Prolonged Islet Allograft Survival by Adenovirus-Mediated Transfer of sICAM-1/Ig Immunoadhesin Gene

Administration of monoclonal antibodies directed against the leukocyte function-associated antigen 1 (LFA-1)-intercellular adhesion molecule 1 (ICAM-1) pathway showed that these costimulatory molecules play a key role in allograft rejection. Here, adenoviral gene transfer of an immunoadhesin, sICAM-1/Ig, was used to prolong islet allograft survival in a mouse model, and was compared with anti-LFA-1 antibody administration. A replication-deficient recombinant adenoviral vector encoding a chimeric protein, in which the extracellular domain of ICAM-1 is covalently linked to the C_H2-C_H3 domains of an IgG1, was used for gene transfer. C3H murine islets were transplanted under the kidney capsule of streptozotocin-induced diabetic BALB/c mice. Experimental groups underwent adenovirus vector administration either in vivo (intravenous injection) or ex vivo (gene transfer to the graft), and control groups received either an empty vector (Ad.null) or an anti-LFA-1 monoclonal antibody. Graft survival was significantly prolonged by in vivo sICAM-1/Ig gene transfer as compared with both Ad.null and anti-LFA-1 groups, but not by ex vivo gene transfer. Histological examination of the grafts showed the presence of a mononuclear infiltrate within functioning grafts, suggesting that the homing of alloreactive T cells was not altered. In vitro T cell proliferation experiments indicated that sICAM-1/Ig exerted agonist effects on both CD4⁺ and CD8⁺ T cells.