Increased mononuclear cell activation and apoptosis early after human liver transplantation is associated with a reduced frequency of acute rejection.
Experimental models of orthotopic liver transplantation (OLT) have shown that the very early events post-OLT are critical in distinguishing immunogenic and tolerogenic reactions. In rodents, increased leukocyte apoptosis and cytokine expression have been demonstrated in tolerogenic strain combinations. Information from human OLT recipients is less abundant. The aim of this study was to determine the amount of early leukocyte activation and apoptosis following human OLT, and to correlate this with subsequent rejection status. Peripheral blood mononuclear cells (PBMC) were isolated from 76 patients undergoing OLT - on the day prior, 5 hrs after reperfusion (day 0), and 18-24 hrs post-OLT (day 1). The mean level of apoptotic PBMCs on post OLT day 1 was higher than healthy recipients (0.9% +/- 0.2 vs. 0.2% +/- 0.1, p=0.013). Apoptosis was greater in nonrejecting (NR) (1.1% +/- 0.3) compared with acutely-rejecting (R) (0.3% +/- 0.1, p=0.021) patients. On day 1, PBMC from NR patients had increased expression of IFN-gamma (p=0.006), IL-10 (p=0.016), and CD40 ligand (p=0.02) compared with R. Donor cell chimerism on day 1 did not differ between the groups indicating that this was unlikely to account for increased PBMC apoptosis in the NR group. Interestingly, the level of chimerism on day 0 was significantly higher in NR (3.8% +/- 0.6) compared with R (1.2% +/- 0.4, p=0.004) patients and there was a close correlation between chimerism on day 0 and cytokine expression on day 1. These results imply that similar mechanisms are occurring in the human liver to promote graft acceptance as in the experimental models of liver transplantation and suggest that strategies that promote liver transplant acceptance in rodents might be applicable to humans.
University of Queensland School of Medicine, Southern Division, Brisbane, Australia. j.jonsson@uq.edu.au
Julie R
JR
Jonsson
Wenyi
W
Gu
Daina M
DM
Vanags
G Alex
GA
Bishop
Geoffrey W
GW
McCaughan
Jonathon
J
Fawcett
Stephen V
SV
Lynch
Glenda A
GA
Balderson
Elizabeth E
EE
Powell
Andrew D
AD
Clouston
D000208:Acute Disease; D017209:Apoptosis / Q000276:immunology*; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016031:Liver Transplantation / Q000009:adverse effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D013997:Time Factors
D016207:Cytokines