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Park SJ, Hahn YS. Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment. Clin Mol Hepatol 2023; 29:65-76. [PMID: 35957546 PMCID: PMC9845665 DOI: 10.3350/cmh.2022.0032] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 08/11/2022] [Indexed: 02/02/2023] Open
Abstract
Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.
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Affiliation(s)
- Soo-Jeung Park
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA
| | - Young S. Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA,Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA,Corresponding author : Young S. Hahn Department of Microbiology, Immunology and Cancer Biology, University of Virginia, 345 Crispell Dr, Charlottesville, VA 22908, USA Tel: +1-434-924-1275, Fax: +1-434-924-1221, E-mail:
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Rinaldi L, Perrella A, Guarino M, De Luca M, Piai G, Coppola N, Pafundi PC, Ciardiello F, Fasano M, Martinelli E, Valente G, Nevola R, Monari C, Miglioresi L, Guerrera B, Berretta M, Sasso FC, Morisco F, Izzi A, Adinolfi LE. Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study. J Transl Med 2019; 17:292. [PMID: 31462268 PMCID: PMC6712712 DOI: 10.1186/s12967-019-2033-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 08/18/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND An unexpected increased HCC recurrence and occurrence rate among HCV patients treated with direct acting antivirals combination has been reported. Aim of the study was the evaluation of early HCC occurrence rate and its risk factors in a HCV infected population, treated with direct-acting-antivirals. METHODS According to the Italian ministerial guidelines for direct-acting-antivirals treatment, 1022 consecutive HCV patients treated with direct-acting-antivirals were enrolled. Patients either with active HCC at imaging or history of previous treated HCC, HBV or HIV co-infection, or liver transplant recipients were excluded. The SVR, defined as the persistent absence of detectable serum HCV-RNA 12 weeks after the end of treatment (SVR12), was assessed for all enrolled patients. Abdominal ultrasound was performed before starting antiviral therapy, and repeated every 6 months. HCC was diagnosed according to the international guidelines. Patients showing either nodular patterns suggestive of HCC or with uncertain dynamic vascular behaviour were excluded from a further follow-up. RESULTS Nine hundred and eighty-five patients completed the 48 weeks follow-up after the end of treatment. A Sofosbuvir-based regimen was administered in the 74.9% of patients, among whom, the 71.6% underwent a simultaneous Ribavirin administration. A sustained virological response at 12 weeks off treatment was documented in 966 patients (98.2%). During the post treatment follow-up HCC was detected in 35 patients, with a cumulative incidence rate of the 3.55%. At multivariate analysis, four variables resulted independently associated with HCC development, both in a cirrhosis based and a class B Child based model, respectively: cirrhosis/class B Child, therapeutic schedule including Sofosbuvir without Ribavirin, liver stiffness values, male gender and presence of diabetes. A multivariate analysis performed on Child A cirrhotic patients, showed that Sofosbuvir based therapeutic treatment without Ribavirin had a HCC occurrence 5.7 higher than Ribavirin-based schedules with or without Sofosbuvir (p < 0.0001, OR: 5.686, 95% CI 2.455-13.169). CONCLUSIONS Our data suggest that early HCC occurrence appears more frequently related to Sofosbuvir-based therapy without Ribavirin which, indeed, seems to play a protective role on HCC onset. Therefore, a careful follow-up should be mandatory, especially in those regimens including Sofosbuvir without Ribavirin.
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Affiliation(s)
- Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
| | - Alessandro Perrella
- Immunological and Neurological Infectious Diseases Unit, Cotugno Hospital, Naples, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy
| | - Massimo De Luca
- Hepatology and Pancreas Unit, Cardarelli Hospital, Naples, Italy
| | - Guido Piai
- Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy
| | - Nicola Coppola
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Fortunato Ciardiello
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Morena Fasano
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Erika Martinelli
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giovanna Valente
- Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Caterina Monari
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Lucia Miglioresi
- Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy
| | | | - Massimiliano Berretta
- Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori Aviano, Aviano, PN, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy
| | - Antonio Izzi
- Immunological and Neurological Infectious Diseases Unit, Cotugno Hospital, Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Asghar K, Farooq A, Zulfiqar B, Rashid MU. Indoleamine 2,3-dioxygenase: As a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma. World J Gastroenterol 2017; 23:2286-2293. [PMID: 28428708 PMCID: PMC5385395 DOI: 10.3748/wjg.v23.i13.2286] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/23/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
Tumor cells induce an immunosuppressive microenvironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma (HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immunosuppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC.
