title: Reconstitution of hepatitis C virus-specific T-cellmediated immunity after liver transplantation.
abstract: Hepatitis C virus (HCV)-related liver failure is the leading indication for liver transplantation worldwide. After transplantation, virological recurrence is the rule, but the spectrum of histological injury is wide, ranging from the development of allograft cirrhosis within a few years to minimal hepatitis despite long-term follow-up. The immunological correlates of this variable natural history are poorly understood. Here, we studied the kinetics of the cellular immune responses, viral replication, and allograft histology in 24 patients who had undergone liver transplantation for HCV-related liver failure. Using direct ex vivo methodologies (i.e., interferon-gamma ELISPOT and major histocompatibility complex class I-peptide tetrameric complexes), we found that patients who experienced viral eradication after antiviral therapy showed restoration of HCV-specific T-cell responses, whereas patients with progressive HCV recurrence that failed to respond to therapy showed declining frequencies of these viral-specific effector cells. The cytotoxic T lymphocytes that peripherally reconstituted after transplantation were clonotypically identical to those present within the recipient explant liver, defined at the level of the T-cell receptor beta chain (one epitope/one clone). Moreover, the subset of patients who spontaneously demonstrated minimal histologic recurrence had more vigorous CD4+ T-cell responses in the first 3 months, particularly targeting nonstructural proteins. We provide evidence that T-cell responses emerge after liver transplantation, and their presence correlates with improved histological and clinical outcomes. In conclusion, these results may help identify patients more likely to develop severe HCV recurrence and therefore benefit from current antiviral therapy, as well as provide a rationale for the future use of novel immunotherapeutic approaches. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience. wiley.com/jpages/0270-9139/suppmat/index.html).
authors.affiliation: Department of Medicine, Oregon Health & Science University, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Weston
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Leistikow
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.forename: Maria
authors.initials: M
authors.lastname: Torres
authors.forename: Anne M
authors.initials: AM
authors.lastname: Wertheimer
authors.forename: David M
authors.initials: DM
authors.lastname: Lewinsohn
authors.forename: Sunwen
authors.initials: S
authors.lastname: Chou
authors.forename: Michael P
authors.initials: MP
authors.lastname: Davey
authors.forename: Christopher
authors.initials: C
authors.lastname: Corless
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation; D000998:Antiviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000150:complications* / Q000188:drug therapy / Q000517:prevention & control; D006801:Humans; D007109:Immunity; D017093:Liver Failure / Q000601:surgery* / Q000821:virology*; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011184:Postoperative Period; D011446:Prospective Studies; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000998:Antiviral Agents