Progressive Fibrosis Is Driven by Genetic Predisposition, Allo-immunity, and Inflammation in Pediatric Liver Transplant Recipients

• There is a link between genetic predisposition, alloimmune antibodies, allograft inflammation and fibrosis
• Description of allograft natural history by assessing evolution of inflammation, fibrosis in different histological zones
• Allograft inflammation results in allograft fibrosis and is associated with post-LT Class II DSA and non-HLA antibodies
• The HLA-DRB1*03/04 allele causes genetic predisposition for fibrosisAmong pediatric liver transplant recipients, the graft longevity is expected to parallel the life expectancy of the recipient. A major impediment in this is progressive allograft fibrosis, the cause of which is not well understood. If this pathogenesis could be found, then interventions to arrest the progressive fibrosis could be explored. In our 89 patients for whom we did periodic surveillance liver biopsies, inflammation was found to precede the fibrosis and associated with presence of specific antibodies. Certain genetic predisposition for higher fibrogenesis was also found, thus establishing a link between genetic predisposition, alloimmune response, inflammation, and allograft fibrosis.

AimTo determine predisposing factors of idiopathic allograft fibrosis among pediatric liver transplant recipients.BackgroundProtocol 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.Patients and MethodsThis observational study, included 89 stable LT recipient transplanted between 2004–2012 with mean follow-up of 4.3 years, 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 7–10 years 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.FindingsHLA-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.InterpretationWe 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.FundingNone.