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Abstract
Hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are responsible for most cases of viral hepatitis. Infection by each type of virus results in a different typical natural disease course and clinical outcome that are determined by virological and immunological factors. HCV tends to establish a chronic persistent infection, whereas HAV does not. HBV is effectively controlled in adults, although it persists for a lifetime after neonatal infection. In this Review, we discuss the similarities and differences in immune responses to and immunopathogenesis of HAV, HBV and HCV infections, which may explain the distinct courses and outcomes of each hepatitis virus infection.
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Basnayake SK, Easterbrook PJ. Wide variation in estimates of global prevalence and burden of chronic hepatitis B and C infection cited in published literature. J Viral Hepat 2016; 23:545-59. [PMID: 27028545 DOI: 10.1111/jvh.12519] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 01/14/2016] [Indexed: 12/15/2022]
Abstract
To evaluate the extent of heterogeneity in global estimates of chronic hepatitis B (HBV) and C (HCV) cited in the published literature, we undertook a systematic review of the published literature. We identified articles from 2010 to 2014 that had cited global estimates for at least one of ten indicators [prevalence and numbers infected with HBV, HCV, HIV-HBV or HIV-HCV co-infection, and mortality (number of deaths annually) for HBV and HCV]. Overall, 488 articles were retrieved: 239 articles cited a HBV-related global estimate [prevalence (n = 12), number infected (n = 193) and number of annual deaths (n = 82)]; 280 articles had HCV-related global estimates [prevalence (n = 86), number infected (n = 203) and number of annual deaths (n = 31)]; 31 had estimates on both HBV and HCV; 54 had HIV-HBV co-infection estimates [prevalence (n = 42) and number co-infected (n = 12)]; and 68 had estimates for HIV-HCV co-infection [prevalence (n = 40) and number co-infected (n = 28)]. There was considerable heterogeneity in the estimates cited and also a lack of consistency in the terminology used. Although 40% of 488 articles cited WHO as the source of the estimate, many of these were from outdated or secondary sources. Our findings highlight the importance of clear and consistent communication from WHO and other global health agencies on current consensus estimates of hepatitis B and C burden and prevalence, the need for standardisation in their citation, and for regular updates.
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Affiliation(s)
| | - P J Easterbrook
- Global Hepatitis Programme, HIV Department, World Health Organization, Geneva, Switzerland
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Barjon C, Dahlqvist G, Calmus Y, Conti F. Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence. Dig Liver Dis 2015. [PMID: 26216068 DOI: 10.1016/j.dld.2015.06.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis C viral infection persists and becomes chronic in a majority of affected individuals. Numerous factors have been described to explain how the virus manages to escape the host immune system. One important escape mechanism is the increase in regulatory T cells induced by the virus. In this review, we will focus on the status of regulatory T cells throughout the natural history of hepatitis C infection and after liver transplantation. The molecular mechanisms involved in increasing the number of regulatory T cells are also discussed, as are data regarding the impact of regulatory T-cells on hepatic fibrosis in the context of hepatitis C viral infection.
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Affiliation(s)
- Clément Barjon
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France.
| | - Géraldine Dahlqvist
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France
| | - Yvon Calmus
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France; Department of Hepatology and Gastroenterology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Filomena Conti
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France; Department of Hepatology and Gastroenterology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
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Asghar K, Ashiq MT, Zulfiqar B, Mahroo A, Nasir K, Murad S. Indoleamine 2,3-dioxygenase expression and activity in patients with hepatitis C virus-induced liver cirrhosis. Exp Ther Med 2014; 9:901-904. [PMID: 25667650 PMCID: PMC4316896 DOI: 10.3892/etm.2014.2146] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 10/21/2014] [Indexed: 12/20/2022] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme. It plays a key role in various malignancies, infection and autoimmune diseases. IDO induces immunosuppression through the depletion of tryptophan and its downstream metabolites. Hepatitis C virus (HCV) has infected more than 12 million individuals in Pakistan. The aim of the present study was to assess the expression and activity of IDO in HCV-infected patients. The functional enzymatic activity of IDO was measured by colorimetric assay. Serum samples from 100 HCV-infected patients were taken to examine IDO activity and samples from 100 healthy volunteers were used as controls. Liver sections from patients with HCV (n=35) and healthy controls (n=5) were used for immunohistochemical studies. Immunohistochemical analysis revealed that IDO was overexpressed in 28 of 35 (80%) cirrhotic liver samples, whereas 5 of 35 (14.2%) cases presented moderate and 2 of 35 (5.7%) cases presented mild expression of IDO. The enzymatic activity of IDO was significantly higher in the serum samples of HCV-infected patients as compared with those in the control. These data indicate that the expression of IDO correlated with the pathogenesis of disease. In summary, it is suggested that the high expression of IDO in the progressively cirrhotic livers of HCV-infected patients might contribute to the development of hepatocellular carcinoma. IDO may characterize a novel therapeutic target against HCV.
