Mechanisms of liver-induced tolerance.

PURPOSE OF REVIEW: To highlight the results of the ongoing research on the mechanisms of liver-induced tolerance focusing on results from the last year.

RECENT FINDINGS: The liver is exposed to a massive antigenic burden of dietary and commensal products from the gastrointestinal tract via portal vein, most of which are necessary for survival. To prevent the immune system from destroying these foreign yet beneficial elements, the liver has developed unique mechanisms to suppress immune responses. It is thought that these mechanisms of acquired tolerance may also underlie the spontaneous acceptance of liver allografts observed after transplantation in many species. The fact that isolated hepatocyte transplants are acutely rejected, suggests that nonparenchymal liver cells play a critical role in spontaneous liver allograft acceptance. IFN-γ, a key inflammatory cytokine produced by T effector (Tef) cells, is paradoxically compulsory for spontaneous liver allograft acceptance. Analysis of IFN-γ signaling points to liver mesenchymal nonparenchymal liver cell that eliminate infiltrating Tef cells via expression of B7-H1, IL-10, and tumor growth factor-β, as well as the enhancement of Tregs and MDSCs. Thus, liver mesenchymal cells are thought to promote tolerance by eliminating alloreactive Tef cells and enhancing suppressor cells (T and B).

SUMMARY: The research during last year offered some key insights into the mechanisms of liver-induced tolerance. Through interactions with activated T cells and B cells via IFN-γ/B7-H1 pathways, liver mesenchymal cells have been shown to be critical components of liver-specific tolerance induction.