Frequencies of interferon-γ and interleukin-10 secreting cells in peripheral blood mononuclear cells and liver infiltrating lymphocytes in chronic hepatitis B virus infection

N, Hyodo; Tajimi, Morihiro; Ugajin, Takuhiro; Nakamura, Ikuo; Imawari, Michio

doi:10.1016/s1386-6346(03)00199-2

Cited by 43 publications

(41 citation statements)

References 28 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: 78%

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: 78%

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Mizukoshi

Sidney

Livingston³

et al. 2004

The Journal of Immunology

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“…On the contrary, IFNc production was not different between patients and controls. This finding could simply reflect the absence of stimulation of the immune system in healthy subjects, rather than a Th1 polarization in HBV patients, as previously reported [30]. A predominant shift of the immune response towards a Th1 profile has been suggested to be crucial for the eradication of HBV, while a prevalent Th2 response seems to favour viral persistence [21,31].…”

Section: Discussionsupporting

confidence: 51%

In vitro effect of thymosin‐alpha1 and interferon‐alpha on Th1 and Th2 cytokine synthesis in patients with eAg‐negative chronic hepatitis B

Loggi¹,

Gramenzi²,

Margotti³

et al. 2008

Journal of Viral Hepatitis

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Thymosin alpha-1 (Talpha1) has been shown to be effective in chronic hepatitis B treatment. This study investigated the effect of Talpha1 and interferon-alpha (IFNalpha) on cytokine production by peripheral blood mononuclear cells (PBMCs) of 12 patients with eAg-negative chronic hepatitis B (HBV). We evaluated the effect of incubation with Talpha1, IFNalpha or both on the synthesis of T-helper 1 (Th1) cytokines [interleukin-2 (IL-2), IFNgamma] and Th2 cytokines (IL-4, IL-10) and of antiviral protein 2',5'-oligoadenylate synthetase (2',5'-OAS) in patients and in a group of 10 healthy controls. Concerning Th1 profile, controls showed lower IL-2 synthesis than HBV patients. In HBV setting, IFNalpha/Talpha1 combination was able to increase IL-2 production significantly, when compared with baseline condition. About the Th2-cytokines, controls showed statistically lower synthesis of IL-4 and higher production of IL-10, than HBV patients. In these latter, IFNalpha increased the synthesis of IL-10 compared with baseline. Interestingly, both Talpha1 alone and the IFNalpha/Talpha1 combination reversed this effect. Finally, compared with baseline, the synthesis of 2',5'-OAS was significantly higher in the presence of Talpha1 and IFNalpha alone, and in the presence of IFNalpha/Talpha1 association, while no differences were found between controls and HBV patients. In conclusion, in PBMCs from eAg-negative HBV patients, Talpha1 alone was able to increase the antiviral protein synthesis, while in association with IFNalpha, it stimulated the IL-2 synthesis and inhibited the IFN-induced IL-10 production. These results need further investigations, but reinforce the idea of an immunotherapeutic approach for chronic hepatitis B.

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“…This coincides with a surge in IL-10 production [49]. A positive correlation between viral load and the frequency of IL-10-producing HBV-specific T cells has also been demonstrated [50]. Notably, EBV and CMV express genes that encode for a viral homolog of IL-10 that has the same immunosuppressive potency as human IL-10 [51].…”

Section: Hbv Infectionmentioning

confidence: 78%