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Affiliation(s)
- Kashif Asghar
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - M Taimour Ashiq
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - Bilal Zulfiqar
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - Amnah Mahroo
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - Kaenat Nasir
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - Sheeba Murad
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
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Hetta HF, Mehta MJ, Shata MTM. Gut immune response in the presence of hepatitis C virus infection. World J Immunol 2014; 4:52-62. [DOI: 10.5411/wji.v4.i2.52] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/22/2014] [Accepted: 06/20/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) is an important etiologic agent of hepatitis and a major cause of chronic liver infection that often leads to cirrhosis, fibrosis and hepatocellular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extra-hepatic in the gastrointestinal tissue which could serve as a reservoir for HCV. The outcome of HCV infection depends mainly on the host innate and adaptive immune responses. Innate immunity against HCV includes mainly nuclear factor cells and activation of IFN-related genes. There is an immunologic link between the gut and the liver through a population of T-cells that are capable of homing to both the liver and gut via the portal circulation. However, little is known on the role of Gut immune response in HCV. In this review we discussed the immune regulation of Gut immune cells and its association with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver inflammation. Additionally, we investigated the relationship between Gut immune responses to HCV and IL28B genotypes, which were identified as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.
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Rathod SB, Das R, Thanapati S, Arankalle VA, Tripathy AS. Suppressive activity and altered conventional phenotype markers/mediators of regulatory T cells in patients with self-limiting hepatitis E. J Viral Hepat 2014; 21:141-51. [PMID: 24383927 DOI: 10.1111/jvh.12125] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 06/05/2013] [Indexed: 01/01/2023]
Abstract
Hepatitis E virus (HEV) is a major cause of self-limiting acute viral hepatitis in several developing countries. Elevated levels of peripheral CD4(+) CD25(+) Foxp3(+) , CD4(+) CD25(-) Foxp3(+) and rise in IL-10 in hepatitis E have been associated with the involvement of regulatory T cells (Treg). The functional role of the same is yet elusive. In the current study, we have assessed (i) Foxp3 expression by real-time PCR and by flow cytometry, (ii) the levels of antigen-specific IL-10 and TGF-β by ELISA, (iii) functional analysis of Treg cells and (iv) expression of Treg-associated conventional phenotypes by flow cytometry in 54 acute patients, 44 recovered individuals from hepatitis E and in 33 healthy controls. Foxp3 mRNA elevation in the acute compared with recovered group and elevation in Foxp3(+) cells in both patient groups were significantly elevated. The levels of IL-10 and TGF-β in the acute patients and TGF-β in the recovered individuals were elevated. Significantly higher expression of CTLA-4, PD1, GITR, CD95, CD103 and CD73 on Treg and T effector (Teff) cells was detected in the patient groups. Treg cells of acute patients and recovered individuals exhibited suppressive activity indicating that the Treg cells of hepatitis E patients are functional. The suppressive capacity of Treg cells in acute hepatitis E patients was significantly higher compared with the recovered individuals. Based on our findings, the suppressive functionality of these key markers associated with hepatitis E Treg function need further exploration to get a better understanding of the mechanisms of Treg-mediated suppression.
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Affiliation(s)
- S B Rathod
- Hepatitis Group, National Institute of Virology, Pune, India
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Cao H, Wen P, Ye H, Sun Z, Shen X, Wu X, Dai C, Yang J. A study of the immunoloregulation of double filtration plasmapheresis in maintenance hemodialysis patients with chronic hepatitis C. PLoS One 2013; 8:e82524. [PMID: 24358197 PMCID: PMC3864956 DOI: 10.1371/journal.pone.0082524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 10/24/2013] [Indexed: 11/29/2022] Open
Abstract
Although a large number of drugs have been used to treat chronic hepatitis C (CHC), there still remains a great challenge to treat maintenance hemodialysis (MHD) patients with chronic hepatitis C. To clarify the immunnoloregulation of double filtration plasmapheresis (DFPP) in MHD patients with CHC, DFPP was performed in 20 MHD patients with CHC (HCV-antibody positive, serum HCV RNA >500 IU/ml more than 6 months and HCV genotype 1b). The clinical data was collected and peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry at the time of hour 0, hour 3, day 3, day 7 and day 28 after the DFPP, respectively. Serum HCV particles could be removed partially by the DFPP. The titer of serum HCV RNA could remain in a lower level even 28 days after the treatment. Compared to MHD patients without HCV infection, the frequencies of innate immune cells were similar in MHD patients with CHC, while Th1/Th2 was elevated and the frequencies of regulatory T (Treg) cells were higher in those MHD patients with CHC. The frequencies of monocytes and natural killer (NK) cells remained after the DFPP in MHD patients with CHC. There were no significant changes of Th1, Th2 and Th1/Th2 in PBMC after DFPP. DFPP could reduce the frequencies of Th17 cells and Treg cells in PBMC from 7 days after DFPP in MHD patients with CHC. DFPP could partially remove the serum HCV particles mechanically. The titer of HCV RNA could remain in a lower level at least for 28 days probably due to the redistribution of the immunocytes in circulation.
