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 endot helial surfaces, and of LFA-1 (CD11a) on migratory mononuclear cells. The possible participation of cellular adhesion systems in the evoluti on of these complex lesions was suggested by the increased expression of intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-a ssociated antigen-1 (LFA-1) and also by our previous studies with this experimental system, In our studies, we have found that administratio n of a monoclonal antibody (mAb) to gamma-interferon will greatly supp ress 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 corona ry 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 m ore effective when extended to 60 days (P<0.003). The mAbs to ICAM-1 a nd LFA-1 bound their targets in vivo (primarily endothelium and mononu clear cells, respectively), but complete, long-term saturation of comb ining sites was not attained, even with very high doses. No appreciabl e 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.