Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis

Penna, Amalia; Laccabue, Diletta; Libri, Irene; Giuberti, T.; Schivazappa, Simona; Alfieri, Arianna; Mori, Cristina; Canetti, Diana; Lampertico, Pietro; Viganò, Mauro; Colombo, Massimo; Loggi, Elisabetta; Missale, Gabriele; Ferrari, Carlo

doi:10.1016/j.jhep.2011.12.032

Cited by 75 publications

(59 citation statements)

References 37 publications

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“…The wider range of activity of type I IFN is crucial for the control of systemic viral infection, but the risk of increased disease severity is always looming. Multiple reports describe the deleterious effects of inappropriate type I IFN responses during infection 73 , including massive induction of proinflammatory cytokines and production of apoptosis-inducing molecules on immune cells during acute infection 74 and also in chronic disease [75][76][77][78][79] , where the source of disease-promoting type I IFN often appears to be pDCs. Furthermore, the blockade of adaptive immune responses by excessive production of type I IFN during chronic infection has been described in detail for T cells 80,81 and to a lesser degree for B cells 71 .…”

Section: Effects Of Type III Ifn On Immune Cellsmentioning

confidence: 99%

Guarding the frontiers: the biology of type III interferons

2015

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Type III interferons (IFNs) or IFN-λs regulate a similar set of genes as type I IFNs, but whereas type I IFNs act globally, IFN-λs primarily target mucosal epithelial cells and protect them against the frequent viral attacks that are typical for barrier tissues. IFN-λs thereby help to maintain healthy mucosal surfaces through immune protection, without the significant immune-related pathogenic risk associated with type I IFN responses. Type III IFNs also target the human liver, with dual effects: they induce an antiviral state in hepatocytes, but specific IFN-λ4 action impairs the clearance of hepatitis C virus and could influence inflammatory responses. This constitutes a paradox that has yet to be resolved.

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Section: Effects Of Type III Ifn On Immune Cellsmentioning

confidence: 99%

Guarding the frontiers: the biology of type III interferons

2015

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“…This analysis indicated that such results may be related to antiviral actions of partially activated effector T cells included in CD4 + CD25 + (17). Therefore, recent international and local studies have considered that specific T cells containing CTLA-4, GITR, OX-40 and FoxP3, as well as other surface markers, were more suitable for the features of Treg cells (18). Hence, some scholars considered that highly expressed FoxP3CD4 + CD25 + T was a specific marker for Treg cells (4).…”

Section: Discussionmentioning

confidence: 99%

Influence of Treg cells and HBV genotype on sustained response and drug resistance in the treatment with nucleoside drugs

Zhang

Wang

et al. 2017

Braz J Med Biol Res

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We aimed to investigate the influence of regulatory T cells including CD4+CD25+, CD8+CD28- and hepatitis B virus (HBV) genotype on sustained virological response and tolerance of nucleoside drugs. One hundred and thirty-seven patients were enrolled. Lamivudine was administered to 84 patients. Entecavir was administered to the other 53 patients. Before treatment, biochemical tests, HBV DNA load, HBV serum level, HBV genotype, PB CD3+, CD4+, CD8+, CD4+CD25+/CD3+, and CD8+CD28-/CD3+ frequencies were measured. Based on HBV DNA loads after 4 weeks of therapy, patients were divided into response group and suboptimal response group. The lamivudine group received treatment continuously, and then patients were categorized into non-resistance group and resistance group. Compared with the suboptimal response and resistance groups for lamivudine, CD4+CD25+/CD3+ levels were higher in the response and non-resistance groups (t=4.372, P=0.046; t=7.262, P=0.017). In the non-resistance group, CD8+CD28-/CD3+ frequency was lower than in the resistance group (t=5.527, P=0.037). Virus load and hepatitis B E antigen (HBeAg)-positive rate were significantly lower than in the response and resistance group (t=2.164, P=0.038; X 2=4.239, P=0.040; t=2.015, P=0.044; X 2=16.2, P=0.000). Incidence of drug resistance was high in patients with virogene type C. For the virological response to entecavir, CD8+CD28-/CD3+ level was significantly lower than that of the suboptimal response group (t=6.283, P=0.036). Response and suboptimal response groups were compared in CD3+, CD4+, CD8+, CD4+CD25+/CD3+ and virus genotype, and differences were not statistically significant (P>0.05). Baseline regulatory T cells including CD4+CD25+/CD3+ and CD8+CD28-/CD3+ frequencies have a relationship with the incidence of rapid virological response and the resistance to nucleoside drugs. Patients with HBV genotype C receiving lamivudine more often underwent drug resistance. Antiviral efficacy and the resistance to lamivudine were closely correlated with baseline factors; the same cannot be found for entecavir.

