title: Tissue biopsy monitoring of operational tolerance in liver allograft recipients.
abstract: OBJECTIVE
  Highly selected, long-surviving, liver allograft recipients with normal/near normal liver injury tests can be weaned from immunosuppression. Baseline biopsies document changes before weaning and can help stratify risk of rejection or dysfunction after weaning; biopsies after weaning are used to study mechanisms of operational tolerance and to monitor for subclinical events.
  
  
  RESULTS
  Clinicopathological features associated with successful weaning include a lack of sensitization [negative donor-specific antibodies (DSA) and lack of tissue C4d deposits]; 'inexperienced' recipient immune system with limited potential for cross-reactivity (less immunological memory; infant recipients); noninflamed allograft in those with nonviral, nonimmunological original diseases; upregulation of liver genes associated with iron metabolism; allograft colonization with 'immunosuppressive' cells (Treg and γδ-1>γδ-2); and longer time on immunosuppression, which might signal slow clonal deletion or silencing. The differential diagnosis of histopathological findings detected before and after weaning includes emerging infections, typical and atypical cellular rejection, indolent antibody-mediated rejection, 'autoimmunity', and other causes of progressive fibrosis.
  
  
  CONCLUSIONS
  Operationally tolerant liver allograft recipients can be successfully managed with very low, and sometimes no immunosuppression, but challenges exist. Newer approaches to tissue pathology and tissue, serum, and cross-platform analytics are needed to predict successful weaning and to monitor for subclinical events.
authors.affiliation: Department of Pathology, Division of Liver and Transplantation Pathology, and Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. demetrisaj@upmc.edu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
mesh_terms: D001706:Biopsy; D015935:Complement C4b / Q000276:immunology; D006084:Graft Rejection / Q000175:diagnosis* / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008099:Liver / Q000502:physiology*; D008111:Liver Function Tests; D016031:Liver Transplantation; D010446:Peptide Fragments / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d