Virus-Specific Lymphokine Production Differs Quantitatively but Not Qualitatively in Acute and Chronic Hepatitis B Infection

Jung, Maria–Christina; Hartmann, Beate; Gerlach, J. Tilman; Diepolder, Helmut M.; Gruber, Rudolf; Schraut, W.; Grüner, N.; Zachoval, Reinhart; Hoffmann, Robert M.; Santantonio, T.; Wächtler, Martin; Pape, Gerd R.

doi:10.1006/viro.1999.9833

Cited by 94 publications

(83 citation statements)

References 16 publications

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“…In contrast, none of the other patients responded to more than five epitopes, and the overall response of patients with chronic hepatitis B was weak. As previously reported for other HBV epitopes and proteins (35,43,44), the frequency of HBV epitopespecific cells was low, i.e., between ϳ10 and 50 peptide-specific cells per 300,000 PBMC. Tetanus toxoid-specific responses were tested as a positive control, and the frequency of responses did not differ significantly among patient subgroups (Fig.…”

Section: Immunogenicity Of Hbv Polymerase Peptides As Assessed By Ifnsupporting

confidence: 77%

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Cellular Immune Responses to the Hepatitis B Virus Polymerase

Mizukoshi

Sidney

Livingston³

et al. 2004

The Journal of Immunology

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CD4+ T cells play an important role in hepatitis B virus (HBV) infection by secretion of Th1 cytokines that down-regulate HBV replication, and by promoting CD8+ T cell and B cell responses. We have identified and characterized 10 CD4+ T cell epitopes within polymerase and used them to analyze the immunological effects of long-term antiviral therapy as compared with spontaneous recovery from HBV infection. Candidate epitopes were tested for binding to 14 HLA-DR molecules and in IFN-γ ELISPOT and cytotoxicity assays using peripheral blood lymphocytes from 66 HBV-infected patients and 16 uninfected controls. All 10 epitopes bound with high affinity to the most prevalent HLA-DR Ags, were conserved among HBV genomes, and induced IFN-γ responses from HBV-specific CD4+ T cells. Several epitopes contained nested MHC class I motifs and stimulated HBV-specific IFN-γ production and cytotoxicity of CD8+ T cells. HBV polymerase-specific responses were more frequent during acute, self-limited hepatitis and after recovery (12 of 18; 67%) than during chronic hepatitis (16 of 48 (33%); p = 0.02). Antiviral therapy of chronic patients restored HBV polymerase and core-specific T cell responses during the first year of treatment, but thereafter, responses decreased and, after 3 years, were no more frequent than in untreated patients. Decreased T cell responsiveness during prolonged therapy was associated with increased prevalence of lamivudine-resistant HBV mutants and increased HBV titers. The data provide a rationale for the combination of antiviral and immunostimulatory therapy. These newly described HBV polymerase epitopes could be a valuable component of a therapeutic vaccine for a large and ethnically diverse patient population.

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Section: Immunogenicity Of Hbv Polymerase Peptides As Assessed By Ifnsupporting

confidence: 77%

“…A response was scored as positive if it was 1) greater than the mean response plus 2 SD in healthy, anti-HCV negative control subjects and 2) greater than 10 specific spots (spots in the presence of Ag minus spots in the absence of Ag) (35).…”

Section: Elispot Assaymentioning

confidence: 99%

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Mizukoshi

Sidney

Livingston³

et al. 2004

The Journal of Immunology

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“…In humans a predominance of Th0 cells was detected in the liver, thus favoring the persistence of the virus (55,56). In contrast to what was observed during chronic hepatitis, a strong IFN-␥ production by Th1 cells in the peripheral blood was detected following antigenic stimulation of PBMC from acutely infected patients (57). Thus, it is tempting to speculate that IFN-␥-secreting T cells induced after DNA-based immunization could facilitate eradication of HBV infection in the liver.…”

