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Chua C, Salimzadeh L, Ma AT, Adeyi OA, Seo H, Boukhaled GM, Mehrotra A, Patel A, Ferrando-Martinez S, Robbins SH, La D, Wong D, Janssen HL, Brooks DG, Feld JJ, Gehring AJ. IL-2 produced by HBV-specific T cells as a biomarker of viral control and predictor of response to PD-1 therapy across clinical phases of chronic hepatitis B. Hepatol Commun 2023; 7:e0337. [PMID: 38055623 PMCID: PMC10984660 DOI: 10.1097/hc9.0000000000000337] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 09/05/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND There are no immunological biomarkers that predict control of chronic hepatitis B (CHB). The lack of immune biomarkers raises concerns for therapies targeting PD-1/PD-L1 because they have the potential for immune-related adverse events. Defining specific immune functions associated with control of HBV replication could identify patients likely to respond to anti-PD-1/PD-L1 therapies and achieve a durable functional cure. METHODS We enrolled immunotolerant, HBeAg+ immune-active (IA+), HBeAg- immune-active (IA-), inactive carriers, and functionally cured patients to test ex vivo PD-1 blockade on HBV-specific T cell functionality. Peripheral blood mononuclear cells were stimulated with overlapping peptides covering HBV proteins +/-α-PD-1 blockade. Functional T cells were measured using a 2-color FluoroSpot assay for interferon-γ and IL-2. Ex vivo functional restoration was compared to the interferon response capacity assay, which predicts overall survival in cancer patients receiving checkpoint inhibitors. RESULTS Ex vivo interferon-γ+ responses did not differ across clinical phases. IL-2+ responses were significantly higher in patients with better viral control and preferentially restored with PD-1 blockade. Inactive carrier patients displayed the greatest increase in IL-2 production, which was dominated by CD4 T cell and response to the HBcAg. The interferon response capacity assay significantly correlated with the degree of HBV-specific T cell restoration. CONCLUSIONS IL-2 production was associated with better HBV control and superior to interferon-γ as a marker of T cell restoration following ex vivo PD-1 blockade. Our study suggests that responsiveness to ex vivo PD-1 blockade, or the interferon response capacity assay, may support stratification for α-PD-1 therapies.
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Affiliation(s)
- Conan Chua
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Loghman Salimzadeh
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Ann T. Ma
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Oyedele A. Adeyi
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hobin Seo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Giselle M. Boukhaled
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Aman Mehrotra
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Anjali Patel
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | | | - Scott H. Robbins
- Late Stage Oncology Development, Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Danie La
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - David Wong
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Harry L.A. Janssen
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - David G. Brooks
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Jordan J. Feld
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Adam J. Gehring
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
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Komatsu H, Inui A, Yoshio S, Fujisawa T. Pharmacotherapy options for managing hepatitis B in children. Expert Opin Pharmacother 2021; 22:449-467. [PMID: 33090882 DOI: 10.1080/14656566.2020.1841165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION To eliminate viral hepatitis by 2030, the World Health Organization (WHO) launched the first global health sector strategy on viral hepatitis, with particular focus given to hepatitis B and C in 2016. To achieve the reduction of mortality in children, it is indispensable to know which children should be treated and how to treat them. AREA COVERED In this article, the authors review the antiviral treatment of children with chronic hepatitis B virus (HBV) infection including antivirals available for children with chronic HBV infection. EXPERT OPINION The approvals of nucleos(t)ide analogues (NAs) and pegylated interferon (PEG-IFN) for children have lowered a hurdle to the initiation of antiviral treatment in children. The international guidelines use nearly the same criteria of antiviral treatment for children with chronic HBV infection, but the WHO guidelines provide a cautious stance on the antiviral treatment of children. Not only PEG-IFN but also NAs with a high genetic barrier to drug resistance should be the first-line treatment for children. In settings with limited medical resources, NAs can be the first-line treatment for children. Although the concept of an 'immune-tolerant phase' is challenged, evidence is not sufficient to recommend the treatment of HBeAg-positive immune-tolerant children.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, Chiba, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Sachiyo Yoshio
