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(H)2-C(H)3 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.
Barrou
Benoît
B
Unité de Transplantation Rénale et Pancréatique du Service d'Urologie, Groupe Hospitalier Pitié Salpêtrière, 75651 Paris, France.
Bertry-Coussot
Lydia
L
Morin
Sylvie
S
Sainz
Julie
J
Lucas
Bruno
B
Bitker
Marc Olivier
MO
Debré
Patrice
P
Lemarchand
Patricia
P
D000256:Adenoviridae; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006085:Graft Survival / Q000235:genetics*; D007074:Immunoglobulin G / Q000235:genetics*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011993:Recombinant Fusion Proteins; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1