肝内乙肝病毒特异性T细胞中的治疗性DNA疫苗诱导功能方面

StephenW

Molecular Therapy (2015); 23 3, 578–590. doi:10.1038/mt.2014.233
Functional Aspects of Intrahepatic Hepatitis B Virus-specific T Cells Induced by Therapeutic DNA Vaccination
MTOpen

Anette Brass1, Lars Frelin1, David R Milich2, Matti Sällberg1 and Gustaf Ahlén1

    1Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    2Vaccine Research Institute of San Diego, San Diego, California, USA

Correspondence: Gustaf Ahlén, Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden. E-mail: [email protected]

Received 28 July 2014; Accepted 2 December 2014
Accepted article preview online 10 December 2014; Advance online publication 6 January 2015
Top of page
Abstract

Current therapies for the hepatitis B virus (HBV), a major cause of severe liver disease, suppress viral replication but replication rebounds if therapy is withdrawn. It is widely accepted that immune activation is needed to control replication off-therapy. To specifically activate T cells crossreactive between the hepatitis B core and e antigens (HBcAg/HBeAg) in chronically infected patients, we developed a therapeutic vaccine candidate. The vaccine encompass codon-optimized HBcAg and IL-12 expressing plasmids delivered using targeted high-pressure injection combined with in vivo electroporation. One dose of the vaccine primed a B-cell-independent polyfunctional T-cell response, in wild-type, and in HBeAg-transgenic mice with an impaired ability to respond to HBc/eAg. The response peaked at 2 weeks and contracted at week 6 after vaccination. Coadministration of IL-12 improved antibody levels, and T-cell expansion and functionality. The vaccine primed T cells that, 2 weeks after a single dose, cleared hepatocytes transiently expressing HBcAg in vaccinated wild-type and HBeAg-transgenic mice. However, 4 weeks later, these functional responses were lost. Booster doses after 8–12 weeks effectively restored function and expansion of the rapidly contracting T cells. Thus, this vaccine strategy primes functional HBcAg-specific T cells in a host with dysfunctional response to HBV.

StephenW

分子疗法（2015年）; 23 3，578-590。 DOI：10.1038 / mt.2014.233
肝内乙肝病毒特异性T细胞中的治疗性DNA疫苗诱导功能方面
MTOpen

安妮特Brass1，拉尔斯Frelin1，大卫 - [R Milich2，马蒂Sällberg1和古斯塔夫Ahlén1

    检验医学，临床微生物科，卡罗林斯卡医学院，瑞典卡罗林斯卡大学医院的胡丁厄，瑞典斯德哥尔摩教研室
    圣地亚哥，圣地亚哥，美国加利福尼亚州的2Vaccine研究所

函授：古斯塔夫阿伦，检验医学，临床微生物学学科，F68，卡罗林斯卡医学院，瑞典卡罗林斯卡大学医院的胡丁厄系，S-141 86，瑞典斯德哥尔摩。电子邮件：[email protected]

收到2014年7月28日;接受2014年12月2日
你可以在网上的文章预览二零一四年十二月十日;推进网上公布的2015年1月6日
返回页首
抽象

目前的治疗方法对乙型肝炎病毒（HBV），严重的肝脏疾病的主要病因，抑制病毒复制，但复制篮板如果治疗被撤回。它已被广泛接受的免疫激活是必要的，以控制复制偏离疗法。特异性激活乙型肝炎核心以及e抗原（HBcAg的/ e抗原）在慢性感染患者之间的T细胞交叉反应性，我们开发了一种治疗性的疫苗候选者。该疫苗的内容包括密码子最优化的HBcAg和IL-12的表达使用有针对性的高压喷射结合在体内电穿孔递送质粒。一个剂量致敏的B细胞非依赖性的多官能的T细胞应答，在野生型，而在e抗原的转基因小鼠，为的HBc / EAG响应能力受损的疫苗。响应峰值在2周和第6周接种后收缩。合用的IL-12改进的抗体的水平，和T细胞的扩展和功能。该疫苗引发的T细胞，2周后，单次剂量，清除的肝细胞瞬时表达的HBcAg在接种野生型和e抗原的转基因小鼠。然而，4周后，这些官能应答丢失。 8-12周后加强剂量有效恢复功能和扩展的快速萎缩T细胞。因此，该疫苗策略素数在宿主与对HBV失调响应功能的HBcAg特异性T细胞。