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Affiliation(s)
- Hongdi Cao
- Center for Kidney Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ping Wen
- Center for Kidney Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Hong Ye
- Center for Kidney Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zhiping Sun
- Center for Kidney Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xia Shen
- Center for Kidney Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xiaochun Wu
- Center for Kidney Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Chunsun Dai
- Center for Kidney Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Junwei Yang
- Center for Kidney Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- * E-mail:
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Langhans B, Krämer B, Louis M, Nischalke HD, Hüneburg R, Staratschek-Jox A, Odenthal M, Manekeller S, Schepke M, Kalff J, Fischer HP, Schultze JL, Spengler U. Intrahepatic IL-8 producing Foxp3⁺CD4⁺ regulatory T cells and fibrogenesis in chronic hepatitis C. J Hepatol 2013; 59:229-35. [PMID: 23624000 DOI: 10.1016/j.jhep.2013.04.011] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/04/2013] [Accepted: 04/07/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions. METHODS Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C. RESULTS We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody. CONCLUSIONS Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.
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Affiliation(s)
- Bettina Langhans
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
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Kobayashi T, Nakatsuka K, Shimizu M, Tamura H, Shinya E, Atsukawa M, Harimoto H, Takahashi H, Sakamoto C. Ribavirin modulates the conversion of human CD4(+) CD25(-) T cell to CD4(+) CD25(+) FOXP3(+) T cell via suppressing interleukin-10-producing regulatory T cell. Immunology 2012; 137:259-70. [PMID: 22891772 DOI: 10.1111/imm.12005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Because regulatory T (Treg) cells play an important role in modulating the immune system response against both endogenous and exogenous antigens, their control is critical to establish immunotherapy against autoimmune disorders, chronic viral infections and tumours. Ribavirin (RBV), an antiviral reagent used with interferon, is known to polarize the T helper (Th) 1/2 cell balance toward Th1 cells. Although the immunoregulatory mechanisms of RBV are not fully understood, it has been expected that RBV would affect T reg cells to modulate the Th1/2 cell balance. To confirm this hypothesis, we investigated whether RBV modulates the inhibitory activity of human peripheral CD4(+) CD25(+) CD127(-) T cells in vitro. CD4(+) CD25(+) CD127(-) T cells pre-incubated with RBV lose their ability to inhibit the proliferation of CD4(+) CD25(-) T cells. Expression of Forkhead box P3 (FOXP3) in CD4(+) CD25(-) T cells was down-modulated when they were incubated with CD4(+) CD25(+) CD127(-) T cells pre-incubated with RBV without down-modulating CD45RO on their surface. In addition, transwell assays and cytokine-neutralizing assays revealed that this effect depended mainly on the inhibition of interleukin-10 (IL-10) produced from CD4(+) CD25(+) CD127(-) T cells. These results indicated that RBV might inhibit the conversion of CD4(+) CD25(-) FOXP3(-) naive T cells into CD4(+) CD25(+) FOXP3(+) adaptive Treg cells by down-modulating the IL-10-producing Treg 1 cells to prevent these effector T cells from entering anergy and to maintain Th1 cell activity. Taken together, our findings suggest that RBV would be useful for both elimination of long-term viral infections such as hepatitis C virus infection and for up-regulation of tumour-specific cellular immune responses to prevent carcinogenesis, especially hepatocellular carcinoma.