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
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Optimized ex vivo stimulation identifies multi-functional HBV-specific T cells in a majority of chronic hepatitis B patients. Sci Rep 2020; 10:11344. [PMID: 32647116 PMCID: PMC7347526 DOI: 10.1038/s41598-020-68226-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 06/15/2020] [Indexed: 02/07/2023] Open
Abstract
High antigen burden during chronic hepatitis B (CHB) results in a low frequency HBV-specific T cell response with restricted functionality. However, this observation is based on limited data because low T cell frequencies have hindered effective ex vivo analysis. We adapted the ELISpot assay to overcome this obstacle to measure ex vivo T cell responses in CHB patients. We modified the key variables of cell number and the peptide pulsing method to improve ex vivo detection of HBV-specific T cells. We detected IFN-γ responses in 10/15 vaccinated controls and 20/30 CHB patients, averaging 195 and 84 SFUs/2 × 106 PBMCs respectively. Multi-analyte FluoroSpots improved functional characterization of T cells. We detected IFN-γ responses in all tested vaccinated controls (n = 10) and CHB patients (n = 13). IL-2 responses were detectable in 9/10 controls and 10/13 patients. TNF-α displayed less sensitivity, detectable in only 7/10 controls and 7/13 patients. Antigen-specific analysis demonstrated that IFN-γ responses were dominated by polymerase and core, with weak responses to envelope and X. IL-2 responses were found in 3/5 patients and equally directed towards polymerase and core. While their ex vivo frequency is extremely low, a fraction of HBV-specific T cells are detectable and display multi-functionality ex vivo.
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Mohamed AA, Abd-Elsalam S, Zaghloul M, Attala M, Khattab RA, Khater A, El-damasy DA, El-Sayed E, Hassanin S, Hawash N, Mohamed MR. Association between Human Leukocyte Antigen-DQ Polymorphisms and Treatment Response in Chronic Hepatitis B Egyptian Population: A Prospective Study. THE OPEN BIOMARKERS JOURNAL 2020; 10:55-59. [DOI: 10.2174/1875318302010010055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/03/2020] [Accepted: 05/12/2020] [Indexed: 02/08/2023]
Abstract
Background & Aims:
Several studies, in different populations, have focused on the role of HLA-DQ gene polymorphism in the pathogenesis of HBV infection. However, these findings are still controversial. This study aimed to determine HLA-DQ polymorphism in Chronic HBV patients and its impact on the response to antiviral therapy.
Methods:
This study was carried out on a total number of 188 participants, they were subdivided as follows: Group I (patients’ group): included 97 patients with chronic hepatitis B viral infection that was further subdivided according to response to treatment into responder and non-responder subgroups, Group II (Control group): included 91 normal healthy subjects who were matched to the patient group by sex and age. PCR (Polymerase Chain Reaction) testing, for HBV-DNA, was done for all participants enrolled in the study to measure the viral virus load before and after treatment. HLA- DQ polymorphism allelic discrimination assay was assayed using the Real-time equipment.
Results:
In a general analysis for the SNP rs7453920, the overall genotypes frequencies were 37% for A/A, 60.6% for A/G, and 37% for G/G. The G alleles of HLA-DQ rs7453920 were significantly increased in chronic HBV infection patients. A total of 77 (79.4%) patients were responders. Among this group, 72.7% were male, and the average age was 38.59 ±9.15 years. On evaluation of the association between polymorphisms in HLA-DQ gene and treatment response, the results indicated that response to treatment declined when patients were carrying the more unfavorable rs 7453920 GG with a response rate of 64%. Patients carrying the mutant allele AG, or the wild type allele AA were more likely to achieve a higher rate of response (84.8% and 83.3%, respectively).
Conclusion:
The presence of HLA-DQB2 rs 7453920-G serves as a risk factor for chronic HBV infection and treatment failure in the Egyptian population.
