Prospective study of natural killer cell phenotype in recurrent hepatitis C virus infection following liver transplantation

Varchetta, Stefania; Oliviero, Barbara; Donato, M. Francesca; Agnelli, F.; Rigamonti, Cristina; Paudice, E.; Arosio, E.; Berra, Mauro; Rossi, G.; Tinelli, Carmine; Fagnoni, Francesco; Colombo, Massimo; Mavilio, Domenico; Mondelli, Mario U.

doi:10.1016/j.jhep.2008.10.018

Cited by 17 publications

(17 citation statements)

References 37 publications

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“…Thus, our finding of decreased NKG2D surface expression in hepatitis C would be an intriguing explanation for our observation of impaired NK cell activity against HSC. However, the role of NKG2D in HCV infection is discussed controversially as some authors reported down-regulated expression of this NK cell receptor [25] whereas other studies found increased surface expression in hepatitis C [26], [27]. In line with data presented by Sène and colleagues we found that differences in HCV(+) patients and healthy controls only affected expression levels of NKG2D, but not the frequency of NKG2D-positive cells [25].…”

Section: Discussionsupporting

confidence: 86%

The CXCR3(+)CD56Bright Phenotype Characterizes a Distinct NK Cell Subset with Anti-Fibrotic Potential That Shows Dys-Regulated Activity in Hepatitis C

et al. 2012

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BackgroundIn mouse models, natural killer (NK) cells have been shown to exert anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Chemokines and chemokine receptors critically modulate hepatic recruitment of NK cells. In hepatitis C, the chemokine receptor CXCR3 and its ligands have been shown to be associated with stage of fibrosis suggesting a role of these chemokines in HCV associated liver damage by yet incompletely understood mechanisms. Here, we analyzed phenotype and function of CXCR3 expressing NK cells in chronic hepatitis C.MethodsCirculating NK cells from HCV-infected patients (n = 57) and healthy controls (n = 27) were analyzed with respect to CXCR3 and co-expression of different maturation markers. Degranulation and interferon-γ secretion of CXCR3(+) and CXCR3(−) NK cell subsets were studied after co-incubation with primary human hepatic stellate cells (HSC). In addition, intra-hepatic frequency of CXCR3(+) NK cells was correlated with stage of liver fibrosis (n = 15).ResultsWe show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. In healthy controls CXCR3(+)CD56Bright NK cells displayed strongest activity against HSC. Chronic hepatitis C was associated with a significantly increased frequency of CXCR3(+)CD56Bright NK cells which showed impaired degranulation and impaired IFN-γ secretion in response to HSC. Of note, we observed intra-hepatic accumulation of this NK cell subset in advanced stages of liver fibrosis.ConclusionWe show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. Intra-hepatic accumulation of the functionally impaired CXCR3(+)CD56Bright NK cell subset might be involved in HCV-induced liver fibrosis.

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Section: Discussionsupporting

confidence: 86%

The CXCR3(+)CD56Bright Phenotype Characterizes a Distinct NK Cell Subset with Anti-Fibrotic Potential That Shows Dys-Regulated Activity in Hepatitis C

et al. 2012

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“…The role of NKG2D in HCV infection is discussed controversially as some authors reported downregulated expression of this NK cell receptor, 22 whereas other studies found an increased surface expression in hepatitis C. 23,24 Upregulated expression of NKG2D would be an intriguing explanation for our observation of increased NK cell activity against HSCs. However, in line with our previous findings, 25 we did not observe any significant differences regarding NKG2D expression between HCV-positive and healthy individuals.…”

