免疫 HBsAg-Fc 融合蛋白可诱导 Th1 细胞因子的优势产生，并降低转基因小鼠的 HBsAg 水平。

Immunization with HBsAg-Fc fusion protein induces a predominant production of Th1 cytokines and reduces HBsAg level in transgenic mice.

机构信息

Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

出版信息

Chin Med J (Engl). 2012 Sep;125(18):3266-72.

Abstract

BACKGROUND

The Fc receptor associated pathway might improve the immune responses against hepatitis B virus (HBV) as previously described by us. In addition, the Flt3 ligand (FL) has been reported to potentiate antigen presenting cells in vivo and may act as a potential adjuvant to boost antigen-specific immune responses. In this study, the immune efficacies of a set of fusion proteins of HBsAg and Fc and/or FL were evaluated in HBsAg transgenic mice.

METHODS

The fusion proteins composed of HBsAg and the Fc domain of murine IgG1 (HBsAg-Fc) and/or the Flt3 ligand, and yeast-derived recombinant HBsAg were used as immunogen to immunize HBsAg transgenic mice, respectively. Serum and liver HBsAg levels, serum anti-HBsAg and cytokine profile, and the activities of alanine aminotransferase (ALT)/AST were investigated after immunization.

RESULTS

After six injections, the most pronounced decrease in serum and liver HBsAg levels was observed in the HBsAg-Fc immunized group. In addition, serum Th1 cytokines and ALT/AST activities were highest in this group, indicating an effective induction of a favorable cellular immune response. Interestingly, the fusion protein containing HBsAg-Fc and the Flt3 ligand stimulated an alternative Th1-type immune response featured with high level productions of tumor necrosis factor α (TNF-α) and monocyte chemoabstractant protein 1 (MCP-1), causing a more severe cytotoxicity in hepatocytes while showed less effective in reducing serum HBsAg level.

CONCLUSION

HBsAg-Fc is effective in eliciting both the humoral and cellular immune responses against HBsAg in HBsAg transgenic mice, which makes it a potential immunogen for the immunotherapy of chronic hepatitis B.

摘要

背景

我们之前曾描述过，Fc 受体相关途径可以改善针对乙型肝炎病毒（HBV）的免疫反应。此外，Flt3 配体（FL）已被报道能增强体内抗原呈递细胞的功能，并可能作为一种潜在的佐剂来增强抗原特异性免疫反应。在这项研究中，我们评估了一组 HBsAg 和 Fc 及/或 FL 融合蛋白在 HBsAg 转基因小鼠中的免疫效果。

方法

我们分别使用由 HBsAg 和鼠 IgG1 的 Fc 结构域（HBsAg-Fc）和/或 Flt3 配体组成的融合蛋白以及酵母来源的重组 HBsAg 作为免疫原免疫 HBsAg 转基因小鼠。免疫后检测血清和肝 HBsAg 水平、血清抗-HBsAg 及细胞因子谱和丙氨酸氨基转移酶（ALT）/天冬氨酸氨基转移酶（AST）活性。

结果

经过六次注射后，在 HBsAg-Fc 免疫组中观察到血清和肝 HBsAg 水平下降最为明显。此外，该组血清 Th1 细胞因子和 ALT/AST 活性最高，表明有效地诱导了有利的细胞免疫反应。有趣的是，含有 HBsAg-Fc 和 Flt3 配体的融合蛋白刺激了一种替代的 Th1 型免疫反应，其特征是 TNF-α 和单核细胞趋化蛋白 1（MCP-1）的高水平产生，导致肝细胞的细胞毒性更严重，而降低血清 HBsAg 水平的效果则较差。