Background Intercellular adhesion molecule-1 (ICAM-1, CD54) is a cell
adhesion molecule that interacts with the leukocyte beta 2 integrins,
lymphocyte function-associated antigen-1, and macrophage antigen-1. IC
AM-1 is postulated to play a key role in several cell-cell interaction
s that are important in allograft rejection, including antigen present
ation, transendothelial migration of leukocytes, and leukocyte-mediate
d myocyte injury. Methods and Results Mice homozygous for a gene-targe
ted mutation of ICAM-1 were used in two different cardiac transplant m
odels to further define the role of ICAM-1 in the process of allograft
rejection. In the first model, hearts from newborn mice were implante
d in the ear pinnae of H-2-incompatible recipients. In the second mode
l, intra-abdominal transplantation by direct vascular anastomosis was
performed. Time to rejection was defined by the loss of pulsatile acti
vity assessed by Visual inspection in the ear model or by cessation of
palpable cardiac impulse in the abdominal model. Allograft survival d
id not differ significantly between control groups that express normal
levels of ICAM-1 and those groups using ICAM-1-deficient mutants as e
ither donors or recipients. Histological examination of rejection of b
oth normal and mutant (ICAM-1-deficient) cardiac allografts revealed s
imilar patterns of infiltration of mononuclear and granulocytic leukoc
ytes and myocyte necrosis. Immunostaining with anti-ICAM-1 antibodies
showed ICAM-1-positive infiltrating cells in both mutant (ICAM-1-defic
ient) and normal allografts, with the graft endothelium negative for I
CAM-1 staining in the mutant allografts. Conclusions The absence of su
rface expression of ICAM-1 in the donor allograft or recipient is insu
fficient to produce a significant impact on cardiac allograft survival
. This study highlights the need to understand more precisely the mech
anism of action whereby monoclonal antibodies to ICAM-1 prolong cardia
c allograft survival before new therapeutic strategies based on gene t
ransfer technology or small molecule inhibitors are developed. Mutant
mice with targeted mutations in cell adhesion molecules provide powerf
ul tools to study the complex role that cell adhesion molecules play i
n the cellular interactions between donor graft tissue and the recipie
nt that culminate in graft rejection.