Dissertation

Influence of hepatitis C virus heterologous immunity on alloreactive T cell responses in liver transplantation

Merritt, Elliot Richard

2019

Overview

Heterologous immunity induced by infections is considered a potent barrier to transplantation tolerance. Hepatitis C virus (HCV)-infected liver transplant recipients can maintain allograft tolerance after successful immunosuppression withdrawal despite these suggested detrimental effects of anti-viral heterologous immunity, however. The availability of direct-acting antiviral (DAA) therapy will drastically change the impact of chronic HCV infection on clinical outcomes following liver transplantation. It is therefore essential to understand the extent to which HCV eradication modulates heterologous immunity. DAA-induced HCV clearance offers a unique setting to study the effect of viral heterologous immunity on alloreactive T-cell responses. A cohort of HCV-infected liver allograft recipients was recruited to enable retrospective analysis of alloreactive T cell responses, T cell exhaustion, immunophenotype and type I interferon (IFN-I) signalling. An in vitro assay was developed to investigate the extent to which HCV-specific T-cells cross-react with HLA antigens. HCV+ and HCV- CD8 Tcells were sorted and expanded to generate T-cell libraries, which were subsequently cultured with a panel of cell lines expressing single-HLA molecules. Cross-reactivity against allo-HLA was detected in 10% of T cell libraries. This frequency increased in the presence of donor-specific HLA. Our group has previously reported that type I IFN signalling and T cell exhaustion are associated with allograft tolerance. In this current study links between type I IFN signalling, T cell exhaustion and HLA-alloreactive T cell responses are demonstrated. The effects of HCV clearance on alloreactive T-cell responses were investigated. Here, HCV clearance resulted in decreased type I IFN signalling and diminished T cell exhaustion. The extent of donor-HLA-alloreactivity of HCV-specific CD8 T cells was also shown to increase after viral clearance. Additional examination of this effect using PD-1/CTLA-4 co-blockade provided further evidence for the role of T cell exhaustion regulating the HLA-alloreactive response. These findings demonstrate that viral clearance modulates the HCV heterologous immune response, which, should be considered to optimally manage immunosuppressive therapy following SVR.

• Publisher: ProQuest Dissertations & Theses
• Subject: Hepatitis C / Interferon / Liver / Lymphocytes / Transplants & implants