Enhanced donor-specific alloreactivity occurs independently of immunosuppression in children with early liver rejection

Abstract

To determine whether early acute cellular rejection (ACR) is associated with sub-optimal immunosuppression in children with liver transplants (LTx). Methods: Twenty-five children with primary LTx after pre-transplant rabbit anti-thymocyte globulin (rATG), and steroid-free tacrolimus (TAC) were evaluated. Mitogen-stimulated T- and B-cell responses and mixed lymphocyte response to donor and third-party antigens were performed at several time points between two consecutive TAC doses. TAC concentrations (C) associated with half-maximal effect (EC50) on lymphocytes was determined by pharmacodynamic equations. Results: Mean age was 7.2 ± 6.2 years, mean time to lymphocyte function studies was 25 ± 19 days. Acute rejection occurred at a mean interval of 31 ± 19 days after LTx. Rejectors (n = 16) demonstrated significantly higher EC50 of TAC for the intra-cellular IFN-γ in T cells (p = 0.005) and its CD8+ sub-population (p = 0.027) as well as the co-stimulatory/activation receptor CD54 on B cells (p = 0.0001). The response of recipient lymphocytes to donor antigen was significantly higher in rejectors, compared with non-rejectors (p = 0.015). The patient groups demonstrated no differences in third-party MLR, or in C of TAC. Conclusions: Independent of the amount of immunosuppressant, ACR of liver allografts in children is associated with enhanced donor-specific alloreactivity. This is accompanied by a cytotoxic T-cell sub-population with increased requirement for TAC.