Induction of strong hepatitis B virus (HBV) specific T helper cell and cytotoxic T lymphocyte responses by therapeutic vaccination in the trimera mouse model of chronic HBV infection

Böcher, Wulf O.; Dekel, Benjamin; Schwerin, Wibke; Geißler, Michael; Hoffmann, Sandra; Rohwer, Andreas; Arditti, Fabian D.; Cooper, Aric; Bernhard, Helga; Berrébi, Alain; Rose-John, Stefan; Shaul, Yosef; Galle, Peter R.; Löhr, Hanns; Reisner, Yaīr

doi:10.1002/1521-4141(200107)31:7<2071::aid-immu2071>3.0.co;2-d

Cited by 43 publications

(22 citation statements)

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“…It has been shown that T-cell mediated immune responses are very important in overcoming HBV infection [1,2] and DCs can efficiently prime T-cell response, so the development of a vaccine of DCs has attracted considerable interest [18,19] .…”

Section: Discussionmentioning

confidence: 99%

Uric acid enhances T cell immune responses to hepatitis B surface antigen-pulsed-dendritic cells in mice

Tian²,

Xu³

et al. 2007

WJG

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INTRODUCTIONIt is generally accepted that dendritic cells (DCs) are the most efficient and powerful antigen presenting cells and play a center role in exciting T cell immune reactions. T-cell mediated immune responses, especially Hepatitis B virus (HBV) specific-cytotoxic T lymphocyte (CTL) response, may play an important role in resolving HBV infection [1,2] . hepatitis B surface antigen (HBsAg) pulsed DCs can activate lymphocytes to become HBsAg-specific CTLs or specific CD4 + T cells in vivo [3] . Shimizu et al [4] immunized HBV transgenic mice with DCs loading HBsAg, and found that DC vaccine could break tolerance to HBV and induce an effective anti-viral immune response. Chen et al [5] reported that HBsAg-pulsed DCs from the peripheral blood could effectively suppress HBV replication in chronic hepatitis B patients. However, anti-HBV immune effects of DC vaccine are varied and instable. This may be due to the diversity of DC vaccine preparations; however, the main cause may be the insufficiency of DC vaccines. For example, some researchers carried out similar immune therapy in volunteers, but no evident immune response was shown [3,[6][7][8] . Therefore, the basic research of DC vaccine as well as how to improve the immune response to DC vaccine is still a significant challenge.Recently, it was reported that uric acid (UA) could stimulate DCs to mature, promote DCs to present foreign antigens and stimulate T lymphocytes [9,10] . These findings demonstrate the adjuvant effects of uric acid and encourage the potential application of uric acid in RESULTS:The cytotoxicities of HBsAg-specific-CTLs, generated after immunization of HBsAg-pulsed-DCs and uric acid, were 68.63% ± 11.32% and significantly stronger than that in the control groups (P < 0.01).Compared with control groups, in mice treated with uric acid and HBsAg-pulsed-DCs, the spleen T cell proliferation to HBsAg re-stimulation was stronger (1.34 ± 0.093 vs 1.081 ± 0.028, P < 0.01), the level of IFN-γ secreted by splenocytes was higher (266.575 ± 51.323 vs 135.223 ± 32.563, P < 0.01) , and IL-4 level was

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Section: Discussionmentioning

confidence: 99%

Uric acid enhances T cell immune responses to hepatitis B surface antigen-pulsed-dendritic cells in mice

Tian²,

Xu³

et al. 2007

WJG

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“…CTL play a key role in the control of HBV infection, and it is generally thought that they do so by destroying infected cells through cellular immune responses (11)(12)(13)(14). Because CTLs recognize complexes of antigenic peptides and MHC, considerable effort is currently ongoing to develop epitope-based vaccines to stimulate HBV-specific CTL responses (14,15).…”

Section: Tumor Eradication By Hepatitis B Virus X Antigen-specific Cdmentioning

confidence: 99%

“…Because CTLs recognize complexes of antigenic peptides and MHC, considerable effort is currently ongoing to develop epitope-based vaccines to stimulate HBV-specific CTL responses (14,15). Many different CTL epitopes derived from hepatitis B surface Ag (HBsAg), hepatitis B core Ag, and hepatitis B polymerase Ag have been reported, and some of them have shown significant results in both animal models and patients with human acute hepatitis B (11)(12)(13)(14)(15)(16).…”

Section: Tumor Eradication By Hepatitis B Virus X Antigen-specific Cdmentioning

confidence: 99%

“…It is generally thought that class I-restricted CD8 ϩ CTL play a key role in the control of HBV infection (11)(12)(13)(14). Furthermore, it has been reported that, when the HBsAg-specific CTL is adoptively transferred to HBV transgenic mice, HBV gene expression and replication are abolished by the secretion of IFN-␥ and TNF-␣ after Ag recognition (17,18).…”