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Affiliation(s)
- Tamaki Kobayashi
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
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Dolganiuc A, Kodys K, Marshall C, Saha B, Zhang S, Bala S, Szabo G. Type III interferons, IL-28 and IL-29, are increased in chronic HCV infection and induce myeloid dendritic cell-mediated FoxP3+ regulatory T cells. PLoS One 2012; 7:e44915. [PMID: 23071503 PMCID: PMC3468613 DOI: 10.1371/journal.pone.0044915] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 08/09/2012] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) is difficult to eradicate and type III interferons (IFN-λ, composed of IL-28A, IL-28B and IL-29) are novel therapeutic candidates. We hypothesized that IFN-λ have immunomodulatory effects in HCV- infected individuals. MATERIALS AND METHODS We analyzed the expression of IFN-λ and its receptor (composed of IL-10R2 and IFN-λR subunits) in the blood and livers of patients with chronic (c)HCV infection compared to controls (those who cleared HCV by sustained virological response, SVR, and those with liver inflammation of non-viral origin, non-alcoholic steatohepatitis, NASH). We also compared the proliferative capacity of dendritic cells (DCs) obtained from healthy individuals and those with chronic HCV using a mixed leukocyte reaction combined with 3H-Td incorporation. In addition, the composition of the IFN-λ receptor (IFN-λR) on myeloid DCs, plasmacytoid DCs, PBMCs, and T cells was determined by FACS analysis. RESULTS We report that the expression of IFN-λ protein in serum and mRNA in liver is increased in cHCV patients, but not in those with HCV SVR or NASH, compared to controls. Liver level of IFN-λR mirrored the expression of serum IFN-λ and was higher in cHCV, compared to controls and HCV-SVR patients, suggesting that elevation of IFN-λ and IFN-λR are HCV-dependent. We further identified that innate immune cell populations expressed complete IFN-λ receptor. In vitro, recombinant IFN-λ promoted differentiation of monocyte-derived dendritic cells (DCs) into a phenotype with low T cell stimulatory capacity and high PD-L1 expression, which further promoted expansion of existing regulatory T cells. IFN-λ-DCs failed to induce de novo generation of regulatory T cells. The inhibitory capacity of IFN-λ-DCs was counteracted by recombinant IL-12 and by neutralization of the PD-1/PD-L1 system. CONCLUSIONS Our novel findings of the immunomodulatory effect of IFN-λ contribute to the understanding of the anti-inflammatory and/or anti-viral potential of IFN-λ in cHCV.
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Affiliation(s)
- Angela Dolganiuc
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Christopher Marshall
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Banishree Saha
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Shuye Zhang
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
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Brenndörfer ED, Sällberg M. Hepatitis C virus-mediated modulation of cellular immunity. Arch Immunol Ther Exp (Warsz) 2012; 60:315-29. [PMID: 22911132 DOI: 10.1007/s00005-012-0184-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2011] [Accepted: 03/09/2012] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic liver disease globally. A chronic infection can result in liver fibrosis, liver cirrhosis, hepatocellular carcinoma and liver failure in a significant ratio of the patients. About 170 million people are currently infected with HCV. Since 80 % of the infected patients develop a chronic infection, HCV has evolved sophisticated escape strategies to evade both the innate and the adaptive immune system. Thus, chronic hepatitis C is characterized by perturbations in the number, subset composition and/or functionality of natural killer cells, natural killer T cells, dendritic cells, macrophages and T cells. The balance between HCV-induced immune evasion and the antiviral immune response results in chronic liver inflammation and consequent immune-mediated liver injury. This review summarizes our current understanding of the HCV-mediated interference with cellular immunity and of the factors resulting in HCV persistence. A profound knowledge about the intrinsic properties of HCV and its effects on intrahepatic immunity is essential to be able to design effective immunotherapies against HCV such as therapeutic HCV vaccines.
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Affiliation(s)
- Erwin Daniel Brenndörfer
- Division of Clinical Microbiology F68, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
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15
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Autoimmune manifestations in viral hepatitis. Semin Immunopathol 2012; 35:73-85. [PMID: 23010889 DOI: 10.1007/s00281-012-0328-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 07/01/2012] [Indexed: 02/06/2023]
Abstract
Infections by the viruses responsible for hepatitis B, C and D are accompanied by a number of immunopathological manifestations. A link between infection and autoimmunity is particularly well documented for the hepatitis C virus. Immunopathological manifestations range from production of autoantibodies to overt autoimmune disease, including thyroiditis and autoimmune hepatitis, and to immune-complex-mediated disorders, including cryoglobulinaemia, glomerulonephritis and vasculitis. Several of these manifestations improve with successful antiviral treatment, directly incriminating the virus in their pathogenesis. Mechanisms considered responsible for hepatitis virus-related immunopathology, including molecular mimicry, impairment of regulatory T cells and activation of B lymphocytes, will be examined in this review.
