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DNA immunization with fusion of CTLA-4 to hepatitis B virus (HBV) core protein enhanced Th2 type responses and cleared HBV with an accelerated kinetic.

Yin Y, Wu C, Song J, Wang J, Zhang E, Liu H, Yang D, Chen X, Lu M, Xu Y - PLoS ONE (2011)

Bottom Line: However, plasmids expressing viral proteins fused to cytotoxic T lymphocyte antigen 4 (CTLA-4) primed Th2-biased responses and were able to induced effective protection against viral challenge in the woodchuck model.HBV surface antigen (HBsAg) and DNA in peripheral blood and HBcAg in liver tissue were cleared with significantly accelerated kinetics in both groups.Viral clearance could be efficiently achieved by Th1/Th2-balanced immune response, with a small but significant shift in T-cell and B-cell immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT

Background: Typically, DNA immunization via the intramuscular route induces specific, Th1-dominant immune responses. However, plasmids expressing viral proteins fused to cytotoxic T lymphocyte antigen 4 (CTLA-4) primed Th2-biased responses and were able to induced effective protection against viral challenge in the woodchuck model. Thus, we addressed the question in the mouse model how the Th1/Th2 bias of primed immune responses by a DNA vaccine influences hepatitis B virus (HBV) clearance.

Principal findings: Plasmids expressing HBV core protein (HBcAg) or HBV e antigen and HBcAg fused to the extracellular domain of CTLA-4 (pCTLA-4-HBc), CD27, and full length CD40L were constructed. Immunizations of these DNA plasmids induced HBcAg-specific antibody and cytotoxic T-cell responses in mice, but with different characteristics regarding the titers and subtypes of specific antibodies and intensity of T-cell responses. The plasmid pHBc expressing HBcAg induced an IgG2a-dominant response while immunizations of pCTLA-4-HBc induced a balanced IgG1/IgG2a response. To assess the protective values of the immune responses of different characteristics, mice were pre-immunized with pCTLA-4-HBc and pHBc, and challenged by hydrodynamic injection (HI) of pAAV/HBV1.2. HBV surface antigen (HBsAg) and DNA in peripheral blood and HBcAg in liver tissue were cleared with significantly accelerated kinetics in both groups. The clearance of HBsAg was completed within 16 days in immunized mice while more than 50% of the control mice are still positive for HBsAg on day 22. Stronger HBcAg-specific T-cell responses were primed by pHBc correlating with a more rapid decline of HBcAg expression in liver tissue, while anti-HBs antibody response developed rapidly in the mice immunized with pCTLA-4-HBc, indicating that the Th1/Th2 bias of vaccine-primed immune responses influences the mode of viral clearance.

Conclusion: Viral clearance could be efficiently achieved by Th1/Th2-balanced immune response, with a small but significant shift in T-cell and B-cell immune responses.

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HBcAb and HBsAb responses in mice after HI.At day 30 after HI of pAAV/HBV1.2, the titers of HBcAb and HBsAb IgG2a and IgG1 subtypes in mice sera were determined by ELISA. (A) IgG2a and IgG1 subtypes of HBcAb. (B) The ratios of IgG2a/IgG1 of HBcAb. (C) IgG2a and IgG1 subtypes of HBsAb. (D) The ratios of IgG2a/IgG1 of HBsAb. (E) The kinetics of HBsAb IgG1 response in mice was monitored at days 4, 7, 10, 20, and 30 after HI.
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pone-0022524-g005: HBcAb and HBsAb responses in mice after HI.At day 30 after HI of pAAV/HBV1.2, the titers of HBcAb and HBsAb IgG2a and IgG1 subtypes in mice sera were determined by ELISA. (A) IgG2a and IgG1 subtypes of HBcAb. (B) The ratios of IgG2a/IgG1 of HBcAb. (C) IgG2a and IgG1 subtypes of HBsAb. (D) The ratios of IgG2a/IgG1 of HBsAb. (E) The kinetics of HBsAb IgG1 response in mice was monitored at days 4, 7, 10, 20, and 30 after HI.

Mentions: Control and immunized mice developed specific antibody responses to HBV proteins after HI. The immunizations with pHBc and pCTLA-4-HBc induced HBcAb responses in mice (Fig. 2). After HI challenge, HBcAb responses in immunized mice were only slightly boosted. At day 30 post HI, the end of the follow up, the titers of HBcAb IgG including subtypes IgG2a and IgG1 were increased and higher in immunized mice than in control mice (Fig 5A). The ratio of HBcAb IgG2a/IgG1 decreased slightly after the HBV challenge in immunized mice due to the increase of IgG1 fractions (Fig.5A and B). Nevertheless, IgG2a-dominant HBcAb response was found in pHBc immunized mice. Control mice developed a mixed IgG2a/IgG1 HBcAb response, which was similar to pCTLA-4-HBc immunized mice (Fig. 5B).


