State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing, People's Republic of China.
PLoS One. 2011;6(10):e25525. doi: 10.1371/journal.pone.0025525. Epub 2011 Oct 5.
CD8(+) cytotoxic T lymphocytes (CTLs) are crucial for eliminating hepatitis B virus (HBV) infected cells. DNA vaccination, a novel therapeutic strategy for chronic virus infection, has been shown to induce CTL responses. However, accumulated data have shown that CTLs could not be effectively induced by HBV DNA vaccination.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that praziquantel (PZQ), an anti-schistoma drug, could act as an adjuvant to overcome the lack of potent CTL responses by HBV DNA vaccination in mice. PZQ in combination with HBV DNA vaccination augmented the induction of CD8(+) T cell-dependent and HBV-specific delayed hypersensitivity responses (DTH) in C57BL/6 mice. Furthermore, the induced CD8(+) T cells consisted of both Tc1 and Tc17 subtypes. By using IFN-γ knockout (KO) mice and IL-17 KO mice, both cytokines were found to be involved in the DTH. The relevance of these findings to HBV immunization was established in HBsAg transgenic mice, in which PZQ also augmented the induction of HBV-specific Tc1 and Tc17 cells and resulted in reduction of HBsAg positive hepatocytes. Adoptive transfer experiments further showed that PZQ-primed CD8(+) T cells from wild type mice, but not the counterpart from IFN-γ KO or IL-17 KO mice, resulted in elimination of HBsAg positive hepatocytes.
CONCLUSIONS/SIGNIFICANCE: Our results suggest that PZQ is an effective adjuvant to facilitate Tc1 and Tc17 responses to HBV DNA vaccination, inducing broad CD8(+) T cell-based immunotherapy that breaks tolerance to HBsAg.
CD8(+)细胞毒性 T 淋巴细胞（CTLs）对于清除乙型肝炎病毒（HBV）感染细胞至关重要。DNA 疫苗是一种治疗慢性病毒感染的新策略，已被证明可以诱导 CTL 反应。然而，积累的数据表明，HBV DNA 疫苗不能有效地诱导 CTL 反应。
方法/主要发现：我们报告称，抗血吸虫病药物吡喹酮（PZQ）可以作为佐剂，克服 HBV DNA 疫苗在小鼠中诱导有效 CTL 反应的不足。PZQ 联合 HBV DNA 疫苗增强了 C57BL/6 小鼠 CD8(+)T 细胞依赖性和 HBV 特异性迟发型超敏反应（DTH）的诱导。此外，诱导的 CD8(+)T 细胞包括 Tc1 和 Tc17 两种亚型。通过使用 IFN-γ 敲除（KO）小鼠和 IL-17 KO 小鼠，发现这两种细胞因子都参与了 DTH。在 HBsAg 转基因小鼠中建立了这些发现与 HBV 免疫的相关性，在这些小鼠中，PZQ 也增强了 HBV 特异性 Tc1 和 Tc17 细胞的诱导，并导致 HBsAg 阳性肝细胞减少。过继转移实验进一步表明，来自野生型小鼠的 PZQ 致敏的 CD8(+)T 细胞，但不是来自 IFN-γ KO 或 IL-17 KO 小鼠的对应细胞，导致 HBsAg 阳性肝细胞的消除。
结论/意义：我们的结果表明，PZQ 是促进 HBV DNA 疫苗诱导 Tc1 和 Tc17 反应的有效佐剂，诱导广泛的基于 CD8(+)T 细胞的免疫疗法，打破对 HBsAg 的耐受。
