Expression of apoptosis and apoptosis-related peptides in various stages of rejection in the human transplanted liver.
OBJECTIVE
In the transplanted liver, the role of apoptosis and apoptosis-related proteins are largely unknown. This study addresses the question whether hepatocyte or leukocyte apoptosis plays an important role in acute rejection of the transplanted human liver and which pathways are involved.


METHODS
Cryosections from liver biopsies with acute rejection were stained with the TUNEL technique for detection of apoptosis and labeled immunohistochemically with antibodies against CD95, bcl-2, TGF-beta and iNOS. A double-labeling protocol was developed for simultaneous detection of iNOS and apoptosis. Liver tissue with chronic viral hepatitis, with hepatitis reinfection and tissue without pathological findings served as a control.


RESULTS
Leukocyte apoptosis was markedly reduced in severe compared to mild or moderate acute rejection. Hepatocyte apoptosis is detected rarely in acute rejection with a slight increase from mild to severe despite a strong expression of CD95 and TGF-beta on hepatocytes. The hepatocyte expression of iNOS is weak in acute rejection but strong in control slides with hepatitis B/C reinfection. In acute rejection, simultaneous expression of iNOS and apoptosis could be demonstrated in Kupffer-cells.


CONCLUSIONS
Severe acute rejection in the human transplanted liver is characterized by a lack of apoptosis of infiltrating portal lymphocytes probably caused by a reduced downregulation of lymphocyte function. Secondly, in spite of the strong expression of CD95 and TGF-alpha, hepatocyte apoptosis plays a limited role for liver damage in acute rejection. Finally, Kupffer cell apoptosis is increased in acute rejection and seems to be induced by nitric oxide.
Töx
U
U
Department of Medicine IV, University of Cologne, D-50924 Köln, Germany. ulrich.toex@.uni-koeln.de
Burkhardt
M A
MA
Benz
C
C
Arnold
J C
JC
Otto
G
G
Theilmann
L
L
Goeser
T
T
D017209:Apoptosis / Q000502:physiology*; D006084:Graft Rejection / Q000503:physiopathology*; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007962:Leukocytes / Q000502:physiology*; D016031:Liver Transplantation / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II
C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II