On the impact of hepatitis C virus and heterologous immunity on alloimmune responses following liver transplantation

Abstract

Virus‐induced heterologous immunity is considered a barrier to transplantation tolerance. Yet, hepatitis C (HCV)‐infected liver transplant (LT) patients occasionally achieve operational tolerance. We investigated the mechanisms through which HCV infection modulates donor‐specific T cell responses following LT and the influence of HCV eradication. We generated T cell lines from HCV‐infected LT and non‐LT patients before and after HCV eradication and quantified alloreactive responses using cell lines expressing single‐HLA class‐I antigens in the presence/absence of PD‐1/CTLA‐4 blockade. HCV‐specific CD8+ T cells cross‐reacted with allogeneic class‐I HLA molecules. HCV‐positive LT recipients exhibited a higher proportion of CD8+ T cells coexpressing inhibitory receptors (PD‐1/CTLA4) than HCV‐negative LT, and their expression correlated with CXCL10 plasma levels. This resulted in decreased antidonor and third‐party proliferative responses, which were significantly reversed by HCV eradication. PD‐1/CTLA‐4 blockade increased the proportion of HCV‐specific CD8+ T cells reacting against donor only before viral clearance. In conclusion, HCV infection results in the generation of HCV‐specific CD8+ T cells capable of reacting against allogeneic HLA molecules. Following LT, this results in a PD‐1/CTLA4‐dependent decrease in alloimmune responses. Our findings challenge the notion that heterologous immunity is necessarily detrimental in LT and provide an explanation for the association between HCV eradication and immune‐mediated allograft damage.

Identification and Internal Validation of a Novel Pre-Transplant Biomarker Panel to Predict Mortality Following Liver Transplantation: The Liver Immune Frailty Index

“…69,70 These changes may persist even after recovery from HCV infection, 69,71 and HCV-induced immune dysfunction can hinder development of heterologous immunity to other antigens, thereby promoting immune frailty. 72 With FDA approval of DAAs for treatment of HCV in 2014, the incidence of transplant for viral positive HCV has declined over time. 73 In creation of the LIFI, we initially evaluated both positive HCV viral load and HCV IgG as potential covariates in multivariate analysis (not shown).…”

Limitations of current liver donor allocation systems and the impact of newer indications for liver transplantation

“…Review chronic rejection has been reported when DAA therapy is delayed, 76,77 highlighting the importance of monitoring for immunemediated events in the context of DAA therapy. 79,80…”

Strategies for Liver Transplantation Tolerance

“…However, it has also been suggested that incidence of certain γδ T-cells is driven by systemic viral infections [112,113]. Recently, in vitro experiments have described a role for virus-specific cells in suppression of alloresponses, which provides a possible explanation for the prevalence of γδ T-cells in operationally tolerant as well as hepatitis C virus-positive LT recipients [114]. The functional significance of DCs and γδ T-cells in the development of tolerance requires further investigation.…”