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Wang M, Hou Y, Meng SH, Yang B, Yang P, Zhang H, Zhu Y. Abnormal IL-10 levels were related to alanine aminotransferase abnormalities during postpartum in HBeAg positive women with chronic hepatitis B. Medicine (Baltimore) 2019; 98:e17969. [PMID: 31725660 PMCID: PMC6867749 DOI: 10.1097/md.0000000000017969] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Alanine transaminase (ALT) abnormalities are common in chronic hepatitis B (CHB) carriers during postpartum period. Disturbances in cytokines are considered to be associated with hepatitis Flares. There are limited data on cytokines changes in HBeAg positive patients with ALT abnormalities.This is an observational study. Pregnant patients with hepatitis B e-antigen (HBeAg) positive were enrolled from January 2014 to September 2018. Patients were assigned into three groups based on ALT levels in postpartum 6 to 8 weeks: ALT in normal range, ALT in 1 to 2-fold upper limits of normal (ULN) and ALT >2-fold ULN. Serum cytokines, ratios of regulatory T cells, and the concentration of cortisol were collected and compared among the three groups.Of the 135 mothers enrolled, 80.7% (109/135) completed the postpartum 6-week study. 13.8% (15/109) patients had postpartum ALT higher than 2ULN, 27.5% (30/109) patients had ALT in 1 to 2ULN and 58.7% (64/109) patients had ALT in normal range. Compared to control group, patients with ALT >2ULN had a higher IL-10 level (P < .05). No differences of IL-10 levels were found in the comparison of other inter comparison among three groups. No differences were found in the levels of other collected serum cytokines, cortisol, and regulatory T cells among three groups. On multivariate analysis, abnormal IL-10 level was independent risk factor for postpartum ALT elevating >2ULN. At the same time, the incidence of postpartum ALT elevated >2ULN were higher in patients with abnormal elevation IL-10 level than in patients with normal IL-10 level (14/68 vs 1/41, P = .008).CHB patients with postpartum ALT abnormalities show higher IL-10 level and postpartum ALT abnormalities were mainly occurred in patients with abnormal IL-10 level. IL-10 may be an underlying predictor and treatment target of hepatitis B, and further studies are needed.
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Affiliation(s)
- Ming Wang
- Department of Obstetrics and Gynecology, Beijing YouAn Hospital
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital
| | - Ying Hou
- Department of Obstetrics and Gynecology, Beijing YouAn Hospital
| | - Shi-Hui Meng
- Department of Obstetrics and Gynecology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Bo Yang
- Department of Obstetrics and Gynecology, Beijing YouAn Hospital
| | - Ping Yang
- Department of Obstetrics and Gynecology, Beijing YouAn Hospital
| | - Hua Zhang
- Department of Obstetrics and Gynecology, Beijing YouAn Hospital
| | - Yunxia Zhu
- Department of Obstetrics and Gynecology, Beijing YouAn Hospital
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Hepatitis B virus X protein modulates renal tubular epithelial cell-induced T-cell and macrophage responses. Immunol Cell Biol 2015; 94:266-73. [PMID: 26365016 DOI: 10.1038/icb.2015.85] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 07/31/2015] [Accepted: 09/02/2015] [Indexed: 12/13/2022]
Abstract
Renal tubular epithelial cells (RTECs) have an active role in renal inflammation, functioning as antigen-presenting cells as they constitutively express major histocompatibility complex-II and co-stimulatory molecules that can activate T cells and macrophages. Previous studies indicate that inflammatory cell infiltration and tubulointerstitial fibrosis are present in renal biopsies from Hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN) patients. We hypothesized that disorder RTECs may be involved in the progression of HBV-GN. Here, we measured renal function and inflammatory cells infiltration in C57BL/6J-TgN mice, and data showed that in C57BL/6J-TgN mice HBV x protein (HBx) mainly deposited in RTECs, and CD4(+) T cells and macrophages infiltrated into the interstitium. In vitro HBx upregulated CD40 expression in RTECs. In HK-2/CD4(+) T cells co-culture system, we found that HBx-stimulated HK-2 cells could activate CD4(+) T cells, promote their proliferation, and lead to an imbalance of interleukin (IL)-4 and interferon-γ. In HK-2/macrophages co-culture system, we found that HBx-stimulated HK-2 cells also increased macrophage adherent capacity and promoted MCP-1 and tumor necrosis factor-α and IL-1β secretion. These immune dysfunction may contribute to the pathogenesis of HBV-GN.
