Transforming growth factor β1 and Fas ligand synergistically enhance immune tolerance in dendritic cells in liver transplantation

Background: Long-term survival of patients following liver transplantation can be achieved by application of genetically modified, immune tolerogenic immature dendritic cells (imDCs) to overcome allograft-induced acute cellular rejection, a major cause of death. In this study, using a rat model of liver transplantation, we determined whether cotransfection of transforming growth factor β1 (TGF-β1) and Fas ligand (FasL) in imDCs synergistically enhances immune tolerance.

Materials and methods: We first determined the immune tolerogenic effects of TGF-β1 and FasL independently or together in imDCs by measuring the levels of CD86 and CD80 and by assessing T-cell proliferation using mixed lymphocyte reaction tests. Next, a rat model of liver transplantation, in which dark agouti and Lewis rats treated with DCs exogenously expressing TGF-β1 and/or FasL served as donors and recipients, respectively, was used to examine TGF-β1/FasL-induced immune tolerance. Specifically, we assessed the Banff rejection activity index (RAI), liver functions (alanine transaminase and total bilirubin levels), serum levels of interleukin (IL)-1, IL-10, and IL-12, apoptosis by TUNEL, and posttransplant survival.

Results: TGF-β1/FasL cotransfection of imDCs resulted in greater reduction of CD85 and CD80 expression and T-cell proliferation than a monotransfection. Cotransfected imDCs also showed reduced RAI scores, decreased plasma alanine transaminase and total bilirubin, altered cytokine levels, increased apoptosis, and prolonged survival than monotransfected imDCs in liver-allografted rats.

Conclusions: By enhancing immune tolerance, reducing liver damage, and achieving long-term postsurgery survival, TGF-β1/FasL cotransfection of imDCs may prove more beneficial for patients undergoing liver transplantation.