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Crosignani A, Riva A, Della Bella S. Analysis of peripheral blood dendritic cells as a non-invasive tool in the follow-up of patients with chronic hepatitis C. World J Gastroenterol 2016; 22:1393-1404. [PMID: 26819508 PMCID: PMC4721974 DOI: 10.3748/wjg.v22.i4.1393] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 09/11/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) has a high propensity to establish chronic infections. Failure of HCV-infected individuals to activate effective antiviral immune responses is at least in part related to HCV-induced impairment of dendritic cells (DCs) that play a central role in activating T cell responses. Although the impact of HCV on DC phenotype and function is likely to be more prominent in the liver, major HCV-induced alterations are detectable in peripheral blood DCs (pbDCs) that represent the most accessible source of DCs. These alterations include numerical reduction, impaired production of inflammatory cytokines and increased production of immunosuppressive IL10. These changes in DCs are relevant to our understanding the immune mechanisms underlying the propensity of HCV to establish persistent infection. Importantly, the non-invasive accessibility of pbDCs renders the analysis of these cells a convenient procedure that can be serially repeated in patient follow-up. Accordingly, the study of pbDCs in HCV-infected patients during conventional treatment with pegylated interferon and ribavirin indicated that restoration of normal plasmacytoid DC count may represent an additional mechanism contributing to the efficacy of the dual therapy. It also identified the pre-treatment levels of plasmacytoid DCs and IL10 as putative predictors of response to therapy. Treatment of chronic HCV infection is changing, as new generation direct-acting antiviral agents will soon be available for use in interferon-free therapeutic strategies. The phenotypic and functional analysis of pbDCs in this novel therapeutic setting will provide a valuable tool for investigating mechanisms underlying treatment efficacy and for identifying predictors of treatment response.
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Contradictory immune response in post liver transplantation hepatitis B and C. Int J Inflam 2014; 2014:814760. [PMID: 25215259 PMCID: PMC4158295 DOI: 10.1155/2014/814760] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 08/10/2014] [Accepted: 08/10/2014] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B and C often progress to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). After OLT, hepatitis B recurrence is clinically controlled with a combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using a HBV envelope antigen vaccine. Patients who had not been HBV carriers such as acutely infected liver failure or who received liver from HBV self-limited donor are good candidate. For chronic HBV carrier patients, a successful response can only be achieved in selected patients such as those treated with experimentally reduced immunosuppression protocols or received an anti-HBV adaptive memory carrying donor liver. Hepatitis C virus (HCV) reinfects transplanted livers at a rate of >90%. HCV reinfected patients show different severities of hepatitis, from mild and slowly progressing to severe and rapidly progressing, possibly resulting from different adaptive immune responses. More than half the patients require interferon treatment, although the success rate is low and carries risks for leukocytopenia and rejection. Managing the immune response has an important role in controlling recurrent hepatitis C. This study aimed to review the adaptive immune response in post-OLT hepatitis B and C.
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Sehgal M, Khan ZK, Talal AH, Jain P. Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle? Virology (Auckl) 2013; 4:1-25. [PMID: 25512691 PMCID: PMC4222345 DOI: 10.4137/vrt.s11046] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them. Modulation of the immunological synapse between DC and T-cell, as well as dysregulation of the crosstalk between DCs and natural killer (NK) cells, are emerging as two crucial mechanisms. This review focuses on understanding the interaction of HIV-1 and HCV with DCs not only to understand the immunopathogenesis of chronic HIV-1 and HCV infection, but also to explore the possibilities of DC-based immunotherapeutic approaches against them. Host genetic makeup is known to play major roles in infection outcome and rate of disease progression, as well as response to anti-viral therapy in both HIV-1 and HCV-infected individuals. Therefore, we highlight the genetic variations that can potentially affect DC functions, especially in the setting of chronic viral infection. Altogether, we address if DCs’ potential as critical effectors of antiviral immune response could indeed be utilized to combat chronic infection with HIV-1 and HCV.