DNA immunization with fusion of CTLA-4 to hepatitis B virus (HBV) core protein enhanced Th2 type responses and cleared HBV with an accelerated kinetic.

Yin Y, Wu C, Song J, Wang J, Zhang E, Liu H, Yang D, Chen X, Lu M, Xu Y - PLoS ONE (2011)

HBcAb and HBsAb responses in mice after HI.At day 30 after HI of pAAV/HBV1.2, the titers of HBcAb and HBsAb IgG2a and IgG1 subtypes in mice sera were determined by ELISA. (A) IgG2a and IgG1 subtypes of HBcAb. (B) The ratios of IgG2a/IgG1 of HBcAb. (C) IgG2a and IgG1 subtypes of HBsAb. (D) The ratios of IgG2a/IgG1 of HBsAb. (E) The kinetics of HBsAb IgG1 response in mice was monitored at days 4, 7, 10, 20, and 30 after HI.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3142188&req=5

pone-0022524-g005: HBcAb and HBsAb responses in mice after HI.At day 30 after HI of pAAV/HBV1.2, the titers of HBcAb and HBsAb IgG2a and IgG1 subtypes in mice sera were determined by ELISA. (A) IgG2a and IgG1 subtypes of HBcAb. (B) The ratios of IgG2a/IgG1 of HBcAb. (C) IgG2a and IgG1 subtypes of HBsAb. (D) The ratios of IgG2a/IgG1 of HBsAb. (E) The kinetics of HBsAb IgG1 response in mice was monitored at days 4, 7, 10, 20, and 30 after HI.
Mentions: Control and immunized mice developed specific antibody responses to HBV proteins after HI. The immunizations with pHBc and pCTLA-4-HBc induced HBcAb responses in mice (Fig. 2). After HI challenge, HBcAb responses in immunized mice were only slightly boosted. At day 30 post HI, the end of the follow up, the titers of HBcAb IgG including subtypes IgG2a and IgG1 were increased and higher in immunized mice than in control mice (Fig 5A). The ratio of HBcAb IgG2a/IgG1 decreased slightly after the HBV challenge in immunized mice due to the increase of IgG1 fractions (Fig.5A and B). Nevertheless, IgG2a-dominant HBcAb response was found in pHBc immunized mice. Control mice developed a mixed IgG2a/IgG1 HBcAb response, which was similar to pCTLA-4-HBc immunized mice (Fig. 5B).

Bottom Line: However, plasmids expressing viral proteins fused to cytotoxic T lymphocyte antigen 4 (CTLA-4) primed Th2-biased responses and were able to induced effective protection against viral challenge in the woodchuck model.HBV surface antigen (HBsAg) and DNA in peripheral blood and HBcAg in liver tissue were cleared with significantly accelerated kinetics in both groups.Viral clearance could be efficiently achieved by Th1/Th2-balanced immune response, with a small but significant shift in T-cell and B-cell immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT

Background: Typically, DNA immunization via the intramuscular route induces specific, Th1-dominant immune responses. However, plasmids expressing viral proteins fused to cytotoxic T lymphocyte antigen 4 (CTLA-4) primed Th2-biased responses and were able to induced effective protection against viral challenge in the woodchuck model. Thus, we addressed the question in the mouse model how the Th1/Th2 bias of primed immune responses by a DNA vaccine influences hepatitis B virus (HBV) clearance.

Principal findings: Plasmids expressing HBV core protein (HBcAg) or HBV e antigen and HBcAg fused to the extracellular domain of CTLA-4 (pCTLA-4-HBc), CD27, and full length CD40L were constructed. Immunizations of these DNA plasmids induced HBcAg-specific antibody and cytotoxic T-cell responses in mice, but with different characteristics regarding the titers and subtypes of specific antibodies and intensity of T-cell responses. The plasmid pHBc expressing HBcAg induced an IgG2a-dominant response while immunizations of pCTLA-4-HBc induced a balanced IgG1/IgG2a response. To assess the protective values of the immune responses of different characteristics, mice were pre-immunized with pCTLA-4-HBc and pHBc, and challenged by hydrodynamic injection (HI) of pAAV/HBV1.2. HBV surface antigen (HBsAg) and DNA in peripheral blood and HBcAg in liver tissue were cleared with significantly accelerated kinetics in both groups. The clearance of HBsAg was completed within 16 days in immunized mice while more than 50% of the control mice are still positive for HBsAg on day 22. Stronger HBcAg-specific T-cell responses were primed by pHBc correlating with a more rapid decline of HBcAg expression in liver tissue, while anti-HBs antibody response developed rapidly in the mice immunized with pCTLA-4-HBc, indicating that the Th1/Th2 bias of vaccine-primed immune responses influences the mode of viral clearance.

Conclusion: Viral clearance could be efficiently achieved by Th1/Th2-balanced immune response, with a small but significant shift in T-cell and B-cell immune responses.

Show MeSH
Related in: MedlinePlus