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7
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Affiliation(s)
- Nadia Alatrakchi
- Massachusetts General Hospital, Harvard Medical School, GI Unit/Warren 10, 55 Fruit St., Boston, MA, 02114, USA,
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8
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Gong Y, Zhao C, Zhao P, Wang M, Zhou G, Han F, Cui Y, Qian J, Zhang H, Xiong H, Sheng J, Jiang T. Role of IL-10-Producing Regulatory B Cells in Chronic Hepatitis B Virus Infection. Dig Dis Sci 2015; 60:1308-14. [PMID: 25260658 DOI: 10.1007/s10620-014-3358-1] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 09/06/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND A subset of interleukin (IL)-10-producing regulatory B (Breg) cells that suppress T-cell-mediated immunity was recently identified; however, their role in chronic hepatitis B (CHB) remains elusive. AIM To explore the possible role of Breg in the interaction with Th cells and consequent pathogenesis of CHB. METHODS The prevalence of Breg as well as 3 major effector T-cell subsets--CD4(+)CD25(high)Foxp3(+) regulatory T (Treg) cells, T helper 1 cells (Th1), and T helper 2 cells (Th2)--was assessed in the peripheral blood of 31 patients with CHB, 28 patients with acute hepatitis B (AHB), and 25 healthy controls (HC). RESULTS Compared to patients with AHB and HC, the prevalence of Breg and Treg cells and the concentration of IL-10 in the supernatant of cultured peripheral blood mononuclear cells (PBMCs) were greatly increased in patients with CHB. A significantly decreased proportion of Th1 cells was also observed in patients with CHB and was demonstrated to have a negative correlation with the prevalence of Breg. Furthermore, depletion of Treg cells in the PBMCs of patients with CHB did not alter the frequency of Breg cells or their ability to produce IL-10, indicating little, if any, impact of Treg cells on the generation and maintenance of Breg cells. CONCLUSIONS Our data indicate that increased Breg cells might be a major source of elevated IL-10 in CHB and represent a critical and independent regulatory force in the development of impaired anti-HBV immunity, consequently contributing to the pathogenesis of CHB.
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Affiliation(s)
- Yanping Gong
- Institution for Laboratory Medicine, Changshu, China
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Therapeutic vaccines in treating chronic hepatitis B: the end of the beginning or the beginning of the end? Med Microbiol Immunol 2014; 204:121-9. [DOI: 10.1007/s00430-014-0381-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 09/15/2014] [Indexed: 12/13/2022]
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10
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Li X, Wang Y, Chen Y. Cellular immune response in patients with chronic hepatitis B virus infection. Microb Pathog 2014; 74:59-62. [PMID: 25128091 DOI: 10.1016/j.micpath.2014.07.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 07/30/2014] [Accepted: 07/31/2014] [Indexed: 02/08/2023]
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11
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Carey I, D'Antiga L, Bansal S, Longhi MS, Ma Y, Mesa IR, Mieli-Vergani G, Vergani D. Immune and viral profile from tolerance to hepatitis B surface antigen clearance: a longitudinal study of vertically hepatitis B virus-infected children on combined therapy. J Virol 2011; 85:2416-28. [PMID: 21147914 PMCID: PMC3067801 DOI: 10.1128/jvi.01449-10] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Accepted: 12/02/2010] [Indexed: 02/06/2023] Open
Abstract
The aim of the study was to investigate longitudinally hepatitis B virus (HBV)-specific T-cell reactivity and viral behavior versus treatment response in tolerant children during combined antiviral therapy. Twenty-three children with infancy-acquired hepatitis B (HBeAg(+)) belonging to a published pilot study of 1-year treatment with lamivudine/alpha interferon (IFN-α) were investigated. Five seroconverted to anti-HBs (responders). Nine were HLA-A2(+) (4 responders and 5 nonresponders). Mutations within the HBV core gene were determined at baseline in liver and in serial serum samples by direct sequencing at baseline; during treatment week 2 (TW2), TW9, TW28, and TW52; and after follow-up week 24 (FUW24) and FUW52. HBV-specific reactivity was evaluated by T-cell proliferation with 16 HBV core 20-mer overlapping peptides and by HLA-A2-restricted core(18-27) pentamer staining and CD8(+) IFN-γ enzyme-linked immunospot (ELISPOT) assay. HBV core-specific T-cell proliferative and CD8 responses were more vigorous and broader among responders than among nonresponders at TW28 and TW52, while the number of mutations within HBV core gene immunodominant epitopes was lower at TW28 and was negatively associated with HBV-specific T-cell proliferative responses at both time points. The HBV DNA viral load was negatively associated with HBV-specific T-cell proliferative and CD8 responses during treatment, especially at TW28. Treatment-induced transition from immunotolerance to HBV immune control is characterized by the emergence of efficient virus-specific immune responses capable of restraining mutations and preventing viral evasion.
