Early Changes in Natural Killer Cell Function Indicate Virologic Response to Interferon Therapy for Hepatitis C

Ahlenstiel, Golo; Edlich, Birgit; Hogdal, Leah J.; Rotman, Yaron; Noureddin, Mazen; Feld, Jordan J.; Holz, Lauren E.; Titerence, Rachel; Liang, T. Jake; Rehermann, Barbara

doi:10.1053/j.gastro.2011.06.069

Cited by 134 publications

(148 citation statements)

References 30 publications

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“…RBV and peg-IFN-α combination therapy down-regulated the CD5 + population and peripheral B-cell CD81 expression, either directly or by its influence on HCV RNA load (Zuckerman et al, 2003). Within hours of IFN-α injection, NK cells were strongly activated with increased cytotoxicity and decreased IFN-γ production (Ahlenstiel et al, 2011). This response pattern is rendered to the ability of IFN-α to mediated induction of STAT1 in NK cells, which replaces STAT4 at the IFN-a/b receptor (Miyagi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Assessment of immunological, haematological and biochemical status after sofosbuvir-based combination therapy in HCV Egyptian patients from Menoufia Province

Ibrahim¹,

Soliman²,

El-Elaimy³

et al. 2016

J App Pharm Sci

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Chronic hepatitis C virus (HCV) is a serious health problem in Egypt. Although the effectiveness of pegylated interferon (peg-IFN) and ribavirin (RBV) combined therapy, poor response rates and lamentable tolerability were recorded in the chronically HCV infected patients. Sofosbuvir ( SOF) target the highly conserved active site of the HCV-specific NS5B polymerase that affect directly the viral replication and has broad genotypic coverage. In the present study we investigated the efficacy of SOF-based combination therapy and its effects on the status of immune cells from chronically infected HCV Egyptian patients. HCV Patients were treated with a combination treatment of SOF, RBV and peg-IFN-α or SOF and RBV for either 12 or 24 weeks. Then biochemical, hematological parameters, immunological phenotyping, PBMCs proliferation and apoptosis were detected pre-and post-treatment. While SOF-based combination therapy improved the liver function, anemia, leucopenia and thrombocytopenia were detected especially after treatment with SOF, RBV and peg-IFN-α-2a.We observed significant reduction in the percentage of CD3 + CD4 + and CD3 + CD8 + cells post-treatment with either SOF and RBV or SOF, RBV and peg-IFN-α-2a as compared to the baseline. Moreover, SOF-based combination therapy altered the percentage of CD3 -CD8 + , CD14 + and CD20 + cells. The proliferative capacity of PBMCs was significantly decreased in both regimens, whilst the percentage of apoptotic cells was significantly augmented. SOF-based therapy regimens are efficacious in reducing HCV load in the current study with some adverse effects that include the reduction of the mononuclear cells from the blood periphery by apoptosis.

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Section: Discussionmentioning

confidence: 99%

Assessment of immunological, haematological and biochemical status after sofosbuvir-based combination therapy in HCV Egyptian patients from Menoufia Province

Ibrahim¹,

Soliman²,

El-Elaimy³

et al. 2016

J App Pharm Sci

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“…Cytokines produced by NK cells, such as IFN-g and TNF-a, play a synergistic role in innate and adaptive immune responses (61). Several studies suggest that NK cells play a role in clearance or control of HCV infection or associate NK cell dysfunction with HCV infection (42,62,63). In this study, we directly assessed the ability of HCV-infected cells to inhibit NK cells in short-term assays with freshly isolated NK cells.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus–Infected Cells Downregulate NKp30 and Inhibit Ex Vivo NK Cell Functions