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Affiliation(s)
- Mohit Sehgal
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Andrew H Talal
- Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
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Kanto T, Inoue M, Oze T, Miyazaki M, Sakakibara M, Kakita N, Matsubara T, Higashitani K, Hagiwara H, Iio S, Katayama K, Mita E, Kasahara A, Hiramatsu N, Takehara T, Hayashi N. Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-α and ribavirin therapy for chronic hepatitis C patients. J Gastroenterol 2012; 47:169-78. [PMID: 21947705 DOI: 10.1007/s00535-011-0466-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 08/03/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND For the treatment of chronic hepatitis C, a combination of pegylated interferon-α (PEG-IFNα) and ribavirin has been widely used as a standard of care. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. Our aim was to elucidate whether or not the frequency or function of blood cells is related to the outcome of the therapy. METHODS Sixty-seven chronic hepatitis C patients with high viral load of HCV genotype 1 infection who underwent 48 weeks of PEG-IFNα2b and ribavirin therapy were examined. During the treatment, frequencies of myeloid or plasmacytoid dendritic cells, Th1, Th2 cells, NK cells, and regulatory T cells were phenotypically determined. RESULTS Among the patients enrolled, 29 showed a sustained virological response (SVR), 18 a transient response (TR) and 17 no response (NR). The clinical and immunological markers were compared between the SVR and non-SVR patients, including TR and NR. Based on clinical, histological, immunological parameters, and cumulative dosage of PEG-IFNα2b and ribavirin, multivariate analyses revealed that higher platelet counts and higher regulatory T cell frequency at week 12 are indicative of SVR. Even in patients who attained complete early virological response at week 12, multivariate analyses disclosed that higher platelet counts and higher plasmacytoid dendritic cell frequency are indicative of SVR. CONCLUSIONS In PEG-IFNα and ribavirin combination therapy for chronic hepatitis C patients, the increments of regulatory T cells and plasmacytoid dendritic cell frequency are independently related to favorable virological response to the therapy.
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Affiliation(s)
- Tatsuya Kanto
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
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Hammond T, Lee S, Watson MW, Flexman JP, Cheng W, Price P. Decreased IFNγ production correlates with diminished production of cytokines by dendritic cells in patients infected with hepatitis C virus and receiving therapy. J Viral Hepat 2011; 18:482-92. [PMID: 20529204 DOI: 10.1111/j.1365-2893.2010.01331.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Toll-like receptor (TLR) expression and the signalling pathways that lead to the production of accessory cytokines by antigen-presenting cells (APCs) both have potential to limit T-cell responses to viral antigens. Here, expression of TLR and retinoic acid inducible gene I (RIG-I) and responses evoked through these proteins were evaluated in patients chronically infected with HCV, before and during pegylated interferon-α (IFNα) and ribavirin therapy. Expression of TLR2, 3, 4, 7, 9 and RIG-I on APCs and cytokine production by DCs were measured by flow cytometry. Production of IL-12 by myeloid dendritic cells (mDCs), IFNα by plasmacytoid cells (pDCs) and IFNγ by peripheral blood mononuclear cells was measured after stimulation with TLR ligands. IFNγ ELISpot responses to HCV and CMV antigens declined on therapy. TLR and RIG-I expression on mDCs, pDCs, B cells and monocytes was either similar or higher in patients than that in controls and generally increased during therapy. Therapy impaired IL-12 and IFNα production by DCs and reduced production of IFNγ by PBMCs after stimulation with ligands for TLR3, TLR7/8, TLR9 and RIG-I. This was independent of whether patients attained a sustained virological response. HCV disease and interferon-based therapy reduced IFN-γ responses to HCV antigens and TLR agonists. This was not accompanied by reduced expression of pertinent TLR but correlated with diminished production of co-stimulatory cytokines by DCs stimulated via TLR.
