The Journal of Immunology, Vol 144, Issue 12 4604-4612, Copyright © 1990 by American Association of Immunologists
In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts
AB Cosimi, D Conti, FL Delmonico, FI Preffer, SL Wee, R Rothlein, R Faanes and RB Colvin
Transplantation Unit, Massachusetts General Hospital, Boston 02114.
These studies test whether allograft rejection can be blocked by
interference with leukocyte adhesion, using a murine IgG2a mAb (R6.5)
reactive with monkey ICAM-1 (CD54). In 16 Cynomolgus renal allograft
recipients, R6.5 was administered prophylactically as the sole
immunosuppressive agent for 12 days (0.01 to 2 mg/kg/day). Survival in 14
recipients with technically successful grafts was significantly prolonged
(24.2 +/- 2.4 vs 9.2 +/- 0.6 days for controls; p less than 0.001).
Intercellular adhesion molecule-1 (CD54) (ICAM-1) was expressed on vascular
endothelium in the kidney and other organs in the monkey in a pattern
similar to that in humans. During cellular rejection in controls, ICAM-1
expression increased on endothelial cells, infiltrating mononuclear
leukocytes and tubular cells. Biopsies during R6.5 administration showed
decreased T cell infiltration (CD2, CD8, CD4) compared with controls and
decreased arterial endothelial inflammation. No changes occurred in
circulating T cells, aside from variable coating with mIgG. In six of eight
other recipients R6.5 administration (0.5 to 2 mg/kg/day for 10 days)
reversed preexisting rejection that resulted from taper of Cyclosporine to
subtherapeutic levels. Responding grafts showed decreased edema and
hemorrhage but no consistent change in the infiltrate. At 1 h after the
first dose, mouse IgG deposited primarily on the graft vascular endothelium
without any change in the inflammatory infiltrate. Mouse IgG also deposited
on the endothelium of normal organs without eliciting an inflammatory
response and was cleared from the endothelium within 4 days. Inasmuch as
the principal site of binding was the vascular endothelium, we hypothesize
that the antibody blocks adhesion to graft ICAM-1 molecules on the vessels.
Anti-ICAM-1 also binds to recipient cells and may interfere with Ag
presentation and/or T cell interactions. Whatever the mechanism(s), these
studies indicate that an anti-ICAM-1 antibody inhibits T cell mediated
injury in vivo, and that ICAM-1 is a critical molecule in the pathogenesis
of allograft rejection.
