Praziquantel Facilitates IFN-γ-Producing CD8+ T Cells (Tc1) and IL-17-Producing CD8+ T Cells (Tc17) Responses to DNA Vaccination in Mice

Abstract

BackgroundCD8+ 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 FindingsHere, 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/SignificanceOur 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.

Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice

“…Similar results were also observed in previous studies. 59,60 Therefore, we can conclude that small-scale antigen-specific killing of the hepatocytes may cause little or no damage to the liver. 60 In summary, we found that an enhanced regimen of GM-CSF as an HBV vaccine adjuvant could promote the breaking of immune tolerance in HBsAg-Tg mice.…”

“…This discrepancy may be due to the fact that a few HBsAg-positive hepatocytes could produce and maintain detectable amounts of HBsAg in the serum, even if a large proportion of HBsAg-positive hepatocytes are cleared. 12,49 In this regard, HBV-specific CD8 1 T cells are the key effector cells that mediate the clearance of HBsAg-positive hepatocytes from the liver. 50 IFN-c-and TNF-a-producing CD81 T cells have been demonstrated to contribute to the antiviral immune response through cytolytic and non-cytolytic pathways in the HBV-transgenic mouse model.…”

“…Several potential adjuvants have been examined in various systems, and the results have been reviewed. [11][12][13] Granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine produced by macrophages, T cells, NK cells, endothelial cells, and fibroblasts, has been used clinically as a hematopoietic growth factor for more than 20 years. 14 It can increase neutrophil counts and induce the differentiation and maturation of myeloid dendritic cells (DCs) to improve the functions of antigen-presenting cells (APCs), as well as promote the development and perpetuation of Th1 responses.…”

Interleukin-22 as a molecular adjuvant facilitates IL-17-producing CD8+T cell responses against a HBV DNA vaccine in mice

“…Two subsets of CD8 + T cells are now known to enhance cytotoxic responses, namely IFN-γ-producing CD8 + T cells (Tc1) and IL-17-producing CD8 + T cells (Tc17). 10,11,42,43 Zou showed that a chemical adjuvant, praziquantel (PZQ), could be used to elicit Tc17 cells in HBV DNA vaccination and contributed to viral antigen clearance in a HBsAg-transgenic mouse model. 11 Tc1 is a classical cytotoxic CD8 + T cell, producing IFN-γ and TNF-α and cytolytic effects by secreting perforin and granzyme B when in contact with target cells.…”

Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8+T cell

“…[14][15][16] Praziquantel (PZQ), an effective anthelmintic drug against all forms of schistosomiasis, 17,18 is explored as an adjuvant for HBV DNA vaccines to facilitate virus specific Tc1 and Tc17 responses via the decreased expression of TGF-β from T regulatory cells. 19,20 In addition, cimetidine (CIM), a drug that is prescribed for the treatment of heartburn and peptic ulcers, 21 is a H 2 -receptor antagonist, which also could be used as an adjuvant for HBV DNA vaccines to increase the secretion pro-inflammatory cytokines and decrease the production of antiinflammatory cytokine, IL-10. [22][23][24] Interestingly, CIM also could Previously, we have reported that either cIM or PZQ, two clinical drugs, could be used to develop as adjuvants on HBV DNa vaccine to elicit both humoral and cellular immune responses.…”