Limited humoral immunity in hepatitis C virus infection

Chen, Margaret; Sällberg, Matti; Sönnerborg, Anders; Weiland, Ola; Mattsson, Lars; Jin, Ling; Birkett, Ashley; Peterson, Darrell L.; Milich, David R.

doi:10.1016/s0016-5085(99)70237-4

Cited by 150 publications

(127 citation statements)

References 54 publications

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“…If we assume that this results in impaired antigen presentation, which in turn fails to result in an expansion of the Th cell population, then the result will be a limited expansion of the humoral and cell-mediated immune response. Indeed, characteristics of HCV infection include low HCV-specific antibody (Chen et al, 1999) and a low frequency of HCV-specific CTLs (Rehermann & Chisari, 2000), both of which are consistent with a failure of CD4 + Th cells to induce proliferation of the B-and CTLeffector cells. IFN treatment of HCV carriers indicates that the frequency of HCV core-specific Th cell precursors is significantly higher in sustained responders than in transient or non-responders (Lasarte et al, 1998), suggesting that the expansion of Th cell precursors correlates with and is critical for HCV elimination.…”

Section: Discussionmentioning

confidence: 88%

Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3

Huang

Xiang

et al. 2006

Journal of General Virology

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Infections with Hepatitis C virus (HCV) pose a serious health problem worldwide. In this study, the hypothesis that adoptive transfer of dendritic cells (DCs) pulsed with HCV NS3 protein and matured with an oligodeoxynucleotide (ODN) containing CpG motifs (CpG) ex vivo would initiate potent HCV-specific protective immune responses in vivo was tested. NS3 protein was efficiently transduced into DCs and treatment of DCs with CpG ODN induced phenotypic maturation and specifically increased the expression of CD40. DCs matured with CpG ODN produced higher interleukin 12 levels and a stronger allogeneic T-cell response compared with untreated DCs. Notably, there were no differences between NS3-pulsed DCs and DCs pulsed with a control protein with respect to phenotype, cytokine production or mixed lymphocyte reaction, indicating that transduction with NS3 protein did not impair DC functions. Compared with the untreated NS3-pulsed DCs, the NS3-pulsed DCs matured with CpG ODN induced stronger cellular immune responses including enhanced cytotoxicity, higher interferon-c production and stronger lymphocyte proliferation. Upon challenge with a recombinant vaccinia virus expressing NS3, all mice immunized with NS3-pulsed DCs showed a significant reduction in vaccinia virus titres when compared with mock-immunized mice. However, the NS3-pulsed DCs matured with CpG ODN induced higher levels of protection compared with the untreated NS3-pulsed DCs. These data are the first to show that NS3-pulsed DCs induce specific immune responses and provide protection from viral challenge, and also demonstrate that CpG ODNs, which have a proven safety profile, would be useful in the development of DC vaccines. INTRODUCTIONInfections with Hepatitis C virus (HCV) pose a serious health problem worldwide. An estimated 170 million people are currently infected, which amounts to 3 % of the world population. About 80 % of infected people remain chronic carriers and are at high risk of developing severe liver disease including cirrhosis and hepatocellular carcinoma (WHO, 1999). Treatment with interferon-a (IFN-a) and ribavirin is the only effective therapy against HCV infection, but the overall response rate is only 40-50 % (Fried et al., 2002;Manns et al., 2001). Currently, there is no licensed vaccine against HCV; therefore, developing strategies for vaccination as well as for treatment of HCV infection is of great importance.Dendritic cells (DCs) are the most potent type of antigen presenting cells (APCs) and are responsible for the initiation and maintenance of immune responses. Situated in peripheral tissues and in lymphoid organs, DCs are uniquely suited to detect and capture pathogens. They express members of the recently identified Toll-like receptor (TLR) family, which bind common chemical moieties associated with microbial organisms. TLR ligands include bacterial lipopolysaccharide, lipopeptides, hypomethylated CpG DNA motifs, dsRNA and flagellin (Akira et al., 2001;Iwasaki & Medzhitov, 2004). TLR signalling triggers a maturation program...

