End-stage liver disease related to chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation (LT) in the United States. Recurrence is almost universal, and HCV infection significantly impairs patient and allograft survival following LT.1 The spectrum of histologic injury related to HCV recurrence is highly variable, ranging from mild histologic abnormalities to allograft cirrhosis in up to 30% of recipients by the fifth postoperative year.2 Although this is an active and promising area of research, we currently cannot reliably identify patients who will develop progressive HCV recurrence. Thus, identifying variables before LT that predict more aggressive HCV recurrence is of importance, particularly in the context of donor organ shortage. The immune response is a critical determinant of clinical outcome in both the acute and chronic phases of HCV infection.3 Liver injury secondary to HCV infection is thought to be immune-mediated and not to result from the direct cytopathic effects of the virus.4, 5 Considerable gaps exist in our understanding of how the immune response influences HCV recurrence post-LT. In this setting, the infection of an HCV-naïve allograft in some ways resembles acute HCV infection, and this suggests a role for innate immune mechanisms in recurrent HCV disease outcome.6, 7 In this issue of Liver Transplantation, Espadas de Arias and colleagues8 contribute to our understanding of the potential role of natural killer (NK) cells in the antiviral immune response of LT recipients, adding important information to an emerging area of research.
NK CELLS AND KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTORS (KIRS)
NK cells play a critical role in the first line of defense against viral infection. NK cells contribute to control of viral replication and spread through cytolysis of infected cells, production of cytokines and chemokines, and activation of both dendritic cells and antigen-specific T cells.9 The intrahepatic immune system is characterized by a predominance of innate lymphocytes, up to 50% of which are NK cells; thus, it is likely that this population is intimately involved in the immune response to hepatotrophic viruses such as HCV.10 The activity of NK cells is controlled through a complex quantitative and qualitative balance of cell surface activating and inhibitory receptors that react with major histocompatibility complex (MHC) class I and class I–like molecules.11 In humans, KIRs represent one of the key NK receptor families. KIRs are a diverse family of activatory and inhibitory receptors interacting with self-MHC class I ligands. Rapid evolution of KIR genes and haplotype diversity suggest selection that is pathogen-driven, which makes the KIR locus an attractive target for disease association studies.12 KIR genes are named on the basis of the structures of the molecules that they encode. The first digit following the KIR prefix corresponds to the number of Ig-like domains in the molecule, the domain is designated by “D,” and this is followed by either “L” or “S” indicating a long or short cytoplasmic tail, respectively (“P” denotes pseudogenes). The final digit indicates the number of the gene encoding a protein with this structure. Thus, KIR2DL3 encodes a receptor with 2 extracellular Ig-like domains and a long cytoplasmic tail.13 Both activating and inhibitory KIRs and their ligands have been associated with outcome in chronic viral infections including HCV.14 KIRs have also been implicated as playing a role in self-tolerance as well as semi-allogeneic and allorejection.15–17
KIR–HUMAN LEUKOCYTE ANTIGEN C (HLA-C) IN RECURRENT HCV
In the current issue of Liver Transplantation, Espadas de Arias et al.8 explore the role of KIR genotypes and their HLA ligands in HCV disease recurrence and progression in the setting of LT. The patient cohort is small but well defined. They use standard methods for analysis in a well-defined cohort of 151 Caucasian-Italian patients and highlight associations that remain statistically significant following multivariate analysis. The main findings of this study were mismatching of KIR–HLA-C ligands between donor-recipient pairs associated with recurrent hepatitis; the presence of KIR2DL3 in the recipient correlated with fibrosis progression; and furthermore, in the presence of KIR2DL3, mismatching of KIR–HLA-C ligands favored progression of recurrent hepatitis to fibrosis. KIR-HLA disease association studies are complex and difficult to interpret. Our knowledge of the functional consequences of genetic disease associations at the KIR locus is relatively sparse, so by necessity, interpretation of these data is largely speculative and often based on simplified models of MHC-KIR functional interactions. Nonetheless, these results might have important implications in terms of frequency of protocol biopsies and consideration of antiviral therapy. Overall, the data support the idea that a genetic component contributes to NK cell–mediated control of the virus as well NK cell–mediated hepatic injury in the setting of LT for HCV.
Although this is an interesting study appropriately designed and conducted, it has shortcomings that should be acknowledged. HCV recurrence is almost universal in the LT setting, and this observation is underscored by the small number of patients in the present study (15/151) that showed no evidence of HCV recurrence. Although the authors did observe significant associations linked to recurrent hepatitis, most parameters tested showed no association with HCV recurrence. The patient numbers with no recurrence are too small to test associations adequately and should be interpreted with caution. The data describing associations with severity of recurrence are stronger, although the numbers in the severe group are relatively small (n = 30). Furthermore, acute rejection and hepatocellular carcinoma are important issues that cannot be adequately addressed in this study.
The authors acknowledge that the data set presented is preliminary in nature and that further studies are required to confirm their findings. Nevertheless, despite this shortcoming, this study has revealed interesting associations that provide valuable insight for the design of future studies.
Overall, the study is clinically relevant and well described, was conducted well, and provides evidence that a genetic component contributes to NK cell activity in the setting of LT for chronic HCV. The data will be useful in contributing to future strategies that will ensure optimum use of limited donor organs. This study supports a model in which activation of NK cells in this setting has both beneficial and detrimental influences on HCV recurrence in HCV-infected LT recipients, that is, protection versus injury of the allograft. Confirmation of these results in larger natural history studies is warranted.