Induction of hepatitis C virus-specific cytotoxic T lymphocytes in mice by immunization with dendritic cells transduced with replication-defective recombinant adenovirus

Matsui, Masanao; Moriya, Osamu; Abdelaziz, Nada A.; Matsuura, Yoshiharu; Miyamura, Tatsuo; Akatsuka, Toshitaka

doi:10.1016/s0264-410x(02)00460-7

Cited by 34 publications

(28 citation statements)

References 46 publications

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“…However, if intracellular expression of the proteins is preferred in order to induce CTL responses, maturation of the DC should be carried out before transfection of the cells with the vector encoding HCV core. Recently, efficient anti-core CTL responses were obtained with DC engineered to produce HCV core, and in that study DC were matured with LPS before transduction (28).…”

Section: Vol 77 2003 Impairment Of DC Maturation By Hcv Proteins 10867mentioning

confidence: 99%

Hepatitis C Virus Structural Proteins Impair Dendritic Cell Maturation and Inhibit In Vivo Induction of Cellular Immune Responses

Sarobe

Lasarte

Zabaleta

et al. 2003

J Virol

119

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Hepatitis C virus (HCV) chronic infection is characterized by low or undetectable cellular immune responses against HCV antigens. Some studies have suggested that HCV proteins manipulate the immune system by suppressing the specific antiviral T-cell immunity. We have previously reported that the expression of HCV core and E1 proteins (CE1) in dendritic cells (DC) impairs their ability to prime T cells in vitro. We show here that immunization of mice with immature DC transduced with an adenovirus encoding HCV core and E1 antigens (AdCE1) induced lower CD4؉ -and CD8 ؉ -T-cell responses than immunization with DC transduced with an adenovirus encoding NS3 (AdNS3). However, no differences in the strength of the immune response were detected when animals were immunized with mature DC subsequently transduced with AdCE1 or AdNS3. According to these findings, we observed that the expression of CE1 in DC inhibited the maturation caused by tumor necrosis factor alpha or CD40L but not that induced by lipopolysaccharide. Blockade of DC maturation by CE1 was manifested by a lower expression of maturation surface markers and was associated with a reduced ability of AdCE1-transduced DC to activate CD4 ؉ -and CD8 ؉ -T-cell responses in vivo. Our results suggest that HCV CE1 proteins modulate T-cell responses by decreasing the stimulatory ability of DC in vivo via inhibition of their physiological maturation pathways. These findings are relevant for the design of therapeutic vaccination strategies in HCV-infected patients.Hepatitis C virus (HCV) is an enveloped, single-stranded RNA virus belonging to the family Flaviviridae that is responsible for the majority of non-A, non-B hepatitis (29), which affects an estimated 170 million people worldwide. Infection by HCV is characterized by a high tendency to evolve to chronicity and by the ability to cause chronic hepatitis that may progress to liver cirrhosis and eventually to hepatocellular carcinoma (10). In acute HCV infection, strong T-cell responses against viral antigens are associated with viral clearance, mediated by both CD4 ϩ and CD8 ϩ T cells (11,14,30,46). However, chronically infected patients show very weak or undetectable antiviral T-cell reactivity (6,21,34,37), while maintaining immune competence against other antigens. These findings suggest that HCV may have developed strategies to specifically inhibit the induction of responses toward its constituents. The great variability of HCV, as evidenced by the existence of quasispecies in the same infected individual (26), may allow the emergence of escape mutants, which cannot be efficiently recognized by the immune system. Indeed, several escape mutants have been described that not only affect antibody recognition but also T-cell recognition (7,41,47). Although sequence variability is one of the most important mechanisms used by HCV to evade immune response, there are other viral mechanisms of evasion. HCV not only infects hepatocytes but can also infect hematopoietic cells. Viral replication has been described in differe...

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Section: Vol 77 2003 Impairment Of DC Maturation By Hcv Proteins 10867mentioning

confidence: 99%

Hepatitis C Virus Structural Proteins Impair Dendritic Cell Maturation and Inhibit In Vivo Induction of Cellular Immune Responses

Sarobe

Lasarte

Zabaleta

et al. 2003

J Virol

119

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“…Interestingly, human DCs transduced with an adenovirus coding for HCV core and E1 proteins mature normally but do not efficiently prime CD4 ϩ T cells in vitro (47), while similarly transduced immature murine DCs were inhibited in their maturation capacity, largely due to the expression of structural proteins (48). In contrast to these studies, other investigators have failed to show a detrimental effect of HCV or its proteins on DCs (35,37). Furthermore, fully functional DCs can be generated from monocytes of humans with chronic HIV infections, suggesting that high viral loads do not compromise antigen-presenting-cell (APC) activity or at least precursor APC activity (46).…”

mentioning

confidence: 99%

Lack of Phenotypic and Functional Impairment in Dendritic Cells from Chimpanzees Chronically Infected with Hepatitis C Virus

