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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. 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. 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. 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. Copyright © 2017 Elsevier Inc. All rights reserved.

Citation

Minglian Qiu, Yujuan Chen, Lihong Chen, Jinhua Zeng, Jingfeng Liu. Transforming growth factor β1 and Fas ligand synergistically enhance immune tolerance in dendritic cells in liver transplantation. The Journal of surgical research. 2017 Oct;218:180-193

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PMID: 28985848

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