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

Background/Aims

Graft re-infection invariably occurs after liver transplantation (OLT) for chronic hepatitis C and disease progression is unpredictable. We prospectively examined peripheral blood mononuclear cells (PBMC) subsets and natural killer (NK) cell receptors (NKRs) in patients with recurrent hepatitis C post-OLT.

Methods

PBMC were obtained at baseline and at different time points after OLT. NKRs were identified using monoclonal antibodies by flow cytometry.

Results

The proportions of NK, natural T (NT), total and γδ T cells were significantly reduced (p < 0.01) 7 days post-transplant, probably as a result of graft repopulation. NKG2D+ NK cells were significantly higher compared with healthy controls (p < 0.01), declined post-OLT and subsequently returned to baseline values. This, together with a progressive increase in the proportion of CD94/NKG2C+ NK cells over time (p ⩽ 0.01), appeared to be related to hepatitis C recurrence. There was a statistically significant correlation between expression of the natural cytotoxicity receptors (NCRs) and ALT (p < 0.05), supporting the hypothesis that NK cells participate in the necroinflammatory process.

Conclusions

The data are compatible with homing of immune cells to the liver allograft after surgery, most of which return to pre-OLT levels. HCV recurrence may cause variations in selected NKRs expression akin to other viral infections.

Introduction

Graft re-infection occurs immediately after liver transplantation (OLT) for end-stage liver disease caused by chronic hepatitis C virus (HCV) infection; however, disease progression may rapidly develop and is often unpredictable. Indeed, allograft cirrhosis occurs in up to 30% of liver transplant recipients in the 5 years following surgery, with ensuing graft failure and need for re-transplantation [1]. The causes for such a rapid progression are largely unknown, although it may be inferred that accumulation of highly pathogenic HCV variants associated with dysfunctional host immune responses secondary to immune suppression may be responsible for this phenomenon. Previous findings suggested a role for adaptive immunity in the control of HCV re-infection post-transplant [2], [3]. A possible role for innate immunity has recently been explored only before OLT [4]. However, a systematic prospective study of innate immune cell frequencies and phenotype has never been performed. The importance of innate immune cells is further emphasized by the observation that natural killer (NK) and natural T (NT) cells are uniquely enriched in the inflammatory cell infiltrate of the diseased liver [5], [6]. Moreover, NK cell frequencies have been reported to be reduced in patients with chronic HCV infection [7], [8], [9], [10], but whether this translates into altered function is still controversial [10], [11], [12]. To assess whether variations in the frequency and phenotype of NK and NT cells were associated with clinical, biochemical and virological indicators of disease severity and progression, we prospectively examined these cells in patients with recurrent hepatitis C post-OLT and controls. We found that, in general, modifications of innate and adaptive immune cell frequencies occurred predominantly in the early phase post-transplant, and returned to baseline levels starting from one month after surgery. Prospective phenotypic changes in natural killer receptors (NKRs) were instead solely restricted to NK cells.