CpG ODN TRIGGERS LIVER INFLMMATORY REACTION AND ABROGATES SPONTANEOUS TOLERANCE

Liver allografts are spontaneously accepted in the liver transplantation mouse model; however, the basis for this tolerance and the conditions that abrogate spontaneous tolerance to liver allograft is incompletely understood. We examined the role of CpG ODN in triggering liver inflammatory reaction and allograft rejection. Bioluminescence imaging (BLI) quantified the activation of NF-κB at the different timepoints post-transplantation. Intrahepatic lymphocyte subsets were analyzed by immunofluorescence assay and flow cytometry. The results show that liver allografts survived for more than 100 days without requirement for any immunosuppressive therapy. Donor matched cardiac allografts were permanently accepted while third-party cardiac grafts were rejected with delayed kinetics, confirming donor-specific tolerance. NF-κB activation in the liver allografts was transiently increased at day 1 and diminished by day 4, compared to that was elevated up to 10 days post-transplantation in the cardiac allografts. When CpG ODN was administered as a high dose (50μg per mouse × 1) into the recipients at day 7 post-transplantation, it induced an acute liver inflammatory reaction with elevated NF-κB activation in both allogeneic and syngeneic liver grafts. Multiple doses of CpG ODN (10μg per mouse × 3) elicited acute rejection of the liver allografts with significant T cell infiltration in the liver allografts, reduced regulatory T cells, and enhanced IFN-γ-producing cells in the intrahepatic infiltrating lymphocytes. These data demonstrate that CpG ODN initiates inflammatory reaction and abrogates spontaneous tolerance in the liver transplantation mouse model.