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Ferri S, Lalanne C, Lanzoni G, Bassi M, Asioli S, Cipriano V, Pappas G, Muratori P, Lenzi M, Muratori L. Redistribution of regulatory T-cells across the evolving stages of chronic hepatitis C. Dig Liver Dis 2011; 43:807-813. [PMID: 21684822 DOI: 10.1016/j.dld.2011.04.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 04/06/2011] [Accepted: 04/28/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis C virus infection frequently leads to chronic hepatitis, possibly evolving to end-stage liver disease and hepatocellular carcinoma. Regulatory T cells can affect antiviral immune response thus influencing the outcome of the disease. AIM To determine numeric and functional distribution of regulatory T cells expressing CD4+CD25hiFoxp3+ (T-regs) during the different stages of hepatitis C virus-related liver disease. METHODS 90 hepatitis C viraemic patients and 50 healthy controls were included. Surface and intracellular (Foxp3) T-reg markers were evaluated by flow cytometry. Target cell proliferation and interferon-gamma production were evaluated in 37 HCV patients. In 16 cases intrahepatic distribution of Foxp3 by immuno-histochemistry was assessed. RESULTS T-regs were increased in hepatitis C virus infected patients and correlated inversely with aminotransferases and directly with MELD score and disease duration. A preserved inhibitory ability of interferon-gamma production was distinctive of patients with normal aminotransferases. Circulating T-regs did not correlate with intrahepatic distribution of Foxp3. CONCLUSIONS In chronic hepatitis C, selective expansion of peripheral T-regs in patients with normal aminotransferases and advanced disease suggests that, though a continual low level inflammation does not prevent liver disease progression, once cirrhosis has developed it may represent an attempt to prevent immuno-mediated decompensation.
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Affiliation(s)
- Silvia Ferri
- Department of Clinical Medicine, University of Bologna, Bologna, Italy.
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17
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Hall CHT, Kassel R, Tacke RS, Hahn YS. HCV+ hepatocytes induce human regulatory CD4+ T cells through the production of TGF-beta. PLoS One 2010; 5:e12154. [PMID: 20730048 PMCID: PMC2921368 DOI: 10.1371/journal.pone.0012154] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Accepted: 07/21/2010] [Indexed: 02/07/2023] Open
Abstract
Background Hepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease. Impaired T cell responses facilitate and maintain persistent HCV infection. Importantly, CD4+ regulatory T cells (Tregs) act by dampening antiviral T cell responses in HCV infection. The mechanism for induction and/or expansion of Tregs in HCV is unknown. Methodology/Principal Findings HCV-expressing hepatocytes were used to determine if hepatocytes are able to induce Tregs. The infected liver environment was modeled by establishing the co-culture of the human hepatoma cell line, Huh7.5, containing the full-length genome of HCV genotype 1a (Huh7.5-FL) with activated CD4+ T cells. The production of IFN-γ was diminished following co-culture with Huh7.5-FL as compared to controls. Notably, CD4+ T cells in contact with Huh7.5-FL expressed an increased level of the Treg markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells. Importantly, HCV+ hepatocytes upregulated the production of TGF-β and blockade of TGF-β abrogated Treg phenotype and function. Conclusions/Significance These results demonstrate that HCV infected hepatocytes are capable of directly inducing Tregs development and may contribute to impaired host T cell responses.
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Affiliation(s)
- Caroline H. T. Hall
- Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America
| | - Rachel Kassel
- Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America
| | - Robert S. Tacke
- Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America
| | - Young S. Hahn
- Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America
- Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail:
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Core-specific adaptive regulatory T-cells in different outcomes of hepatitis C. Clin Sci (Lond) 2010; 119:97-109. [PMID: 20222873 DOI: 10.1042/cs20090661] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
CD4+ Treg-cells (regulatory T-cells) probably contribute to the impaired virus-specific T-cell responses in chronic HCV (hepatitis C virus) infection; however, their antigen-specificity has remained elusive. In the present study, we analysed peripheral blood CD4+ Treg-cells in patients with chronic hepatitis C and subjects with self-limited HCV infection and characterized individual Treg-cell clones obtained from both groups at the phenotypic and functional level. Foxp3 (forkhead box p3)+CD25+CD4+ Treg-cells were detected more frequently in patients with chronic hepatitis C than self-limited HCV infection, which responded to HCV core stimulation and inhibited proliferation of reporter cells. Cloning under limiting dilution conditions resulted in 14 and six hypoproliferative Foxp3+CD25+CD127-CD4+ T-cell clones from patients with chronic hepatitis C and subjects with self-limited HCV infection respectively. All clones expressed Treg-cell markers and produced IL (interleukin)-10 upon mitogen stimulation. However, exclusively Treg-cell clones from chronic hepatitis C produced IL-10 in response to HCV core and inhibited proliferation of reporter T-cells. These core-specific Treg-cell clones recognized epitopes in two regions of HCV core (amino acids 1-44 and 79-113). Co-culture inhibition assays demonstrated Treg-cells to inhibit reporter T-cells via secretion of IL-10 and IL-35 rather than cell-contact-dependent mechanisms. Finally, the HCV-specific Treg-cell clones lost their functional capacity, along with Foxp3 expression, if kept in culture without HCV core exposure. In conclusion, we identified functionally active HCV core-specific Treg-cells in patients with chronic hepatitis C, which share their epitopes with conventional T-cells and require the continued presence of antigen to maintain their functional differentiation. Thus HCV core-specific Treg-cells may contribute to the immunoregulatory balance in chronic hepatitis C.
