Hepatic stellate cells promote immunotolerance following orthotopic liver transplantation in rats via induction of T cell apoptosis and regulation of Th2/Th3-like cell cytokine production

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.