Kinetics of intragraft cytokine expression, cellular infiltration, and cell death in rejection of renal allografts compared with acceptance of liver allografts in a rat model: early activation and apoptosis is associated with liver graft acceptance.
BACKGROUND
Liver transplants in the rat strain combination PVG-to-Dark Agouti are spontaneously tolerated, whereas kidney transplants in the same strain combination are rejected in 7-9 days.


METHODS
To identify organ-specific differences that might yield further information about the mechanism of tolerance induction in this strain combination, liver or kidney grafts, spleen, and draining lymph nodes were harvested at days 1, 3, 5, and 7, and examined by immunohistochemistry, terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay, and reverse transcriptase-polymerase chain reaction for interferon-gamma, interleukin (IL)-2, IL-4, and IL-10.


RESULTS
Renal allograft rejection was associated with the progressive development of an intense mononuclear cell infiltrate. Markers of lymphocyte activation and cytokine up-regulation appeared from day 3, and many apoptotic parenchymal cells were noted on days 5-7, at the peak of rejection. Conversely, liver allograft tolerance was associated with more rapid infiltration by activated T cells and earlier increases in cytokine expression, but with a more limited degree of cellular infiltration. Concurrent with the early activation, high levels of apoptosis were found in areas of leukocyte infiltrate, paralleling the disappearance of activated T cells from the graft between days 3 and 5.


CONCLUSIONS
Apoptosis of infiltrating leukocytes in liver allografts may represent an important process in the induction of spontaneous liver transplant tolerance and may underlie the abortive nature of the effector response observed within tolerated livers. In contrast, activated cells in renal allografts in the same strain combination survive and proliferate, express high levels of cytokines, and are efficient in bringing about graft destruction.
Sharland
A
A
AW Morrow Gastroenterology and Liver Laboratory, Centenary Institute, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Shastry
S
S
Wang
C
C
Rokahr
K
K
Sun
J
J
Sheil
A G
AG
McCaughan
G W
GW
Bishop
G A
GA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006085:Graft Survival / Q000502:physiology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D007700:Kinetics; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D016031:Liver Transplantation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014158:Transcription, Genetic; D014184:Transplantation, Homologous
D016207:Cytokines; D012333:RNA, Messenger