Mission poorly accomplished: The protective role of natural killer cells in recurrent hepatitis C after liver transplantation

Recurrent hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) represents a dilemma and has become the most important clinical problem for most OLT programs with limited therapeutic options. At best, viral eradication is achieved in only 20%-35% of patients treated with the standard therapeutic regimen of pegylated interferon and ribavirin. The development of rapidly progressive recurrent hepatitis after OLT in HCV patients is associated with histologic injury and fibrosis. As many as 20% of HCV patients develop cirrhosis within the first 5 years after OLT, and the overall survival of this cohort of patients is substantially compromised compared to that of patients transplanted for indications other than HCV. Until newer and universally effective antiviral medications are identified, studies addressing the pathogenesis of liver injury post-OLT may pave the way for the development of novel strategies to improve outcome despite persistent viremia. Although there is evidence supporting a direct cytopathic effect of HCV in post-OLT liver injury, the evidence supporting an indirect immune-mediated destruction of hepatocytes may even be more convincing. Evidence for a direct cytopathic effect of HCV comes from data demonstrating a substantially higher viral load in a subset of patients with severe histologic injury after OLT known as “fibrosing cholestatic recurrence of HCV” in comparison with patients with milder forms of recurrence. Additionally, it has been demonstrated, in a study using the National Institute of Diabetes and Digestive and Kidney Diseases liver transplant database, that pre-OLT viral burden predicts survival after OLT. Despite this supportive evidence, most studies to date have failed to show a direct association between viral load and histologic injury after OLT in patients with HCV. It is likely that both direct viral cytopathic effect and indirect immune-mediated mechanisms are involved in histologic injury or that the two mechanisms are intimately connected. The role of the host immune response in liver injury associated with post-OLT recurrence of HCV has been the focus of significant research over the past 10 years. The role of adaptive immune responses (CD4 helper T-cells and CD8 cytotoxic T-cells) and more recently innate immune responses [natural killer (NK) and natural killer T (NKT) cells] have been considered and assessed. It is believed that CD4 T-cells have a protective effect against progression of liver disease associated with chronic HCV infection and are essential in the immunological control of viremia. HCV-specific proliferative CD4 T-cell responses to recombinant HCV proteins are associated with self-limited infection. Additionally, HCV-specific CD4 T-cell responses are required to maintain an effective cytotoxic CD8 T-cell response. More recently, a comprehensive characterization of epitopes recognized by CD4 T-cells in patients who had spontaneous resolution of HCV viremia was performed and showed that these epitopes are preferentially situated in the nonstructural proteins. However, the proliferative responses of CD4 T-cells are substantially impaired in immunosuppressed individuals after OLT, and this accounts at least in part for the universal recurrence of viremia. It remains unclear