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

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)247-257
Number of pages11
JournalAmerican Journal of Transplantation
Volume21
Issue number1
DOIs
Accepted/In press1 Jan 2020
PublishedJan 2021

Bibliographical note

Funding Information: The word was funded by the Roche Organ Transplantation Research Foundation (ROTRF), the Medical Research Council Centre for Transplantation (reference J006742/1), and the National Institute for Health Research Biomedical Research Centre based at Guy’s and St Thomas National Health Service Foundation Trust and King’s College London. Funding Information: The word was funded by the Roche Organ Transplantation Research Foundation (ROTRF), the Medical Research Council Centre for Transplantation (reference J006742/1), and the National Institute for Health Research Biomedical Research Centre based at Guy?s and St Thomas National Health Service Foundation Trust and King?s College London. Publisher Copyright: © 2020 The American Society of Transplantation and the American Society of Transplant Surgeons Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

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.

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