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Affiliation(s)
- Ivana Carey
- Institute of Liver Studies and Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, MRC Centre for Transplantation, King's College London School of Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom
| | - Lorenzo D'Antiga
- Institute of Liver Studies and Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, MRC Centre for Transplantation, King's College London School of Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom
| | - Sanjay Bansal
- Institute of Liver Studies and Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, MRC Centre for Transplantation, King's College London School of Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom
| | - Maria Serena Longhi
- Institute of Liver Studies and Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, MRC Centre for Transplantation, King's College London School of Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom
| | - Yun Ma
- Institute of Liver Studies and Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, MRC Centre for Transplantation, King's College London School of Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom
| | - Irene Rebollo Mesa
- Institute of Liver Studies and Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, MRC Centre for Transplantation, King's College London School of Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom
| | - Giorgina Mieli-Vergani
- Institute of Liver Studies and Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, MRC Centre for Transplantation, King's College London School of Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom
| | - Diego Vergani
- Institute of Liver Studies and Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, MRC Centre for Transplantation, King's College London School of Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom
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Kondo Y, Kobayashi K, Ueno Y, Shiina M, Niitsuma H, Kanno N, Kobayashi T, Shimosegawa T. Mechanism of T cell hyporesponsiveness to HBcAg is associated with regulatory T cells in chronic hepatitis B. World J Gastroenterol 2006; 12:4310-4317. [PMID: 16865771 PMCID: PMC4087740 DOI: 10.3748/wjg.v12.i27.4310] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Revised: 01/28/2006] [Accepted: 02/18/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To study the mechanisms of hyporesponsiveness of HBV-specific CD4+ T cells by testing TH1 and TH2 commitment and regulatory T cells. METHODS Nine patients with chronic hepatitis B were enrolled. Peripheral blood mononuclear cells were stimulated with HBcAg or HBsAg to evaluate their potential to commit to TH1 and TH2 differentiation. HBcAg-specific activity of regulatory T cells was evaluated by staining with antibodies to CD4, CD25, CTLA-4 and interleukin-10. The role of regulatory T cells was further assessed by treatment with anti-interleukin-10 antibody and depletion of CD4+CD25+ cells. RESULTS Level of mRNAs for T-bet, IL-12R beta2 and IL-4 was significantly lower in the patients than in healthy subjects with HBcAg stimulation. Although populations of CD4+CD25highCTLA-4+ T cells were not different between the patients and healthy subjects, IL-10 secreting cells were found in CD4+ cells and CD4+CD25+ cells in the patients in response to HBcAg, and they were not found in cells which were stimulated with HBsAg. Addition of anti-IL-10 antibody recovered the amount of HBcAg-specific TH1 antibody compared with control antibody (P < 0.01, 0.34% +/- 0.12% vs 0.15% +/- 0.04%). Deletion of CD4+CD25+ T cells increased the amount of HBcAg-specific TH1 antibody when compared with lymphocytes reconstituted using regulatory T cells (P < 0.01, 0.03% +/- 0.02% vs 0.18% +/- 0.05%). CONCLUSION The results indicate that the mechanism of T cell hyporesponsiveness to HBcAg includes activation of HBcAg-induced regulatory T cells in contrast to an increase in TH2-committed cells in response to HBsAg.