Section: Discussionmentioning

confidence: 94%

Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization

Loirat

Lemonnier

Michel

2000

The Journal of Immunology

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CTL together with anti-envelope Abs represent major effectors for viral clearance during hepatitis B virus (HBV) infection. The induction of strong cytotoxic and Ab responses against the envelope proteins after DNA-based immunization has been proposed as a promising therapeutic approach to mediate viral clearance in chronically infected patients. Here, we studied the CTL responses against previously described hepatitis B surface Ag (HBsAg)-HLA-A*0201-restricted epitopes after DNA-based immunization in HLA-A*0201 transgenic mice. The animal model used was Human Human Db (HHD) mice, which are deficient for mouse MHC class I molecules (β2-microglobulin−/− Db−/−) and transgenic for a chimeric HLA-A*0201/Db molecule covalently bound to the human β2-microglobulin (HHD+/+). Immunization of these mice with a DNA vector encoding the small and the middle HBV envelope proteins carrying HBsAg induced CTL responses against several epitopes in each animal. This study performed on a large number of animals described dominant epitopes with specific CTL induced in all animals and others with a weaker frequency of recognition. These results confirmed the relevance of the HHD transgenic mouse model in the assessment of vaccine constructs for human use. Moreover, genetic immunization of HLA-A2 transgenic mice generates IFN-γ-secreting CD8+ T lymphocytes specific for endogenously processed peptides and with recognition specificities similar to those described during self-limited infection in humans. This suggests that responses induced by DNA immunization could have the same immune potential as those developing during natural HBV infection in human patients.

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“…2,3 The resolution of HBV infection after acute self-limited hepatitis is associated with strong CD4ϩ and CD8ϩ T-cell responses, with a type 1 cytokine profile. [4][5][6][7] In contrast to this strong antiviral T-cell reactivity, which persists in the convalescent phase after hepatitis B surface antigen (HBsAg) clearance, patients with chronic HBV infection have weak or undetectable T-cell reactivity to HBV, which is the dominant factor that permits an ongoing, high level of viral replication. A series of investigations of the mechanisms by which Tcells control HBV replication showed the major role of cytokine-mediated, intracellular inactivation of HBV that does not require cell death.…”

Section: H Epatitis B Virus (Hbv) Is a Noncytopathic Dnamentioning

confidence: 99%

Lamivudine Plus Interleukin-12 Combination Therapy in Chronic Hepatitis B: Antiviral and Immunological Activity *

et al. 2005

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H epatitis B virus (HBV) is a noncytopathic DNAvirus, which can cause acute, self-limited hepatitis or chronic hepatitis, cirrhosis, and/or hepatocellular carcinoma. 1 The diversity of clinical outcomes after exposure to HBV is determined primarily by the host immune response. 2,3 The resolution of HBV infection after acute self-limited hepatitis is associated with strong CD4ϩ and CD8ϩ T-cell responses, with a type 1 cytokine profile. [4][5][6][7] In contrast to this strong antiviral T-cell reactivity, which persists in the convalescent phase after hepatitis B surface antigen (HBsAg) clearance, patients with chronic HBV infection have weak or undetectable T-cell reactivity to HBV, which is the dominant factor that permits an ongoing, high level of viral replication. A series of investigations of the mechanisms by which Tcells control HBV replication showed the major role of cytokine-mediated, intracellular inactivation of HBV that does not require cell death. 8 This noncytolytic antiviral effect, first demonstrated in an HBV transgenic mouse model and subsequently in other animals, is primarily mediated by interferon-gamma (IFN-␥). 9-11 A detailed analysis of HBV clearance during acute infection in chimpanzees showed that the disappearance of viral DNA from the liver coincides with IFN-␥ induction before the increase of serum alanine aminotransferase (ALT), in other words, without destruction of hepatocytes. 11

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Virus-Specific Lymphokine Production Differs Quantitatively but Not Qualitatively in Acute and Chronic Hepatitis B Infection

Cited by 94 publications

References 16 publications

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization

Lamivudine Plus Interleukin-12 Combination Therapy in Chronic Hepatitis B: Antiviral and Immunological Activity *

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