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Affiliation(s)
- T Hammond
- School of Pathology and Laboratory Medicine, University of Western Australia, WA, Australia
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Dolganiuc A, Szabo G. Dendritic cells in hepatitis C infection: can they (help) win the battle? J Gastroenterol 2011; 46:432-47. [PMID: 21327958 DOI: 10.1007/s00535-011-0377-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 12/13/2010] [Indexed: 02/04/2023]
Abstract
Infection with hepatitis C virus (HCV) is a public health problem; it establishes a chronic course in ~85% of infected patients and increases their risk for developing liver cirrhosis, hepatocellular carcinoma, and significant extrahepatic manifestations. The mechanisms of HCV persistence remain elusive and are largely related to inefficient clearance of the virus by the host immune system. Dendritic cells (DCs) are the most efficient inducers of immune responses; they are capable of triggering productive immunity and maintaining the state of tolerance to self- and non-self antigens. During the past decade, multiple research groups have focused on DCs, in hopes of unraveling an HCV-specific DC signature or DC-dependent mechanisms of antiviral immunity which would lead to a successful HCV elimination strategy. This review incorporates the latest update in the current status of knowledge on the role of DCs in anti-HCV immunity as it relates to several challenging questions: (a) the phenotype and function of diverse DC subsets in HCV-infected patients; (b) the characteristics of non-human HCV infection models from the DCs' point of view; (c) how can in vitro systems, ranging from HCV protein- or peptide-exposed DC to HCV protein-expressing DCs, and in vivo systems, ranging from HCV protein-expressing transgenic mice to HCV-infected non-human primates, be employed to dissect the role of DCs in triggering/maintaining a robust antiviral response; and (d) the prospect of DC-based strategy for managing and finding a cure for HCV infection.
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Affiliation(s)
- Angela Dolganiuc
- Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB-270-H, Worcester, MA 01605, USA.
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Takaki A, Tatsukawa M, Iwasaki Y, Koike K, Noguchi Y, Shiraha H, Sakaguchi K, Nakayama E, Yamamoto K. Hepatitis C virus NS4 protein impairs the Th1 polarization of immature dendritic cells. J Viral Hepat 2010; 17:555-562. [PMID: 19804500 PMCID: PMC2916225 DOI: 10.1111/j.1365-2893.2009.01213.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Dendritic cells (DCs) in chronic hepatitis C patients display impaired function, although the details remain unclear. To investigate the hepatitis C virus (HCV) protein that has the most impact on DC function, we compared five recombinant proteins and seven HCV protein genes in modulating DC phenotype and function. Immature DCs (iDCs) were established from healthy donor peripheral blood monocytes with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4. Lipopolysaccharide was used to establish mature DCs (mDCs). Cells were then pulsed with HCV recombinant proteins or transfected with HCV plasmids and subsequently assayed for cell surface marker expression by flow cytometry. For cytokine and proliferative T-cell response analysis, DCs were cultured with autologous CD4 T cells and tuberculin purified protein derivative (PPD). Mean fluorescent intensity of CD86 was reduced in HCV protein-pulsed iDCs. Proliferative T-cell responses and Th1 cytokine concentrations were reduced with HCV nonstructural proteins (NS), particularly with HCV NS4. HCV nonstructural proteins, particularly NS4, change the iDC phenotype and reduce antigen-specific T-cell stimulatory function with Th1 cytokine reductions.
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Affiliation(s)
- A Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
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Lee S, Watson MW, Flexman JP, Cheng W, Hammond T, Price P. Increased proportion of the CD56(bright) NK cell subset in patients chronically infected with hepatitis C virus (HCV) receiving interferon-alpha and ribavirin therapy. J Med Virol 2010; 82:568-74. [PMID: 20166183 DOI: 10.1002/jmv.21742] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Natural killer (NK) cells are implicated in the regulation of a protective immune response in patients chronically infected with hepatitis C virus (HCV), but effects of interferon-alpha/ribavirin therapy on NK cell subsets and the consequences of viral clearance during therapy remain unclear. Samples were collected from chronically infected patients (n = 34) at baseline and from a subset after 3-10 months on pegylated interferon-alpha and ribavirin therapy (n = 19). NK cells present in cryopreserved PBMC were characterized by flow cytometry. Before therapy, the frequency of CD3-CD56+ NK cells was lower in patients than uninfected controls. Therapy increased proportions of CD56(bright) NK cells. Frequencies of CD56(dim) NK cells declined slightly while perforin and CD16 expression on CD56(dim) NK cells decreased compared to baseline samples. Evaluation of NK cell subsets at baseline did not identify patients able to achieve sustained virological response following therapy. However, therapy may promote the expansion of NK cells able to produce interferon-gamma, while minimizing cytotoxicity to limit liver damage.
