CpG oligodeoxynucleotide triggers the liver inflammatory 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 allografts are incompletely understood. We examined the role of CpG oligodeoxynucleotide (ODN) in triggering the liver inflammatory reaction and allograft rejection. Bioluminescence imaging quantified the activation of nuclear transcriptional factor kappaB (NF-kappaB) at different time points post-transplantation. Intrahepatic lymphocyte subsets were analyzed by immunofluorescence assay and flow cytometry. The results showed that liver allografts survived for more than 100 days without a requirement for any immunosuppressive therapy. Donor-matched cardiac allografts were permanently accepted, whereas third-party cardiac grafts were rejected with delayed kinetics; this confirmed donor-specific tolerance. NF-kappaB activation in the liver allografts was transiently increased on day 1 and diminished by day 4; in comparison, it was elevated up to 10 days post-transplantation in the cardiac allografts. When CpG ODN was administered at a high dose (50 microg per mouse x 1) to the recipients on day 7 post-transplantation, it induced an acute liver inflammatory reaction with elevated NF-kappaB activation in both allogeneic and syngeneic liver grafts. Multiple doses of CpG ODN (10 microg per mouse x 3) elicited acute rejection of the liver allografts with significant T cell infiltration in the liver allografts, reduced T regulatory cells, and enhanced interferon gamma-producing cells in the intrahepatic infiltrating lymphocytes. These data demonstrate that CpG ODN initiates an inflammatory reaction and abrogates spontaneous tolerance in the liver transplantation mouse model. Liver Transpl 15:915-923, 2009. (c) 2009 AASLD.
Ma
Lian-Li
LL
Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Gao
Xiudan
X
Liu
Liping
L
Xiang
Zhidan
Z
Blackwell
Timothy S
TS
Williams
Philip
P
Chari
Ravi S
RS
Yin
Deng-Ping
DP
D000818:Animals; D018899:CpG Islands; D005434:Flow Cytometry / Q000379:methods; D007108:Immune Tolerance; D007249:Inflammation; D007700:Kinetics; D008099:Liver / Q000473:pathology*; D016031:Liver Transplantation / Q000276:immunology* / Q000379:methods; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D016328:NF-kappa B / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology
D016328:NF-kappa B; D009841:Oligonucleotides