腺病毒载体HBcAg和三肽基肽酶II基因诱导强大的细胞免疫反应

StephenW

Cell Physiol Biochem. 2017 Jan 27;41(2):423-438. doi: 10.1159/000456579. [Epub ahead of print]
Adenovirus Vector Harboring the HBcAg and Tripeptidyl Peptidase II Genes Induces Potent Cellular Immune Responses In Vivo.Tan Q, Ma S, Hu J, Chen X, Yu Y, Tang Z, Zang G.
AbstractBACKGROUND: Chronic hepatitis B virus (HBV) infection is associated with a weak but specific cellular immune response of the host to HBV. Tripeptidyl peptidaseⅡ (TPPⅡ), an intracellular macromolecule and proteolytic enzyme, plays an important complementary and compensatory role for the proteasome during viral protein degradation and major histocompatibility complex class I antigen presentation by inducing a specific cellular immune response in vivo. Based on a previous study, we aimed to explore the role of MHC class I antigen presentation in vivo and the mechanisms that may be involved.
METHODS: In this study, recombinant adenoviral vectors harboring the hepatitis B core antigen (HBcAg) and the TPPII gene were constructed (Adv-HBcAg and Adv-HBcAg-TPPII), and H-2Kd HBV-transgenic BALB/c mice and HLA-A2 C57BL/6 mice were immunized with these vectors, respectively. We evaluated the specific immune responses induced by Adv-HBcAg-TPPII in the HBV transgenic BALB/c mice and HLA-A2 C57BL/6 mice as well as the anti-viral ability of HBV transgenic mice, and we explored the underlying mechanisms.
RESULTS: We found that immunization with Adv-HBcAg-TPPII induced the secretion of the cytokines interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) as well as the activities of IFN-γ-secreting CD8+ T cells and CD4+ T cells. In addition, HBcAg-specific CTL activity in C57/BL mice and HBV transgenic animals was significantly enhanced in the Adv-HBcAg-TPPII group. Furthermore, Adv-HBcAg-TPPII decreased the hepatitis B surface antigen (HBsAg) and HBV DNA levels and the amount of HBsAg and HBcAg in liver tissues. Moreover, Adv-HBcAg-TPPII enhanced the expression of T-box transcription factor (T-bet) and downregulated GATA-binding protein 3 (GATA-3) while increasing the expression levels of JAK2, STAT1, STAT4 and Tyk2.
CONCLUSIONS: These results suggested that the JAK/STAT signaling pathway participates in the CTL response that is mediated by the adenoviral vector encoding TPPII. Adv-HBcAg-TPPII could therefore break immune tolerance and stimulate HBV-specific cytotoxic T lymphocyte activity and could have a good therapeutic effect in transgenic mice.

© 2017 The Author(s)Published by S. Karger AG, Basel.

PMID:28214886DOI:10.1159/000456579

StephenW

Cell Physiol Biochem。 2017 Jan 27; 41（2）：423-438。 doi：10.1159 / 000456579。 [打印前的电子版]
腺病毒载体HBcAg和三肽基肽酶II基因诱导强大的细胞免疫反应在体内。
Tan Q，Ma S，Hu J，Chen X，Yu Y，Tang Z，Zang G.
抽象
背景：

慢性乙型肝炎病毒（HBV）感染与宿主对HBV的弱但特异性细胞免疫应答相关。三肽基肽酶Ⅱ（TPPⅡ）是一种细胞内大分子和蛋白水解酶，通过在体内诱导特异性细胞免疫应答，在病毒蛋白降解和主要组织相容性复合物I抗原呈递过程中对蛋白酶体起着重要的补充和补偿作用。基于以前的研究，我们旨在探讨MHC I类抗原呈递在体内的作用和可能涉及的机制。
方法：

在本研究中，构建了携带乙型肝炎核心抗原（HBcAg）和TPPII基因的重组腺病毒载体（Adv-HBcAg和Adv-HBcAg-TPPII）和H-2Kd HBV转基因BALB / c小鼠和HLA-A2 C57BL / 6小鼠分别用这些载体免疫。我们评估了Adv-HBcAg-TPPII在HBV转基因BALB / c小鼠和HLA-A2 C57BL / 6小鼠中诱导的特异性免疫应答以及HBV转基因小鼠的抗病毒能力，并且我们探索了基础机制。
结果：

我们发现用Adv-HBcAg-TPPII免疫诱导细胞因子白细胞介素-2（IL-2），干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）的分泌以及活性IFN-γ分泌性CD8 + T细胞和CD4 + T细胞。此外，在Adv-HBcAg-TPPII组中，C57 / BL小鼠和HBV转基因动物中的HBcAg特异性CTL活性显着增强。此外，Adv-HBcAg-TPPII减少肝组织中的乙型肝炎表面抗原（HBsAg）和HBV DNA水平以及HBsAg和HBcAg的量。此外，Adv-HBcAg-TPPII增加T盒转录因子（T-bet）和下调GATA结合蛋白3（GATA-3）的表达，同时增加JAK2，STAT1，STAT4和Tyk2的表达水平。
结论：

这些结果表明JAK / STAT信号传导途径参与由编码TPPII的腺病毒载体介导的CTL应答。 Adv-HBcAg-TPPII因此可以打破免疫耐受性并刺激HBV特异性细胞毒性T淋巴细胞活性，并且在转基因小鼠中具有良好的治疗效果。

©2017作者由S. Karger AG，Basel发行。

PMID：
    28214886
DOI：
    10.1159 / 000456579