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Title: Hepatitis C-induced hepatocyte apoptosis following liver transplantation is enhanced by immunosuppressive agents.
Austin Authors: Lim, Eu Jin ;Chin, Ruth;Nachbur, U;Silke, J;Jia, Zhiyuan;Angus, Peter W ;Torresi, Joseph 
Affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia
Medicine (University of Melbourne)
Victorian Liver Transplant Unit
Walter and Eliza Hall Institute, Parkville, Victoria, Australia
Infectious Diseases
Issue Date: Sep-2016
Date: 2016-05-11
Publication information: Journal of Viral Hepatitis 2016; 23(9): 730-43
Abstract: In recurrent hepatitis C (HCV) post-liver transplantation (OLT), the combination of immunosuppressants and HCV is postulated to increase hepatocyte apoptosis and liver fibrosis. We evaluated hepatocyte apoptosis within the liver tissue of patients with postOLT HCV recurrence compared to HCV-negative individuals and correlated these findings with the effects of immunosuppressants on HCV-induced cell death and its inhibition in primary mouse hepatocytes (PMoH). Liver biopsies from patients with and without HCV were evaluated by immunohistochemistry for markers of apoptosis M30 CytoDEATH (M30) and cleaved PARP (clPARP). PMoH from C57BL/6 mice were infected with recombinant adenoviruses (rAdHCV) that expressed HCV proteins in hepatocytes. Infected cells were treated with cyclosporine, tacrolimus, sirolimus and/or MMF with or without pan-caspase inhibitor Q-VD-Oph. Cell viability and apoptosis were evaluated using crystal violet assays and Western immunoblots probed for cleaved caspase-3 (clCas3) and clPARP. Both M30 and clPARP were increased in the liver biopsies of patients with postOLT HCV recurrence compared to HCV-negative individuals. Treatment of rAdHCV-infected PMoH with cyclosporine, tacrolimus or sirolimus reduced cell viability and increased clCas3 and clPARP compared to rAdHCV infection alone. Addition of MMF to cyclosporine, tacrolimus or sirolimus further reduced cell viability and increased clCas3 and clPARP. Q-VD-Oph improved cell viability in HCV-infected PMoH treated with immunosuppressants alone and in combination and reduced clCas3 and clPARP by approximately 90%. Immunosuppressive agents, especially in combination, enhanced apoptosis in HCV-infected hepatocytes. The finding that Q-VD-Oph reversed hepatocyte death suggests that treatments utilizing apoptosis inhibition might reduce liver injury in postOLT HCV recurrence.
DOI: 10.1111/jvh.12541
ORCID: 0000-0002-8212-0887
Journal: Journal of Viral Hepatitis
PubMed URL: 27167351
Type: Journal Article
Subjects: cyclosporine
liver allograft
Appears in Collections:Journal articles

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