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MESH Headings
- Adult
- CD24 Antigen/analysis
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/pathology
- Cells, Cultured
- Female
- GATA3 Transcription Factor/genetics
- GATA3 Transcription Factor/metabolism
- Gene Expression Regulation
- Hepatitis B Core Antigens/physiology
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/metabolism
- Humans
- Interferon-gamma/genetics
- Interferon-gamma/metabolism
- Interleukin-10/genetics
- Interleukin-10/metabolism
- Interleukin-4/genetics
- Interleukin-4/metabolism
- Lymphocyte Depletion
- Male
- Middle Aged
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Interleukin-2/analysis
- T-Box Domain Proteins
- T-Lymphocytes, Helper-Inducer/drug effects
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
- T-Lymphocytes, Helper-Inducer/pathology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/pathology
- Transcription Factors/genetics
- Transcription Factors/metabolism
- T-bet Transcription Factor
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Affiliation(s)
- Yasuteru Kondo
- Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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Lee HS, Chung YH, Lee K, Byun KS, Paik SW, Han JY, Yoo K, Yoo HW, Lee JH, Yoo BC. A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology 2006; 43:982-8. [PMID: 16628625 DOI: 10.1002/hep.21166] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Clevudine is a nucleoside analog with an unnatural beta-L configuration. In a phase I/II clinical trial, once daily doses ranging from 10 to 200 mg for 28 days were well tolerated, and produced significant antiviral activity. The present study was conducted to assess the degree and durability of the antiviral response to 12 weeks of clevudine treatment, and to investigate its safety and tolerability. A total of 98 patients with HBeAg-positive chronic hepatitis B were randomized to placebo (n=32), 30-mg clevudine (n=32), and 50-mg clevudine (n=34) groups. Patients were followed up after 12 weeks of treatment for a further 24 weeks off-therapy. Median serum hepatitis B virus DNA reductions from baseline at week 12 were 0.20, 4.49, and 4.45 log10 copies/mL in the placebo, 30-mg clevudine, and 50-mg clevudine groups, respectively (P < .0001). Posttreatment antiviral activities were sustained, with 3.32 and 2.99 log10 reductions at week 12 off-therapy and 2.28 and 1.40 log10 reductions at week 24 off-therapies in the 30- and 50-mg clevudine groups, respectively. Median serum alanine aminotransferase (ALT) levels decreased markedly from baseline during clevudine treatment and were maintained below the upper limit of normal throughout the 24 weeks off-therapy in the two clevudine-treated groups. The incidences of adverse events and treatment-emergent grade 3 or 4 laboratory abnormalities were similar for the three groups. In conclusion, clevudine showed potent antiviral activity during therapy and induced a sustained posttreatment antiviral effect for 6 months after a 12-week treatment period, and this was associated with a sustained normalization of ALT levels.
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Affiliation(s)
- Hyo-Suk Lee
- Seoul National University Hospital, South Korea.
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Zhang SY, Li D, Gu HX, Li XK, Jin X, Liu W, Du B, Lu B. Analysis of the polymorphism of human leukocyte antigen (HLA) class and class alleles in HBV infection. Shijie Huaren Xiaohua Zazhi 2006; 14:963-968. [DOI: 10.11569/wcjd.v14.i10.963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To test the polymorphism of human leukocyte antigen (HLA) class and class alleles in HBV infection.
METHODS: The polymeric chain reaction/sequence specific primer (PCR-SSP) technique was used to determine HLA-A, B, DR B1 alleles in 61 patients with chronic hepatitis B (CHB), 30 recovered people from HBV infection and 40 healthy people ready to donate their bone marrow in Heilongjiang.
RESULTS: The allele frequencies of HLA-DRB1*12 in the chronic hepatitis B group were markedly higher than that in the normal group and the recovered group(0.230 vs 0.075, P = 0.004, OR = 3.674, 95%CI = 1.445-9.338 and 0.230 vs 0.063, P = 0.004, OR = 4.468, 95%CI = 1.492-13.377), but the allele frequencies of HLA- B*35, DRB1*13 were markedly lower(0.066 vs 0.163, P = 0.027, OR = 0.362, 95%CI = 0.143~0.918 and 0.016 vs 0.008, P = 0.017, OR = 0.174, 95%CI = 0.035-0.859). The allele frequencies of HLA-B*51, A*02 in the recovered group were markedly higher than that in the normal group (0.125 vs 0.025, P = 0.019, OR = 5.587, 95%CI = 1.139-27.027)and the chronic hepatitis B group(0.221 vs 0.360, P = 0.044, OR = 0.507, 95%CI = 0.260-0.986), respectively. HLA-A*69, B*56 were markedly lower in the chronic hepatitis B group than that in the normal group(0.000 vs 0.037, P = 0.031 and 0.000 vs 0.037, P = 0.031).
CONCLUSION: HLA-DRB1*12 was highly associated with the susceptibility to HBV infection and viral persistence. HLA-B*51, A*02 were closely associated with the susceptibility to HBV infection and viral clearance. HLA-B*35, DRB1*13, B*56 and A*69 were associated with the protection to HBV infection.
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