title: Progressive Fibrosis Is Driven by Genetic Predisposition, Allo-immunity, and Inflammation in Pediatric Liver Transplant Recipients.
abstract: OBJECTIVE
  To determine predisposing factors of idiopathic allograft fibrosis among pediatric liver transplant recipients.
  
  
  BACKGROUND
  Protocol biopsies (PB) from stable liver transplant (LT) recipient children frequently exhibit idiopathic fibrosis. The relation between allograft inflammation, humoral immune response and fibrosis is uncertain. Also the role of HLA-DRB1 genotype has not been evaluated, though it's associated with fibrosis in autoimmune hepatitis.
  
  
  METHODS
  This observational study, included 89 stable LT recipient transplanted between 2004-2012 with mean follow-up of 4.3years, 281 serial PBs (3.1 biopsy/child) and human leukocyte antigen (HLA) antibody data. PBs were taken 1-2, 2-3, 3-5, 5-7, and 7-10years post-LT, and evaluated for inflammation and fibrosis using liver allograft fibrosis score (LAFSc). The evolution of fibrosis, inflammation and related predisposing factors were analysed.
  
  
  RESULTS
  HLA-DRB1*03/04 allele and Class II DSA were significantly associated with portal fibrosis (p=0.03; p=0.03, respectively). Portal inflammation was predisposed by Class II DSA (p=0.02) and non-HLA antibody presence (p=0.01). Non-portal fibrosis wasn't predisposed by inflammation. Lobular inflammation was associated with non-HLA antibodies.
  
  
  CONCLUSIONS
  We conclusively demonstrated that allograft inflammation results in fibrosis and is associated with post-LT Class II DSA and non-HLA antibodies. The HLA-DRB1*03/04 allele caused genetic predisposition for fibrosis.
  
  
  BACKGROUND
  None.
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Department of Pediatrics, Service of pediatric gastroenterology and hepatology, Brussels, Belgium. Electronic address: sharat.varma@uclouvain.be.
authors.forename: S
authors.initials: S
authors.lastname: Varma
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Centre for applied molecular technologies (CTMA), Institute of experimental and clinical research (IREC), Brussels, Belgium. Electronic address: jerome.ambroise@uclouvain.be.
authors.forename: J
authors.initials: J
authors.lastname: Ambroise
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Service of anatomical pathology, Brussels, Belgium. Electronic address: mina.komuta@uclouvain.be.
authors.forename: M
authors.initials: M
authors.lastname: Komuta
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Department of clinical biology, Brussels, Belgium. Electronic address: dominique.latinne@uclouvain.be.
authors.forename: D
authors.initials: D
authors.lastname: Latinne
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Service of anatomical pathology, Brussels, Belgium. Electronic address: pamela.baldin@uclouvain.be.
authors.forename: P
authors.initials: P
authors.lastname: Baldin
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Service of pediatric surgery and transplantation, Brussels, Belgium. Electronic address: raymond.reding@uclouvain.be.
authors.forename: R
authors.initials: R
authors.lastname: Reding
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Department of Pediatrics, Service of pediatric gastroenterology and hepatology, Brussels, Belgium. Electronic address: francoise.smets@uclouvain.be.
authors.forename: F
authors.initials: F
authors.lastname: Smets
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Department of Pediatrics, Service of pediatric gastroenterology and hepatology, Brussels, Belgium. Electronic address: xavier.stephenne@uclouvain.be.
authors.forename: X
authors.initials: X
authors.lastname: Stephenne
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires St Luc, Department of Pediatrics, Service of pediatric gastroenterology and hepatology, Brussels, Belgium. Electronic address: etienne.sokal@uclouvain.be.
authors.forename: E M
authors.initials: EM
authors.lastname: Sokal
mesh_terms: D000367:Age Factors; D000483:Alleles; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D005260:Female; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007107:Immune System / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy; D016031:Liver Transplantation; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D012737:Sex Factors; D014184:Transplantation, Homologous
chemical_list: D006680:HLA Antigens; D059811:HLA-DRB1 Chains
keywords: Donor-specific antibodies; Fibrosis; HLA antibodies; HLA-DRB1; Humoral immunity; Pediatric liver transplantation; Portal inflammation