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Perrella A, Grattacaso S, d'Antonio A, Atripaldi L, Sbreglia C, Gnarini M, Conti P, Vecchiet J, Perrella O. Evidence of hepatitis C virus-specific interferon gamma-positive T cells in health care workers in an infectious disease department. Am J Infect Control 2009; 37:426-429. [PMID: 19155099 DOI: 10.1016/j.ajic.2008.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2008] [Revised: 08/26/2008] [Accepted: 08/28/2008] [Indexed: 02/05/2023]
Abstract
BACKGROUND Few studies are available on possible hepatitis C virus (HCV)-specific T-cell immune response in health care workers (HCWs) involved in the care of patients with HCV infection. We aimed to investigate whether a HCV-specific interferon (IFN)-gamma T-cell response, known to be involved in infection resolution, was present in those HCWs involved in the management of patients with persistent HCV infection. METHODS Our study involved 30 subjects, classified as group A (20 consecutive patients, 16 males and 4 females, with histologically proven chronic hepatitis), or group B (10 HCWs, 7 males and 3 females, with at least 7 years of health care experience and HCV-RNA and anti-HCV negative). As a control group, we used 10 blood samples from healthy donors at a blood donor center (group C). HCV-RNA was measured by real-time polymerase chain reaction. Blood samples (at least 35 mL) were collected from all group A and group B subjects in our hospital. Specific IFN-gamma was stimulated with HCV pool peptides (core, 2 microg/mL), with influenza Mp peptides used as a positive control. RESULTS Levels of HCV-specific IFN-gamma-positive cells were higher in the HCWs (group B) compared with the infected patients (group A) and healthy blood donors (group C) (Mann-Whitney U test, P < .001). CONCLUSION A clinically silent persistent exposure to HCV, through some as-yet undetermined mechanism, may induce a virus-specific IFN-gamma-producing CD8(+) T-cell response in healthy aviremic HCWs. This finding suggests that possible unapparent parenteral routes may stimulate host defenses with no evidence of hepatitis.
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Affiliation(s)
- Alessandro Perrella
- Department of Infectious Disease and Immunology, Hospital D. Cotugno, Naples, Italy.
| | - Stella Grattacaso
- Department of Infectious Disease and Immunology, Hospital D. Cotugno, Naples, Italy
| | - Anna d'Antonio
- Department of Infectious Disease and Immunology, Hospital D. Cotugno, Naples, Italy
| | - Luigi Atripaldi
- Department of Infectious Disease and Immunology, Hospital D. Cotugno, Naples, Italy
| | - Costanza Sbreglia
- Department of Infectious Disease and Immunology, Hospital D. Cotugno, Naples, Italy
| | - MariaRosaria Gnarini
- Department of Infectious Disease and Immunology, Hospital D. Cotugno, Naples, Italy
| | - Pio Conti
- Department of Immunology, School of Medicine, G.D'Annunzio University, Chieti, Italy
| | - Jacopo Vecchiet
- Infectious Disease Department, G.D'Annunzio University, Chieti, Italy
| | - Oreste Perrella
- Department of Infectious Disease and Immunology, Hospital D. Cotugno, Naples, Italy
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Perrella A, Arenga G, Pisaniello D, Rampone B, Di Costanzo GG, Atripaldi L, Esposito C, Di Florio E, Perrella O, Cuomo O. Elevated CD4+/CD25+ T-cell frequency and function during hepatitis C virus recurrence after liver transplantation. Transplant Proc 2009; 41:1761-1766. [PMID: 19545723 DOI: 10.1016/j.transproceed.2009.01.112] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2008] [Accepted: 01/08/2009] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIM Factors involved in hepatitis C virus (HCV) recurrence versus acute cellular rejection are not fully understood. The aim of the present study was to investigate whether patients with recurrence after liver transplantation (OLT) showed similar CD4(+)/CD25(+) cell frequency and function as those who became chronically infected. PATIENTS AND METHODS After written informed consent, we enrolled 20 patients (group A) who underwent OLT with HCV recurrence within 6 months. HCV-RNA and hypertransaminasemia were used to assess the reactivation of viral hepatitis. CD4(+)/CD25(+) T cells were enumerated using a flow cytometry assay, gated on CD3 cells, stained for FoxP3. After immunomagnetic sorting (Dynal, Oslo, NW), Treg