Abstract
Hepatic stellate cells (HSCs) have been demonstrated to have immunoinhibitory activity. The aim of this study was to investigate the role of HSCs in the development of immunotolerance following liver transplantation. A rat liver transplantation tolerance model [donor Lewis into recipient Dark Agouti (DA)] and rejection (donor DA into recipient Lewis) was established. On the 7th day following transplantation, the HSCs and T cells were isolated from the rats of either the tolerance or rejection group and cultured together. The apoptosis rate of the T cells was determined 24 h later by flow cytometry following staining with anti-CD3 mAb and Annexin V-FITC/PI. Additionally, the FasL expression of HSCs was determined by flow cytometry following staining with anti-FasL mAb. The protein levels of IL-2, TNF-α, TGF-β and IL-10 in the supernatant collected from mixed lymphocyte reaction cultures of HSCs and T cells for 5 days were measured using ELISA assays. HSCs isolated from the tolerance group had a higher T-cell apoptosis induction activity compared with those of the rejection group. The activity of the HSCs was partially reversed by FasL blocking mAb. Accordingly, the FasL expression level of HSCs in the tolerance group was revealed to be higher than that of the rejection group. Moreover, HSCs stimulated IL-10 and TGF-β production in the tolerance group. This study suggests that HSCs are involved in liver transplantation immune tolerance via the induction of T-cell apoptosis partially mediated by the Fas/FasL pathway and the activation of Th2/Th3-like cell cytokine production.
Highlights
Organ transplantation has been successful for decades, graft rejection and immunosuppression (IS)‐derived chronic toxicity remain as key problems which need to be overcome
The present study revealed that hepatic stellate cells (HSCs) are involved in liver transplant immunotolerance via T‐cell apoptosis partly mediated by the Fas/FasL pathway and the regulation of TGF‐β and IL‐10 production
Histological analysis confirmed that the liver grafts of the rejection group underwent serious acute rejection, while those of the tolerance group did not
Summary
Organ transplantation has been successful for decades, graft rejection and immunosuppression (IS)‐derived chronic toxicity remain as key problems which need to be overcome. Liver allografts are the most spontaneously accepted transplantations in a number of species, hepatocyte allografts alone are acutely rejected [5,6], suggesting that liver non‐parenchymal cells (NPCs), including resident dendritic cells (DCs), liver sinusoid endothelial cells (LSECs), Kupffer cells (KCs) and hepatic stellate cells (HSCs), are considerably involved in liver immunotolerance. Previous studies have revealed that co‐transplanted HSCs protect islet allografts from rejection and attenuate the severity of graft‐versus‐host disease [10,11], suggesting that the HSCs have immunosuppressive properties. The present study revealed that HSCs are involved in liver transplant immunotolerance via T‐cell apoptosis partly mediated by the Fas/FasL pathway and the regulation of TGF‐β and IL‐10 production
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