和激活内源性DC疫苗与HBV TM任一的HBsAg或HBcAg脉冲直流。 HBsAg脉冲的DC诱导HBsAg特异性免疫接种，但未能引起HBV核心抗原特异性免疫TM。然而，免疫HBV TM与HBcAg的，脉冲直流导致：（1）乙肝表面抗原消极，（2）生产的抗-HBs，和（3）研制的乙型肝炎表面抗原（HBsAg）和乙肝病毒核心抗原特异性T细胞和CTL在脾脏和肝脏。此外，检测到显着更高水平的活化内源性DC在HBV TM免疫HBcAg的直流脉冲HBsAg脉冲的DC（对<0.05）相比。的HBcAg调节能力，同时具有HBsAg和HBV核心抗原特异性免疫TM，激活内源性DC中HBV TM没有引起肝功能损害表明，乙肝病毒核心抗原的慢性乙型肝炎治疗性疫苗应该是一个不可分割的组成部分。
亮点

►HBsAg和HBcAg的树突状细胞（DC）作为治疗性疫苗的制备。
►乙肝表面抗原诱导HBsAg特异性，但不是在HBV TM的HBcAg特异性免疫反应。
►核心抗原诱导较强的HBcAg和HBsAg特异性体液免疫和细胞免疫在HBV TM。
►核心抗原为基础的疫苗激活内源性的树突状细胞中HBV TM。
►应纳入治疗性疫苗治疗慢性HBV核心抗原。