Therapeutic Vaccination in Chronic Hepatitis B:  Preclinical Studies in the Woodchuck

Kosinska, Anna D.; Zhang, Ejuan; Lu, Mengji; Roggendorf, Michael

doi:10.1155/2010/817580

Cited by 12 publications

(10 citation statements)

References 187 publications

(250 reference statements)

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“…HBV DNA immunization is a promising strategy for inducing strong CD8 + T cell-mediated immunity in mice [18] , [19] , [20] , [21] , whereas this effect has been only transient and weak in clinical trials [22] , [23] . To move beyond various approaches already employed to improve DNA vaccination, we have explored the use of novel adjuvants that would specifically potentiate the Tc1 and/or Tc17 type of T cells as a means to overcome the problem.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…It has been reported that the functional defects of antigen-presenting cells, such as DCs, may cause the impaired T cell response during HBV infection. 22,85 Although treatment regimens for chronic hepatitis B have markedly improved outcomes during the last decade, the need for immune system activation to effectively induce sustained off-treatment disease remission and clearance of the hepatitis B surface antigen ('functional cure') still remains a largely unachieved target. 86,87 The host immune system plays a dominant role in the elimination of HBV infection.…”

Section: Discussionmentioning

confidence: 99%

A dendritic cell receptor-targeted chimeric immunotherapeutic protein (C-HBV) for the treatment of chronic hepatitis B

Ma¹,

Motyka

Gutfreund

et al. 2019

Human Vaccines & Immunotherapeutics

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In chronic Hepatitis B Virus (HBV) infections HBV-specific T cells are functionally impaired. Immunotherapy may restore HBV-specific T cell responses essential for sustained disease remission offtreatment and induction of a functional cure. Chimigen® Molecules are fusion proteins of antigen(s) with the Fc fragment of a xenotypic antibody designed to target specific receptors on dendritic cells (DCs). Here we describe the production and pre-clinical evaluation of Chimigen® HBV (C-HBV), containing HBV PreS1 and PreS2 peptide fragments, HBV core and murine Fc, produced in insect cells. C-HBV binding to immature DCs and internalization by endocytosis was FcγRII (CD32) and mannose receptor (CD206) dependent and led to increased MHC I and MHC II surface expression. Upon exposure of human T cells isolated from HBV un-infected healthy and chronically HBV-infected donors to C-HBV-pulsed mature DCs ex vivo, C-HBV induced vigorous T cell proliferation and enhanced expression of IFN-γ, TNF-α, perforin and granzyme B in both CD4 + and CD8 + T cell subsets. Re-stimulation of C-HBV-activated T cells from chronically infected donors with HBV PreS1/PreS2 and core overlapping peptides induced IFN-γ production in both CD4 + and CD8 + populations. C-HBV-activation of peripheral blood mononuclear cells (PBMCs) from chronically HBV-infected patients stimulated granzyme B production by CD4 + CD25 − T responder (Tresp) cells, accompanied by an increase in Annexin V staining on CD4 + CD25 + T regulatory (Treg) cell phenotype, consistent with apoptosis. The observed HBV-specific cellular responses induced by C-HBV ex vivo suggest that C-HBV is a promising immunotherapeutic candidate for the treatment of chronic HBV infections.

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“…Further studies may be needed to adjust the dose and timing of the booster doses to give a sustained immune response. Engaging therapeutic hepatitis B vaccines is a new approach against hepatitis B infection [19,20]. The cytokines (IFN-γ, TNFα, IL-2 and CD69) in CD4+ and CD8+ cells perform a vital role in various stages of viral infection [21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Humoral and cellular immune responses to modified hepatitis B plasmid DNA vaccine in mice

Salem‐Bekhit¹,

Rab²,

Tawfick³

et al. 2016

Trop. J. Pharm Res

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Purpose: To evaluate the immunogenicity and types of immune response of a quality-controlled modified recombinant hepatitis B surface antigen (HBsAg) plasmid encoding HBsAg in mice. Methods: The characterized plasmid DNA was used in the immunization of Balb/c mice. Three groups of mice were intramuscularly injected with three different concentrations (50, 25 and 10 μg/100 μL) of the modified plasmid. Humoral immune response was monitored by enzyme-linked immunosorbent assay (ELISA), while cellular immune response was investigated by analysis of spleen cytokine profile (TNFα, IFN γ and IL2) as well as CD69 expression level in CD4 and CD8 positive cells. Results: In general, the activated CD4 cells showing intracellular cytokines were higher than CD8 positive population of cells (p < 0.05). These findings indicate that the vaccine induced both a humoral and cellular immunity. Cytokine profile also showed high levels of TNFα, IFN γ and IL2 and CD69 expression in the group of animals immunized at a dose of 10 µg when compared to control group (p < 0.05). Conclusion: A 10 µg dose intramuscular injection of the modified DNA-based vaccine encoding HBsAg in mice induces both high humoral and cellular immune responses.

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Therapeutic Vaccination in Chronic Hepatitis B: Preclinical Studies in the Woodchuck

Cited by 12 publications

References 187 publications

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

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

A dendritic cell receptor-targeted chimeric immunotherapeutic protein (C-HBV) for the treatment of chronic hepatitis B

Humoral and cellular immune responses to modified hepatitis B plasmid DNA vaccine in mice

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