CARDIAC ALLOGRAFT SURVIVAL IN MICE DEFICIENT IN INTERCELLULAR-ADHESION MOLECULE-1

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.