Immunological monitoring during therapeutic vaccination as a prerequisite for the design of new effective therapies: induction of a vaccine-specific CD4+ T-cell proliferative response in chronic hepatitis B carriers

Jung, Maria–Christina; Grüner, N.; Zachoval, Reinhart; Schraut, W.; Gerlach, Tilman; Diepolder, Helmut M.; Schirren, Carl-Albrecht; Page, Mark; Bailey, John; Birtles, Emma; Whitehead, E. Douglas; Trojan, Jörg; Zeuzem, Stefan; Pape, Gerd R.

doi:10.1016/s0264-410x(02)00309-2

Cited by 62 publications

(25 citation statements)

References 15 publications

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“…Similarly, providing more antigen to CD8 T cells that are continuously stimulated in vivo and functionally impaired may, in fact, worsen the exhaustion. Indeed, with a recent notable exception (75), therapeutic vaccination has rarely provided benefit when the antigen load is high (32,56,61,126), and most positive results have been achieved when viral replication is suppressed either by drug treatment or latency (52,63,93,114). As with preventive vaccination, the proliferative potential of responding T cells will be an important factor determining the outcome of therapeutic vaccinations (116).…”

Section: Challenges For Preventive and Therapeutic Vaccinesmentioning

confidence: 99%

Memory CD8 T-Cell Differentiation during Viral Infection

Wherry

Ahmed

2004

J Virol

773

781

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Section: Challenges For Preventive and Therapeutic Vaccinesmentioning

confidence: 99%

Memory CD8 T-Cell Differentiation during Viral Infection

Wherry

Ahmed

2004

J Virol

773

781

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“…These two opposite pathogenic events have both been associated with an increase in virus-specific T-cell immunity, but it remains difficult to understand why changes in T-cell immunity can be associated with either an increase or decrease in disease activity (11,28,42,43,50,53,57).…”

Section: Vol 81 2007 Hepatocytes Influence Cd8 T-cell Function 2947mentioning

confidence: 99%

The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function

Gehring

Sun

Kennedy

et al. 2007

J Virol

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CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣).On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-␥ and TNF-␣ production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.Virus-specific CD8 T cells play a major role in viral clearance and disease pathogenesis during infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) (6). The noncytopathic nature of both viruses and their ability to infect hepatocytes (1, 23, 27, 31, 39) necessitate a coordinated mechanism to reach viral clearance and avoid liver destruction (21,64). This is likely facilitated by the fact that virally infected hepatocytes are largely resistant to perforin/granzyme-mediated killing (30) but sensitive to cytokine (gamma interferon [IFN-␥] and tumor necrosis factor alpha [⌻⌵F-␣])-mediated control of viral replication (9, 21).In mouse and chimpanzee models of HBV infection, IFN-␥ produced by virus-specific CD8 T cells correlates with a profound reduction in serum and liver HBV DNA (22,23,25,63) and helps to reduce hepatocyte damage by inducing cyto-protective proteins that confer resistance to granzyme B-mediated killing (4). Similar correlations have been observed in HCVinfected humans and experimentally infected chimpanzees, where the appearance of IFN-␥-producing CD8 T cells coincides with decreases in HCV RNA (51, 52). However, intrahepatic IFN-␥ production is also responsible for triggering the recruitment of inflammatory cells to the liver, which contribute to liver pathology (2,32,45).It has often been assumed that the extent of liver damage in chronic viral hepatitis was directly proportional to the intensity of the virus-specific CD8 response. However, the frequency of circulating HBV-and HCV-specific CD8 T cells correlates more with protection than liver damage (18,29,34,35,58). Furthermore, virus-specific CD8 T cells represent a small minority of the total intrahepatic population in chronic active hepatitis B and C, and their frequencies are inversely related...

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“…Although many experimental, therapeutic HBV vaccines have been developed (17)(18)(19)(20)(21), these have failed so far to reproducibly clear chronic HBV infection. The major problem for therapeutic HBV vaccines is the delivery of Ags into the tolerogen milieu of chronically infected patients.…”

mentioning

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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Immunological monitoring during therapeutic vaccination as a prerequisite for the design of new effective therapies: induction of a vaccine-specific CD4+ T-cell proliferative response in chronic hepatitis B carriers

Cited by 62 publications

References 15 publications

Memory CD8 T-Cell Differentiation during Viral Infection

Memory CD8 T-Cell Differentiation during Viral Infection

The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function

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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