The presence of high amounts of HBV-DNA in serum is associated with suppressed costimulatory effects of interleukin 12 on HBV-induced immune response

Schlaak, Joerg F.; Tully, Glenn; Löhr, Hanns; Gerken, Guido; Büschenfelde, Karl‐Hermann Meyer zum

doi:10.1016/s0168-8278(99)80090-7

Cited by 28 publications

(22 citation statements)

References 24 publications

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“…Although the molecular mechanisms responsible for this defect clearly deserve further investigation, it must be noted that this alteration has also been detected in patients with chronic hepatitis B. The presence of large amounts of HBV DNA in serum is associated with suppressed costimulatory effects of IL-12 on HBV-induced immune responses (24). The elucidation of the mechanism responsible for the IL-12 unresponsiveness will be of great value for the development of more efficient therapies based on the gene delivery of immunostimulatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Chronic Viral Hepatitis in Woodchucks by Prolonged Intrahepatic Expression of Interleukin-12

Crettaz

Otano

Ochoa

et al. 2009

J Virol

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Chronic hepatitis B is a major cause of liver-related death worldwide. Interleukin-12 (IL-12) induction accompanies viral clearance in chronic hepatitis B virus infection. Here, we tested the therapeutic potential of IL-12 gene therapy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), an infection that closely resembles chronic hepatitis B. The woodchucks were treated by intrahepatic injection of a helper-dependent adenoviral vector encoding IL-12 under the control of a liver-specific RU486-responsive promoter. All woodchucks with viral loads below 10 10 viral genomes (vg)/ml showed a marked and sustained reduction of viremia that was accompanied by a reduction in hepatic WHV DNA, a loss of e antigen and surface antigen, and improved liver histology. In contrast, none of the woodchucks with higher viremia levels responded to therapy. The antiviral effect was associated with the induction of T-cell immunity against viral antigens and a reduction of hepatic expression of Foxp3 in the responsive animals. Studies were performed in vitro to elucidate the resistance to therapy in highly viremic woodchucks. These studies showed that lymphocytes from healthy woodchucks or from animals with low viremia levels produced gamma interferon (IFN-␥) upon IL-12 stimulation, while lymphocytes from woodchucks with high viremia failed to upregulate IFN-␥ in response to IL-12. In conclusion, IL-12-based gene therapy is an efficient approach to treat chronic hepadnavirus infection in woodchucks with viral loads below 10 10 vg/ml. Interestingly, this therapy is able to break immunological tolerance to viral antigens in chronic WHV carriers.

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Section: Discussionmentioning

confidence: 99%

Treatment of Chronic Viral Hepatitis in Woodchucks by Prolonged Intrahepatic Expression of Interleukin-12

Crettaz

Otano

Ochoa

et al. 2009

J Virol

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“…Additionally, in concert with high levels of circulating LCMV-clone 13, CD8 T cells of other specificities exhibit various degrees of functional impairment in vitro in response to antigenic stimulation (45,47). The existence of such functionally impaired CD8 T cells has also been reported in simian immunodeficiency virus, HCV, and HIV infections (14,16,20,35,42,46). The role of thymic output in the regulation of virus-specific CD8 T-cell responses during a chronic LCMV infection has not been studied.…”

mentioning

confidence: 95%

Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

Miller

Bonczyk

Nakayama

et al. 2005

J Virol

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Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ϳ6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virusspecific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

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“…Prominent among these are IFNs and TNF that down-regulate HBV replication (10). It is generally assumed that high levels of circulating "free" HBV Ags and/or viral particles induce peripheral tolerance and/or suppress antiviral immunity (11)(12)(13). Defects in anti-HBV immunity are reversible as "spontaneous" or (IFN or lamivudine) induced reconstitution of antiviral immunity has been reported in chronically HBV-infected patients (14 -16).…”

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confidence: 99%

Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential

Riedl

Wieland

Lamberth

et al. 2009

The Journal of Immunology

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Immunodominance limits the TCR diversity of specific antiviral CD8 T cell responses elicited by vaccination or infection. To prime multispecific T cell responses, we constructed DNA vaccines that coexpress chimeric, multidomain Ags (with CD8 T cell-defined epitopes of the hepatitis B virus (HBV) surface (S), core (C), and polymerase (Pol) proteins and/or the OVA Ag as stress protein-capturing fusion proteins. Priming of mono- or multispecific, HLA-A*0201- or Kb-restricted CD8 T cell responses by these DNA vaccines differed. Kb/OVA257–264- and Kb/S190–197-specific CD8 T cell responses did not allow priming of a Kb/C93–100-specific CD8 T cell response in mice immunized with multidomain vaccines. Tolerance to the S- Ag in transgenic Alb/HBs mice (that express large amounts of transgene-encoded S- Ag in the liver) facilitated priming of subdominant, Kb/C93–100-specific CD8 T cell immunity by multidomain Ags. The “weak” (i.e., easily suppressed) Kb/C93–100-specific CD8 T cell response was efficiently elicited by a HBV core Ag-encoding vector in 1.4HBV-Smut tg mice (that harbor a replicating HBV genome that produces HBV surface, core, and precore Ag in the liver). Kb/C93–100-specific CD8 T cells accumulated in the liver of vaccinated 1.4HBV-Smut transgenic mice where they suppressed HBV replication. Subdominant epitopes in vaccines can hence prime specific CD8 T cell immunity in a tolerogenic milieu that delivers specific antiviral effects to HBV-expressing hepatocytes.

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The presence of high amounts of HBV-DNA in serum is associated with suppressed costimulatory effects of interleukin 12 on HBV-induced immune response

Cited by 28 publications

References 24 publications

Treatment of Chronic Viral Hepatitis in Woodchucks by Prolonged Intrahepatic Expression of Interleukin-12

Treatment of Chronic Viral Hepatitis in Woodchucks by Prolonged Intrahepatic Expression of Interleukin-12

Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential

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