The F(ab')2 fragment of an anti-ICAM-1 monoclonal antibody attenuates liver injury after orthotopic liver transplantation.
Long-term storage of liver grafts results in increased adhesion of leukocytes onto the sinusoidal walls. This eventually leads to posttransplant graft damage through disturbances of hepatic microcirculation. Intracellular adhesion molecule-1 (ICAM-1) is known to be involved in attachment of leukocytes. This study was designed to examine whether ICAM-1 participated in the pathogenesis of posttransplant liver injury. Inbred Lewis rats were used as both donors and recipients to avoid immunoreactivity. Donor livers were stored for either 1 or 6 hr in ice-cold Euro-Collins solution and subsequently implanted. Expression of ICAM-1 was examined immunohistochemically. In some rats that received livers stored for 6 hr, the intact IgG (1.0 mg/kg) or the F(ab')2 fragment (0.5 mg/kg) of an anti-ICAM-1 mAb (1A29) was administered via the tail vein immediately after reperfusion of portal blood. In the group receiving livers stored for 6 hr, ICAM-1 began to be expressed on the sinusoidal endothelial cells as early as 15 min after reperfusion of the portal blood. Strong ICAM-1 expression was observed from 2 hr up to 24 hr after reperfusion. In contrast, expression of ICAM-1 was not evident at any time point after surgery in the 1-hr storage group as well as in untransplanted, normal livers. Serum alanine aminotransferase (ALT) levels were significantly higher in the 6-hr storage group compared with those of the 1-hr storage group (1-hr: 171 +/- 9 IU/L; 6-hr: 825 +/- 109 IU/L, P < 0.05; mean +/- SEM) 24 hr after transplantation. Serum ALT levels were markedly reduced by treatment with the F(ab')2 fragment of 1A29 (247 +/- 34 IU/L, P < 0.05 vs. 6-hr storage group). This was associated with reduced accumulation of leukocytes in the liver. In marked contrast, treatment with the intact IgG of 1A29 increased serum ALT levels dramatically (5297 +/- 634 IU/L, P < 0.05 vs. 6-hr storage group) and reduced serum complement. Histological examination revealed focal hepatocellular necrosis 24 hr after surgery in the 6-hr storage group. Treatment with the F(ab')2 fragment decreased the liver damage; in marked contrast, treatment with the intact IgG strikingly aggravated the injury, as characterized by massive necrosis throughout the liver. Liver damage caused by the intact IgG might be related to activation of the complement system by the Fc portion of the antibody. Taken together, these results indicate that ICAM-1 is involved in the mechanism of postoperative liver injury following liver transplantation.
Nishimura
Y
Y
First Department of Medicine, Osaka University School of Medicine, Japan.
Takei
Y
Y
Kawano
S
S
Goto
M
M
Nagano
K
K
Tsuji
S
S
Nagai
H
H
Ohmae
A
A
Fusamoto
H
H
Kamada
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology*; D008099:Liver / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D016031:Liver Transplantation / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000276:immunology* / Q000517:prevention & control
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D018799:Intercellular Adhesion Molecule-1