Success of organ transplantation currently depends on life-time immunosuppression, resulting in severe side effects. Induction of specific tolerance is ideal, which actually spontaneously occurs following liver transplantation in many species. In humans, immunosuppression can be completely weaned off in ∼1/4 patients. The underlying mechanisms remain unknown, but transplant tolerance depends on IFN-Γ stimulation since WT liver allografts in IFN-Γ^-/- recipients are acutely rejected. We demonstrated in this study that when IFN-ΓR1^-/- liver (B6, H2^b) was transplanted into WT C3H (H2^k) recipients (n=6), none of the grafts survived >15 days (WT grafts survived >100 days), suggesting a role of IFN-Γ signaling pathway in liver graft. Both flow and histochemistry showed markedly more CD8⁺ cells and less suppressor cells (MDSC and Tregs) in IFN-ΓR1^-/- liver grafts than WT controls, suggesting a critical role of IFN-Γ signaling in induction of transplant tolerance. To identify the cell components involved in this process, the graft non-parenchymal cells (GNHC) were isolated at various time points. Almost all graft CD45⁺ cells quickly (in one-two days) became recipient origin (H2^k, IFN-ΓR1⁺), while CD45^– cells remain donor type (H2^b, IFN-ΓR1^–), indicating that induction of transplant tolerance by IFN-g stimulation is mediated by the graft non-hematopoietic cells. Addition of the graft CD45^– cells into an MLR culture demonstrated suppressed T cell response. Liver endothelial cells (LEC) have previously been shown some immune regulatory activity, which however, was markedly less potent compared to hepatic stellate cells (HSC). Co-transplantation with LEC slightly prolonged islet allografts (MST increased from 10 days to 18 days), while with HSC achieved long-term survival in >60% islet grafts, associated with elimination of effector T cells, accumulation of MDSC and Tregs in graft. Interestingly, HSC from IFN-gR1^-/- mice failed to protect islet graft, associated with more infiltrating CD8⁺ T cells and less MDSC and Tregs. IFN-Γ stimulated expression of B7-H1 on HSC. B7-H1^-/- HSC lost ability to protect islet graft, suggesting that B7-H1 is a critical effector molecule. In conclusion, liver GNHC, particularly HSC, actively participate in mediating immune regulation via IFN-Γ signaling pathways, better understanding of which holds great potential of clinical application.

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