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Section: Discussionmentioning

confidence: 88%

Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3

Huang

Xiang

et al. 2006

Journal of General Virology

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“…The appearance of HBV-specific CD8 ϩ and CD4 ϩ T cells during the incubation time of acute hepatitis B follows the same pattern. 27 Activation of the virus-specific cellular immunity is followed by the humoral response, which appears at least 10 to 12 weeks after HBV 36 and HCV 37 infections. These data are in line with results obtained in animal models.…”

Section: Profiles Of Adaptive Immune Responses Early After Hbv and Hcmentioning

confidence: 99%

Kinetics of the immune response during HBV and HCV infection

2003

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The innate immune system has a role not only in protecting the host during the initial period of virus infection, but also in shaping the nature of the adaptive immune response. In this review, we follow the kinetics of the virologic and immunologic events occurring from the time of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We primarily discuss how the early events after infection might influence the development of the adaptive immune response in these 2 important viral infections and how new strategies for more efficient preventive and therapeutic vaccines can be derived from this knowledge. (HEPATOLOGY 2003; 38:4-13.)H epatitis B (HBV) and hepatitis C (HCV) viruses are the 2 major causes of chronic liver inflammation worldwide. 1,2 Despite distinct virologic features, both viruses are preferentially hepatotropic, not directly cytopathic, and elicit liver diseases that share several aspects of their natural history. HBV and HCV infections share also some important features of the adaptive immune response. Multispecific antiviral CD4 and CD8 responses with a T-helper type 1 profile of cytokine production are detectable in the blood of subjects with a self-limited infection. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] These responses are stronger than those found in patients with chronic infection. [17][18][19][20][21] Based on these observations, it has been proposed that the ability to mount an efficient cellular immune response is the main mechanism responsible for HBV and HCV control, whereas a defect in this response leads to chronicity. 2,22 However, the lack of suitable animal models to study the pathogenesis of HBV and HCV infections has so far hampered a definitive demonstration that associations between different infection outcomes and different vigor and breadth of T-cell responses have a causative effect. A recent report in HCV-infected chimpanzees, in which a clear association between T-cell response and virus clearance was not found, 23 added a further note of caution. Even so, it is difficult to argue against the importance of the cellular immune response in HBV and HCV control. In chimpanzees infected with HCV, expansion of a multispecific and sustained HCV-specific CD8 ϩ T-cell-mediated response was observed in 2 of 2 animals that cleared the virus, but not in the 4 animals that developed a chronic infection. 24 These results have been confirmed by recent reports showing that expansion of interferon ␥ (IFN-␥) ϩ , CD8 ϩ , and CD4 ϩ T cells precedes viral clearance in patients studied during the incubation phase of acute HCV infection in man 10 and in HCV-infected chimpanzees. 25 Similar findings have been reported in animal models of HBV infection 26 and in patients studied during the incubation phase of HBV infection, 27 in whom reduced early expansion of virusspecific T cells was associated with virus persistence. Moreover, the importance of virus-specific CD8 ϩ T cells in HBV control has been confirmed further by CD8 ϩ T-cell deletion experiments performed in HBV-i...

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“…If we assume that this results in impaired antigen presentation, which in turn fails to result in an expansion of the Th cell population, then the result will be a limited expansion of the humoral and cellmediated immune response. Features of HCV infection include low titres of HCV-specific antibodies (Chen et al, 1999) and a low frequency of HCV-specific CTL (Rehermann and Chisari, 2000), both of which are consistent with a failure of CD4 + Th cells to induce proliferation of the B-and CTL-effector cells. IFN-based treatment of HCV carriers indicate that the frequency of HCV core-specific Th cell precursors is significantly higher in sustained responders than in transient-or non-responders (Lasarte et al, 1998) suggesting that the expansion of Th cell precursors correlates with HCV elimination.…”

Section: Dc-based Immunotherapy In Persistent Hcv Infectionmentioning

confidence: 83%

Prospects for dendritic cell vaccination in persistent infection with hepatitis C virus

Gowans

2004

Journal of Clinical Virology

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Although hepatitis C virus (HCV) is classified in the Hepacivirus genus in the family Flaviviridae, it is unlike most of the other members of this family due to its propensity to cause persistent infections. This persistent infection eventually results in chronic liver disease, cirrhosis and hepatocellular carcinoma in a proportion of infected individuals. It has been difficult to examine correlates of clearance or persistence because most acute phase HCV infections are subclinical or result in symptoms which are non-specific; consequently, acute infections are not generally recognised and patients often present many years later with persistent infection and accompanying chronic liver disease. Nevertheless, seminal studies, performed during the acute phase, have identified a number of factors which are likely to influence the outcome of infection, although it is possible that the mechanism is multifactorial. One of these factors is impairment of dendritic cell function by a mechanism resulting from expression of an HCV protein(s) in these cells. This may be a major factor in the failure of the immune response to expand after HCV infection, leading to persistence. Nevertheless, it may be possible to overcome this defect by autologous transfusion of HCV antigen-loaded, mature dendritic cells and the purpose of this review is to highlight the need and general approaches for developing dendritic cell-based immunotherapy for HCV infection.

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Limited humoral immunity in hepatitis C virus infection

Cited by 150 publications

References 54 publications

Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3

Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3

Kinetics of the immune response during HBV and HCV infection

Prospects for dendritic cell vaccination in persistent infection with hepatitis C virus

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