Role of ICAM-1 in chronic hepatic allograft rejection in the rat.
The pathogenesis of hepatic allograft rejection remains unclear. We aimed to clarify the early role of intercellular adhesion molecule-1 (ICAM-1)-mediated cell recruitment in chronic hepatic rejection. Liver transplantation was performed from Lewis to Lewis rats (isograft controls) and from Lewis to Brown Norway rats (allograft rejection group). The allografted rats were treated with either ICAM-1 antisense oligonucleotides (10 mg. kg(-1). day(-1) x 6 days ip) or a control preparation (either ICAM-1 missense oligonucleotide or normal saline). Hepatic leukocyte recruitment in vivo was studied on day 6 by using intravital microscopy. Liver histology, biochemistry, and survival rates were also examined. Leukocyte adhesion in terminal hepatic venules was significantly increased in the rejection group compared with isograft controls. Antisense ICAM-1 in the allografted group effectively reduced leukocyte adhesion. Histology and liver chemistry were less deranged in the antisense-treated groups compared with control-treated allografted rats. In the allograft groups, survival was significantly prolonged in the antisense-treated rats (42.3 +/- 1.2 days) compared with the controls (25.2 +/- 2.7 days). These results showed that early leukocyte recruitment in the hepatic microvasculature of rejecting allografts is ICAM-1 dependent and suggest that impacting on early cell recruitment can significantly ameliorate chronic rejection.
Wong
John
J
Liver Unit, Gastroenterology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Kubes
Paul
P
Zhang
Yikun
Y
Li
Yang
Y
Urbanski
Stefan J
SJ
Bennett
C Frank
CF
Lee
Samuel S
SS
D000818:Animals; D002448:Cell Adhesion; D002908:Chronic Disease; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D016031:Liver Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D013194:Staining and Labeling; D016019:Survival Analysis; D014184:Transplantation, Homologous
D016376:Oligonucleotides, Antisense; D018799:Intercellular Adhesion Molecule-1