Larsson

Babcock

Grakoui

et al. 2004

J Virol

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Dendritic cells (DCs), which are potent antigen-presenting cells (APCs), are used as adjuvants for the treatment of cancer and infectious diseases in human and nonhuman primates, with documented clinical efficacy. The hepatitis C virus (HCV)-chimpanzee model is the best available model for testing the immunotherapeutic effects of DCs in the setting of a chronic infection, as chimpanzees develop a persistent infection resembling that seen in humans. However, several reports have suggested that DCs derived from chronically infected individuals or nonhuman primates are functionally compromised. As a prelude to clinical studies, we evaluated whether functionally mature DCs could be generated in chimpanzee plasma by good manufacturing practice using CD14 ؉ mononuclear precursors from chronically infected chimpanzees. DCs generated in a medium with HCV-negative plasma and treated with a defined cocktail of cytokines or a CD40 ligand trimer matured fully, as measured by the induction of CD83 expression and the upregulation of costimulatory molecules. Furthermore, the expression of CCR7 was induced, suggesting an acquisition of migration capacity. Mature DCs were capable of stimulating allogeneic T cells, antigen-specific memory CD4؉ T cells, and HCV-specific CD8؉ -T-cell clones. In all cases, there was no evidence of HCV infection in DCs. Furthermore, these DCs maintained their phenotype and APC function after cryopreservation. Finally, no discernible differences were noted between DCs derived from HCV-infected and uninfected chimpanzees. In summary, precursor cells from HCV-infected chimpanzees are fully capable of differentiating into functional, mature DCs, which can now be reproducibly prepared for investigations of their immunotherapeutic potential in the setting of chronic HCV infection.Hepatitis C virus (HCV) infects an estimated 170 million persons worldwide and is a major cause of chronic liver disease, cirrhosis, and hepatocellular cancer (1). Only a portion of infected individuals resolve the infection (ϳ30%), with most developing a chronic infection. Acute infections are characterized by high frequencies of HCV-specific CD8 ϩ T cells (31, 52, 54) and HCV-specific CD4ϩ -T-cell responses that can persist for a long time after the clearance of viremia and the resolution of infection (54, 56). On the other hand, individuals who remain chronically infected display weak and restricted CD4 ϩ -and CD8ϩ -T-cell responses in both the liver and the blood (7,12,27,29,43,49,52). Significantly, only a small percentage respond to approved therapies, e.g., ribavarin and alpha interferon (IFN-␣) therapy.An understanding of viral persistence in HCV infections is essential for developing new strategies for preventing chronic HCV infections and for developing therapies which promote effective T-cell responses in already chronically infected patients. A promising and frequently used method for inducing or augmenting immune responses is dendritic cell (DC) vaccination. DC-based vaccines and immunotherapy against cancers and simi...

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“…In the case of HBV, surface antigen is usually the preferred antigen, [21][22][23] although core and X 24,25 have also been used. Similarly, for HCV, non-structural 3 (NS3) protein, [26][27][28][29][30] and to a lesser extent core protein, 26,27,31 have been employed. In all cases, the selected antigens should be those that in the course of natural infection provoke immune responses capable of clearing the pathogen.…”

Section: Induction Of Antitumor and Antiviral Immunity Using Engineermentioning

confidence: 99%

“…Again, adenoviruses have been the vectors of choice for gene transfer to DCs, [26][27][28][29][30][31] although other systems have been utilized including adeno-associated viruses, 25 retroviruses 24 and mRNA transfection. 31 By employing this strategy, DCs transfected with viral genes have demonstrated a remarkable ability to induce antiviral T-cell responses both in vitro and in vivo, being in some cases stronger than those obtained by direct administration of the vector encoding the viral antigen. 30 There is, therefore, a need for pilot clinical trials to determine whether the injection of transduced DCs could be an effective procedure for therapeutic vaccination against HCV and HBV virus infections.…”

Section: Induction Of Antitumor and Antiviral Immunity Using Engineermentioning

confidence: 99%

Cells as vehicles for therapeutic genes to treat liver diseases

et al. 2008

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Induction of hepatitis C virus-specific cytotoxic T lymphocytes in mice by immunization with dendritic cells transduced with replication-defective recombinant adenovirus

Cited by 34 publications

References 46 publications

Hepatitis C Virus Structural Proteins Impair Dendritic Cell Maturation and Inhibit In Vivo Induction of Cellular Immune Responses

Hepatitis C Virus Structural Proteins Impair Dendritic Cell Maturation and Inhibit In Vivo Induction of Cellular Immune Responses

Lack of Phenotypic and Functional Impairment in Dendritic Cells from Chimpanzees Chronically Infected with Hepatitis C Virus

Cells as vehicles for therapeutic genes to treat liver diseases

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