Section: Discussionmentioning

confidence: 92%

NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner

Glässner

Eisenhardt

Krämer

et al. 2012

Laboratory Investigation

134

114

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In mouse models it has been shown that natural killer (NK) cells can attenuate liver fibrosis via killing of activated hepatic stellate cells (HSCs) in a NKG2D-and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. However, only little data exist regarding interactions of human NK cells with HSCs and their potential role in hepatitis C virus (HCV)-associated fibrogenesis. Therefore, purified NK cells from untreated HCV RNA( þ ) patients (n ¼ 33), interferon-a (IFN-a)-treated patients (n ¼ 17) and healthy controls (n ¼ 18) were coincubated with activated primary HSCs, and were tested for degranulation (CD107a expression) and secretion of IFN-g and TNF-a, respectively. Induction of HSC apoptosis was analyzed using an active caspase-3 assay. We found that following coincubation with HSCs a significant increase in CD107a expression could be observed in both NK cells from HCV( þ ) patients and healthy controls, whereas only negligible secretion of IFN-g and TNF-a could be detected. More importantly, NK cells from untreated HCV RNA( þ ) patients were significantly more effective in induction of HSC apoptosis (17.8 ± 9.2%) than NK cells from healthy controls (6.2 ± 2.1%; Po0.0001). Additionally, we observed an inverse correlation of liver fibrosis stage and the ability of NK cells to induce HSC apoptosis. Induction of HSC apoptosis was contact dependent and could partly be blocked by antibodies specific for TRAIL, NKG2D and FasL, respectively. It is noteworthy that NK cells from IFN-a-treated HCV( þ ) patients displayed the highest capability to kill HSCs (27.6±10.5%). Accordingly, pre-stimulation of NK cells with recombinant IFN-a significantly increased the ability of NK cells to induce cell death in primary HSCs and was dependent on upregulated expression of TRAIL. Here we demonstrate that NK cells from HCV-infected patients are highly efficient in inducing apoptosis of activated HSCs. Thus, NK cells may have an important anti-fibrotic role in chronic hepatitis C.

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“…Although no NCR ligands resulting from HCV infection have yet been identified, studies have reported decreased NK cell activating receptor expression on NK cells from chronically infected individuals. A progressive increase in the proportion of NKG2C + NK cells was reported to occur following liver transplantation for chronic hepatitis C and was initially thought to be associated with HCV recurrence [80]. A similar NK subset observed in human immunodeficiency virus infection expressed reduced levels of the NCRs NKp30, NKp44, and NKp46 [81].…”

Section: Natural Killer Cells In Hcv Infectionmentioning

confidence: 99%

Natural Killer Cell Function and Dysfunction in Hepatitis C Virus Infection

Holder

Russell

Grant

2014

BioMed Research International

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Viruses must continually adapt against dynamic innate and adaptive responses of the host immune system to establish chronic infection. Only a small minority (~20%) of those exposed to hepatitis C virus (HCV) spontaneously clear infection, leaving approximately 200 million people worldwide chronically infected with HCV. A number of recent research studies suggest that establishment and maintenance of chronic HCV infection involve natural killer (NK) cell dysfunction. This relationship is illustrated in vitro by disruption of typical NK cell responses including both cell-mediated cytotoxicity and cytokine production. Expression of a number of activating NK cell receptors in vivo is also affected in chronic HCV infection. Thus, direct in vivo and in vitro evidence of compromised NK function in chronic HCV infection in conjunction with significant epidemiological associations between the outcome of HCV infection and certain combinations of NK cell regulatory receptor and class I human histocompatibility linked antigen (HLA) genotypes indicate that NK cells are important in the immune response against HCV infection. In this review, we highlight evidence suggesting that selective impairment of NK cell activity is related to establishment of chronic HCV infection.

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Prospective study of natural killer cell phenotype in recurrent hepatitis C virus infection following liver transplantation

Cited by 17 publications

References 37 publications

The CXCR3(+)CD56Bright Phenotype Characterizes a Distinct NK Cell Subset with Anti-Fibrotic Potential That Shows Dys-Regulated Activity in Hepatitis C

The CXCR3(+)CD56Bright Phenotype Characterizes a Distinct NK Cell Subset with Anti-Fibrotic Potential That Shows Dys-Regulated Activity in Hepatitis C

NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner

Natural Killer Cell Function and Dysfunction in Hepatitis C Virus Infection

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