Küpffer cells promote acute rejection via induction of Th17 differentiation in rat liver allografts.

BACKGROUND

Th17, a newly identified CD4+ T-cell subset, has been implicated in transplant rejection. Differentiation of Th17 cells is associated with transforming growth factor-β (TGF-β) and interleukin-6 (IL-6), which are the main products of Küpffer cells.

OBJECTIVE

To determine whether Küpffer cells promote acute liver allograft rejection by inducing Th17 cell differentiation.

METHODS

A rat model of allogeneic liver transplantation using Dark Agouti (DA) to Brown Norway (BN) rats was established with or without gadolinium chloride (GdCl(3)) pretreatment. Isogeneic liver transplantation (BN to BN) was performed as a control. Concentrations of cytokines secreted by Küpffer cells or Th17-related cytokines detected in the liver and peripheral blood were analyzed using immunohistochemistry assays, flow cytometry, and enzyme-linked immunosorbent assays. Survival differences were compared between treatment groups. In vitro, Küpffer cells from liver grafts were isolated and co-cultured with naïve CD4 T cells.

RESULTS

Both Küpffer cells and Th17 cells infiltrated liver allografts, accompanied by an increase in concentrations of IL-6 and TGF-β. Pretreatment with GdCl(3) attenuated intragraft infiltration of Küpffer cells and Th17 cells, and decreased IL-6 and TGF-β concentrations. Liver function improved after pretreatment, and mean (SD) survival time was prolonged, compared with the control group (16.33 [0.96] days vs 11.50 [0.99] days, respectively; P < .01). In vitro, Küpffer cells from livers with allografts secreted significantly higher concentrations of IL-6 and TGF-β and induced Th17 differentiation more effectively compared with livers with isografts (30.8% vs 8.1%, respectively).

CONCLUSION

Küpffer cells have the potential to induce Th17 cells by secreting IL-6 and TGF-β, and as a result, promote acute liver allograft rejection.