Section: Regression Of Tumors In Xenografted Nude Micementioning

confidence: 99%

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Tumor Eradication by Hepatitis B Virus X Antigen-Specific CD8+ T Cells in Xenografted Nude Mice

Chun¹,

Lee²,

Cheong³

et al. 2003

The Journal of Immunology

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We have previously reported several CTL epitopes derived from the hepatitis B viral X Ag (HBx). In this study, we evaluated whether HBx-specific CTLs can be effectively used in adoptive cancer immunotherapy. To validate the possibility, four peptides containing a HLA-A2.1-restricted binding consensus motif were identified from the HBx protein and tested for their ability to activate CTL from PBMCs isolated from chronic carriers of HBV (n = 12). We selected two highly potent epitopes, HBx 52–60 (HLSLRGLFV) and HBx 115–123 (CLFKDWEEL), that are capable of inducing Ag-specific cytotoxic T cells in patient PBMCs. For adoptive immunotherapy using HBx-specific CTLs, we generated CTL clones restricted to the HBx 52–60 or HBx 115–123 peptide using a limiting dilution technique. LC-46, an HBx 52–60-specific clone, is CD62L−CD69+CD45RO+CD45RA−CD25dim and is stained by IFN-γ (∼92%), IL-2 (30%), and TNF-α (56%), but not by IL-5, IL-10, IL-12, or TNF-β, indicating that the cells are fully activated T cytotoxic 1-type cells. When LC-46 cells were adoptively transferred into xenografted nude mice bearing human hepatomas expressing HLA-A2.1 molecules and intracellular HBx proteins, the tumors were eradicated. Taken together, our data provide solid evidence for the feasibility of adoptive immunotherapy with HBx-sensitized CTLs in hepatitis disease, including hepatocellular carcinoma (HCC).

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“…It has been shown that DNA immunizations can induce both specific antibodies and cell-mediated responses against the structural and nonstructural (NS) HCV proteins in mice. [6][7][8][9][10][11][12][13][14][15][16] The NS protein 3 of HCV has been considered as a possible vaccine target. The reasons for this are that the NS3 protein shows a limited genetic variability, it performs multiple enzymatic functions, and it is a relatively large protein.…”

Section: Introductionmentioning

confidence: 99%

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

et al. 2004

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We have recently shown that the NS3-based genetic immunogens should contain also hepatitis C virus (HCV) nonstructural (NS) 4A to utilize fully the immunogenicity of NS3. The next step was to try to enhance immunogenicity by modifying translation or mRNA synthesis. To enhance translation efficiency, a synthetic NS3/4A-based DNA (coNS3/4A-DNA) vaccine was generated in which the codon usage was optimized (co) for human cells. In a second approach, expression of the wild-type (wt) NS3/4A gene was enhanced by mRNA amplification using the Semliki forest virus (SFV) replicon (wtNS3/4A-SFV). Transient tranfections of human HepG2 cells showed that the coNS3/4A gene gave 11-fold higher levels of NS3 as compared to the wtNS3/4A gene when using the CMV promoter. We have previously shown that the presence of NS4A enhances the expression by SFV. Both codon optimization and mRNA amplification resulted in an improved immunogenicity as evidenced by higher levels of NS3-specific antibodies. This improved immunogenicity also resulted in a more rapid priming of cytotoxic T lymphocytes (CTLs). Since HCV is a noncytolytic virus, the functionality of the primed CTL responses was evaluated by an in vivo challenge with NS3/4A-expressing syngeneic tumor cells. The priming of a tumor protective immunity required an endogenous production of the immunogen and CD8 þ CTLs, but was independent of B and CD4 þ T cells. This model confirmed the more rapid in vivo activation of an NS3/4A-specific tumor-inhibiting immunity by codon optimization and mRNA amplification. Finally, therapeutic vaccination with the coNS3/4A gene using gene gun 6-12 days after injection of tumors significantly reduced the tumor growth in vivo. Codon optimization and mRNA amplification effectively enhances the overall immunogenicity of NS3/4A. Thus, either, or both, of these approaches should be utilized in an NS3/4A-based HCV genetic vaccine.

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Induction of strong hepatitis B virus (HBV) specific T helper cell and cytotoxic T lymphocyte responses by therapeutic vaccination in the trimera mouse model of chronic HBV infection

Cited by 43 publications

References 50 publications

Uric acid enhances T cell immune responses to hepatitis B surface antigen-pulsed-dendritic cells in mice

Uric acid enhances T cell immune responses to hepatitis B surface antigen-pulsed-dendritic cells in mice

Tumor Eradication by Hepatitis B Virus X Antigen-Specific CD8+ T Cells in Xenografted Nude Mice

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

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