suppressor activity was measured, as the ability to inhibit proliferation of autologous CD4(+)/CD25(-) T cells (anti-CD3/CD28 stimulation-1:2, 1:20 ratio). Eight patients with acute hepatitis C who evolved to a chronic infection after 6 months (group B) were used as positive controls, while 10 healthy individuals were negative controls (group C). RESULTS We did not observe any difference in CD4(+)/CD25(+) frequency or function among group A compared with group B (CD4(+)/CD25(+) = 14% +/- 2% versus CD4(+)/CD25(+) = 16% +/- 3%), although both groups were significantly increased with respect to group A (CD4(+)/CD25(+) = 6% +/- 3%; Mann-Whitney U test, P < .01). CONCLUSION Patients developing HCV recurrence after OLT have the same immunoregulatory network as patients with acute hepatitis C evolving to persistent infection, likely suggesting that CD4(+)/CD25(+) numbers may be a marker to predict recurrence of HCV after OLT.
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Affiliation(s)
- A Perrella
- Liver Transplant Unit Hospital A. Cardarelli, Naples, Italy
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21
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Perrella A, Vitiello L, Atripaldi L, Sbreglia C, Grattacaso S, Bellopede P, Patarino T, Morelli G, Altamura S, Racioppi L, Perrella O. Impaired function of CD4+/CD25+ T regulatory lymphocytes characterizes the self-limited hepatitis A virus infection. J Gastroenterol Hepatol 2008; 23:e105-e110. [PMID: 17645467 DOI: 10.1111/j.1440-1746.2007.05008.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIM Hepatitis A virus (HAV) causes a transient illness leaving permanent protection against reinfection. Few data are available on the regulatory mechanisms involved in the CD4+ T helper activation. We aimed to investigate the frequency and function of CD3+/CD4+/CD25+ T cells with regulatory function (Tregs) during acute HAV infection. METHODS We enrolled 35 consecutive patients and 15 healthy donors, enumerated Tregs by flow cytometry assay and evaluated, after immunomagnetical sorting with magnetic beads, their ability to inhibit the proliferation of CD4+/CD25- T lymphocytes at different ratios (1:1, 1:10, 1:20). RESULTS All patients had the usual course of infection. Our immunological analysis showed Tregs frequency in these patients (6.5% [range, 5-8.8%]; 36 [range, 10-87] cells) did not have any statistical difference compared with healthy donors (6% [range, 5-8%]; 48 (range, 23-71) cells), while their ability to suppress CD4+/CD25- was drastically reduced at different ratios (Mann-Whitney U-test; ratio 1:1, 93% vs 72%, z = -3.34, P < 0.0001; ratio 1:10, 86% vs 51%, z = -4.04, P < 0.001; ratio 1:20, 56% vs 30%, z = -3.43, P < 0.0001). After the seroconversion, CD4+/CD25+ frequency and function in HAV-infected patients did not differ from healthy individuals. CONCLUSION CD4+/CD25+ T cells seem to be impaired in their function during the HAV acute infection. This evidence might help to determine an optimal T helper cell immune network that is a predisposing factor for a self-limiting disease.
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Affiliation(s)
- Alessandro Perrella
- Department of Hepatogastroenterology and Immunology, VII Division of Infectious Disease and Immunology, Hospital D Cotugno, Naples, Italy.
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Dolganiuc A, Szabo G. T cells with regulatory activity in hepatitis C virus infection: what we know and what we don't. J Leukoc Biol 2008; 84:614-22. [PMID: 18495782 DOI: 10.1189/jlb.1107770] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The mechanism behind the apparent lack of effective antiviral immune response in patients with chronic hepatitis C virus (HCV) infection is poorly understood. Although multiple levels of abnormalities have been identified in innate and adaptive immunity, it remains unclear if any of the subpopulations of T cells with regulatory capacity (Tregs) contribute to the induction and maintenance of HCV persistence. In this review, we summarize the current knowledge about Tregs as they relate to HCV infection.
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Affiliation(s)
- Angela Dolganiuc
- Department of Medicine, University of Massachusetts Medical School, LRB 270J, 364 Plantation St., Worcester, MA 01605, USA.
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