CORONARY ATHEROSCLEROSIS IN TRANSPLANTED MOUSE HEARTS .4. EFFECTS OF TREATMENT WITH MONOCLONAL-ANTIBODIES TO INTERCELLULAR-ADHESION MOLECULE-1 AND LEUKOCYTE FUNCTION-ASSOCIATED ANTIGEN-1

Atherosclerotic lesions in the coronary arteries of transplanted mouse hearts manifest high expression of ICAM-1 (CD54), especially on endothelial surfaces, and of LFA-1 (CD11a) on migratory mononuclear cells. The possible participation of cellular adhesion systems in the evolution of these complex lesions was suggested by the increased expression of intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-1 (LFA-1) and also by our previous studies with this experimental system, In our studies, we have found that administration of a monoclonal antibody (mAb) to gamma-interferon will greatly suppress coronary changes, and gamma-interferon is known to stimulate the formation of these adhesion molecules. The present experiments were to evaluate how administration to murine heart transplant recipients of mAbs against ICAM-1, LFA-1, or both affected the development of coronary atherosclerosis, It was found that treatment with either mAb alone did not alter the severity of coronary atherosclerosis, but that both mAbs given together can significantly suppress lesion formation at 30 days compared with controls (P<0.044). Continuing treatment was even more effective when extended to 60 days (P<0.003). The mAbs to ICAM-1 and LFA-1 bound their targets in vivo (primarily endothelium and mononuclear cells, respectively), but complete, long-term saturation of combining sites was not attained, even with very high doses. No appreciable reduction in arterial endothelial ICAM-1 expression was evident. It is concluded that the ICAM-1/LFA-1 system is of central importance in the evolution of accelerated coronary atherosclerosis.