The New Challenge in Pediatric Liver Transplantation: Chronic Antibody-Mediated Rejection

Abstract

Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience in ABO incompatible transplantation and kidney transplantation. Immunosuppression compliance with adequate dose adjustment may prevent cAMR. Conversion of Cyclosporine to Tacrolimus may improve pathological findings if treated in early phase. The association of steroids, Mycophenolate Mofetil (MMF) and mTOR inhibitors have shown some synergistic effects. Second-line treatments such as intravenous immunoglobulin (IVIG) and plasma exchange may decrease antibody titers based on ABO incompatible transplant protocols. The use of anti-CD20 (Rituximab) and proteasome inhibitors (Bortezomib) is controversial due to the lack of qualified studies. Therefore, multicenter randomized trials are needed to establish the best therapeutic strategy. In refractory cases, re-transplantation is the only treatment for allograft failure. (3) Conclusions: This literature review collects recent clinical, histopathological, and therapeutical advances of cAMR in liver allograft transplantation of pediatric patients. There are many physio-pathological aspects of cAMR to be clarified. Further efforts with multicenter prospective protocols to manage patients with cAMR are needed to improve its outcome.

Keywords: chronic antibody-mediated rejection; chronic rejection; humoral rejection; pediatric liver transplantation.

Figure 1

Physiopathology of AMR. HLA (Human leucocyte antigen) molecules present in the liver allograft endothelium are targeted by preformed or de novo donor-specific antibody (DSA), recognizing the graft as non-self. The classical complement cascade is activated, which subsequently activates natural-killer (NK) cells releasing interferon-γ (IFN-γ), tumor necrosis factor (TNF), and granulocyte-macrophage colony-stimulating factor (CSF2), and monocytes releasing TNF, interleukin-1 (IL-1), and interleukin-6 (IL-6), evoking endothelial injury. These cytokines also activate acquired immunity, B cells leading to AMR as well as T cells leading to T cell-mediated rejection (TCMR). DSA also activate Stellate cells, leading to liver fibrosis.