Holder

Stapleton

Gallant

et al. 2013

The Journal of Immunology

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Hepatitis C virus (HCV) successfully evades the immune system and establishes chronic infection in ∼80% of cases. Immune evasion may involve modulating NK cell functions. Therefore, we developed a short-term assay to assess immediate effects of HCV-infected cells on ex vivo NK cytotoxicity and cytokine production. Natural cytotoxicity, Ab-dependent cell–mediated cytotoxicity, IFN-γ production, and TNF-α production were all significantly inhibited by short-term direct exposure to HCV-infected hepatoma–derived Huh-7.5 cells. Inhibition required cell-to-cell contact and increased together with multiplicity of infection and HCV protein levels. Blocking potential interaction between HCV E2 and NK CD81 did not abrogate NK cell inhibition mediated by HCV-infected cells. We observed no change in expression levels of NKG2D, NKG2A, NKp46, or CD16 on NK cells exposed to HCV-infected Huh-7.5 cells for 5 h or of human histocompatibility-linked leukocyte Ag E on HCV-infected compared with uninfected Huh-7.5 cells. Inhibition of ex vivo NK functions did correspond with reduced surface expression of the natural cytotoxicity receptor NKp30, and downregulation of NKp30 was functionally reflected in reduced anti-NKp30 redirected lysis of P815 cells. Infection of Huh-7.5 cells with HCV JFH1T increased surface binding of an NKp30-IgG1 Fcγ fusion protein, suggesting upregulation of an antagonistic NKp30 ligand on HCV-infected cells. Our assay demonstrates rapid inhibition of critical NK cell functions by HCV-infected cells. Similar localized effects in vivo may contribute to establishment of chronic HCV infection and associated phenotypic and functional changes in the NK population.

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“…IFN-a1 stimulated virus-specific cytotoxic T cells, and during treatment with IFN-a11 or IFNa1, both are required for an optimal NK cell response (Gerlach et al, 2009;Gibbert et al, 2012). Others investigated the immunomodulatory effect of IFN-a2 on NK cells during treatment of HCV-infected patients (Ahlenstiel et al, 2011). This dual action, especially the unique immunomodulatory effects of IFN-a subtypes, should be investigated in detail for future treatments of viral infections.…”

Section: Ifn-a Subtypesmentioning

confidence: 99%

IFN‐α subtypes: distinct biological activities in anti‐viral therapy

Gibbert

Schlaak

Yang

et al. 2013

British J Pharmacology

152

140

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During most viral infections, the immediate host response is characterized by an induction of type I IFN. These cytokines have various biological activities, including anti‐viral, anti‐proliferative and immunomodulatory effects. After induction, they bind to their IFN‐α/β receptor, which leads to downstream signalling resulting in the expression of numerous different IFN‐stimulated genes. These genes encode anti‐viral proteins that directly inhibit viral replication as well as modulate immune function. Thus, the induction of type I IFN is a very powerful tool for the host to fight virus infections. Many viruses evade this response by various strategies like the direct suppression of IFN induction or inhibition of the IFN signalling pathway. Therefore, the therapeutic application of exogenous type I IFN or molecules that induce strong IFN responses should be of great potential for future immunotherapies against viral infections. Type I IFN is currently used as a treatment in chronic hepatitis B and C virus infection, but as yet is not widely utilized for other viral infections. One reason for this restricted clinical use is that type I IFN belongs to a multigene family that includes 13 different IFN‐α subtypes and IFN‐β, whose individual anti‐viral and immunomodulatory properties have so far not been investigated in detail to improve IFN therapy against viral infections in humans. In this review, we summarize the recent achievements in defining the distinct biological functions of type I IFN subtypes in cell culture and in animal models of viral infection as well as their clinical usage in chronic hepatitis virus infections.

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Early Changes in Natural Killer Cell Function Indicate Virologic Response to Interferon Therapy for Hepatitis C

Cited by 134 publications

References 30 publications

Assessment of immunological, haematological and biochemical status after sofosbuvir-based combination therapy in HCV Egyptian patients from Menoufia Province

Assessment of immunological, haematological and biochemical status after sofosbuvir-based combination therapy in HCV Egyptian patients from Menoufia Province

Hepatitis C Virus–Infected Cells Downregulate NKp30 and Inhibit Ex Vivo NK Cell Functions

IFN‐α subtypes: distinct biological activities in anti‐viral therapy

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