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“…Recent studies on the kinetics of circulating HBV-specific CD8 cell response during IFN-α treatment were unable to show, at least in HBeAg-negative CHB, any restoration of their effector functions during therapy or in the first 6 months after treatment discontinuation [16,17]. This could be a result of the antiproliferative effect of IFN in a condition of deep functional T cell paralysis that is typical of CHB patients.…”

Section: Mechanisms Of Action Of Ifnmentioning

confidence: 99%

“…Nevertheless, the in vitro reactivity of T cells appeared to be restored in HBeAg-negative CHB patients with a long-term response to IFN-α and HBsAg clearance [15]; accordingly, CD8 T cell responses were more frequently detected (after the in vitro use of autologous DCs cells as presenting cells) in responders after therapy withdrawal [18]. Furthermore, patients with higher CD8 function and IFN-α production at baseline were more likely to show complete viral inhibition early during treatment, confirming a major role of adaptive activity in the overall response to IFN-α treatment [16]. Paradoxically, however, IFN-α treatment could induce an indirect inhibition on T cells by boosting NK activity [17].…”

Section: Mechanisms Of Action Of Ifnmentioning

confidence: 99%

Interferon Therapy of Chronic Hepatitis B

Brunetto¹,

Bonino

2014

Intervirology

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Chronic hepatitis B (CHB) results from the inability of the host's immune system to control viral replication. Interferon-α (IFN-α) therapy can convert CHB into inactive hepatitis B virus (HBV) infection in 20-30% of the treated patients. In spite of the low response rate, IFN-α therapy has the advantage of having a limited duration and being effective even after therapy, as demonstrated by a much higher incidence of HBsAg clearance in responders to IFN-α than in naturally occurring inactive HBsAg carriers. IFN-α has multiple antiviral, antiproliferative, and immunomodulatory activities and targets: cellular genes (IFN-stimulated genes) activating different pathways of antiviral defense in infected and noninfected cells, HBV replication blocking the RNA-containing core particle formation and accelerating their decay, degrading pregenomic RNA, and modulating the nuclear viral minichromosome (covalently closed circular DNA) activity by targeting its epigenetic regulation and both innate and adaptive immune response. The interference of viral heterogeneity and genetic polymorphisms of the host on IFN-α susceptibility is under investigation. Only a better understanding of the complex interplay between the different activities of IFN-α would warrant the amelioration of current therapeutic strategies and the design of new therapeutic approaches. The study of on-treatment dynamics of HBV infection by means of combined quantitative monitoring of serum HBV DNA and HBsAg warrant tailoring treatment at the single-patient level and can help to make treatment more cost-effective by using the different combinations of currently available antivirals, including IFN, more appropriately. Integrated molecular and clinical knowledge in a systems medicine fashion is mandatory to further improve antiviral therapy in CHB.

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Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis

Cited by 75 publications

References 37 publications

Guarding the frontiers: the biology of type III interferons

Guarding the frontiers: the biology of type III interferons

Influence of Treg cells and HBV genotype on sustained response and drug resistance in the treatment with nucleoside drugs

Interferon Therapy of Chronic Hepatitis B

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