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Affiliation(s)
- Silvia Lee
- Department of Microbiology and Infectious Disease, Royal Perth Hospital, Perth, Western Australia, Australia.
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Hiramatsu N, Oze T, Yakushijin T, Inoue Y, Igura T, Mochizuki K, Imanaka K, Kaneko A, Oshita M, Hagiwara H, Mita E, Nagase T, Ito T, Inui Y, Hijioka T, Katayama K, Tamura S, Yoshihara H, Imai Y, Kato M, Yoshida Y, Tatsumi T, Ohkawa K, Kiso S, Kanto T, Kasahara A, Takehara T, Hayashi N. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin. J Viral Hepat 2009; 16:586-94. [PMID: 19552664 DOI: 10.1111/j.1365-2893.2009.01106.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg-IFN) and ribavirin for patients with chronic hepatitis C (CH-C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty-four patients with CH-C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis (P = 0.002), the timing of HCV RNA negativiation (P < 0.001) and the mean doses of ribavirin (P < 0.001) were significantly associated with relapse, but those of Peg-IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c-EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given > or = 12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg-IFN could be reduced to 0.6 microg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose-dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (> or = 12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg-IFN alpha-2b plus ribavirin, especially in c-EVR patients.
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Affiliation(s)
- N Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
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Cicinnati VR, Kang J, Sotiropoulos GC, Hilgard P, Frilling A, Broelsch CE, Gerken G, Beckebaum S. Altered chemotactic response of myeloid and plasmacytoid dendritic cells from patients with chronic hepatitis C: role of alpha interferon. J Gen Virol 2008; 89:1243-1253. [PMID: 18420803 DOI: 10.1099/vir.0.83517-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Dendritic cell (DC) frequencies in the blood of patients with chronic hepatitis C virus (HCV) infection have been shown to be reduced significantly compared with those in healthy individuals. There is a further reduction of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in HCV patients receiving alpha interferon (IFN-alpha)-based antiviral therapy. Altered homing behaviour of DCs may be a possible mechanism for their 'loss' in peripheral blood in these clinical conditions. Systemic chemokine levels were measured by ELISA. Phenotypes and migratory properties of MDCs and PDCs from HCV patients were analysed by flow cytometry and chemotaxis assay. Compared with healthy controls, HCV patients had increased serum levels of inflammatory and constitutively expressed chemokines. Spontaneously generated MDCs from HCV patients were less mature, and both MDCs and PDCs showed intrinsic activation of receptors for inflammatory chemokines, thus suggesting an increased propensity to migrate towards inflammatory sites. IFN-alpha treatment in vitro induced MDC maturation and skewed the migratory response of both MDCs and PDCs towards chemokines expressed constitutively in secondary lymphoid organs. In conclusion, our results hint at altered homing behaviour of DCs during chronic HCV infection. IFN-alpha therapy may redirect DC migration from inflamed hepatic portal areas towards secondary lymphoid tissue.
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Affiliation(s)
- Vito R Cicinnati
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Germany
| | - Jinyu Kang
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Germany
| | - Georgios C Sotiropoulos
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Germany
| | - Philip Hilgard
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Germany
| | - Andrea Frilling
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Germany
| | - Christoph E Broelsch
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Germany
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Germany
| | - Susanne Beckebaum
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Germany
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