title: Accelerated telomere reduction and hepatocyte senescence in tolerated human liver allografts.
abstract: BACKGROUND
  In living donor liver transplantation, the biological organ age of the donated allograft is unknown in young patients who receive grafts from older donors. Few studies have focused on the effects of aging on allografts in the state of tolerance. The purpose of this study was to assess the biological organ age of liver grafts.
  
  
  METHODS
  In 20 tolerated allografts over a 10-year post-transplant follow-up period, the relative telomere lengths were measured by multiplex quantitative polymerase chain reaction, and hepatocyte nuclear size and cell cycle phase markers were determined by immunohistochemistry. The results were compared with the same measurements that had been obtained prior to transplantation in the recipients' pre-implantation donor livers. Tolerance was defined strictly as a condition in which the allograft functioned normally and showed normal histology without any histological signs of rejection, fibrosis or inflammation in the absence of immunosuppression.
  
  
  RESULTS
  First, telomere length correlated with chronological donor age (n=41). Accelerated telomere reduction was seen in tolerated grafts compared with the predicted telomere length of each allograft calculated from the regression line of donor livers. Tolerated grafts were associated with higher hepatocyte p21 expression and greater nuclear area than in the donor livers prior to transplantation.
  
  
  CONCLUSIONS
  These findings suggest that allografts age more rapidly than in the normal population, and that grafts may reach the limit of proliferative capacity even in the state of tolerance.
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Wulamujiang
authors.initials: W
authors.lastname: Aini
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. Electronic address: ayam@kuhp.kyoto-u.ac.jp.
authors.forename: Aya
authors.initials: A
authors.lastname: Miyagawa-Hayashino
authors.affiliation: Department of Forensic Medicine and Molecular Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Munetaka
authors.initials: M
authors.lastname: Ozeki
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Salah
authors.initials: S
authors.lastname: Adeeb
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Department of Forensic Medicine and Molecular Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tamaki
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery and Transplantation, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Haga
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging; D064591:Allografts / Q000276:immunology / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D053145:Cell Nucleus Size / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D005260:Female; D006085:Graft Survival / Q000276:immunology; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D007223:Infant; D008099:Liver / Q000276:immunology / Q000502:physiology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D016615:Telomere / Q000502:physiology*; D059505:Telomere Homeostasis / Q000502:physiology*; D059506:Telomere Shortening / Q000502:physiology*; D023001:Transplantation Tolerance / Q000276:immunology*; D055815:Young Adult
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21
keywords: Cyclin-dependent kinase inhibitor p21; Hepatocyte nuclear area; Liver transplantation; Real-time PCR; Tolerance