Reduction of ICAM-1 and LFA-1-positive leukocytes in the perivascular space of arteries under mycophenolate mofetil therapy reduces rat heart transplant vasculopathy

Background: The interaction of lymphocyte function-associated antigen-1 (LFA-1)-positive host leukocytes with intercellular adhesion molecule-1 (ICAM-1) on graft endothelium may play a key role in allograft recognition, triggering the development of transplant vasculopathy (TVP). We investigated the correlation between TVP and ICAM-1 expression and accumulation of LFA-1-positive leukocytes in the perivascular space (PVS) of arteries under different immunosuppressive drugs. Methods: After cardiac transplantation (Lewis to Fisher) animals were randomized 4 groups: cyclosporine (CsA), 3 mg/kg/day (n = 74); mycophenolate mofetil (MMF), 40 mg/kg/day (n = 96); FK 506, 0.3 mg/kg/day (n = 96); and control, no therapy (n = 74). Three or 4 animals from each group were harvested at intervals of 1 to 4 days within the study period of 60 days. Using immunohistochemistry,LFA-1 -positive leukocytes were analyzed in intra- and epicardial arteries. ICAM-1 expression was scored histologically. TVP was assessed by digitizing morphometry and expressed as mean vascular occlusion. Results: Accumulation of LFA-1-positive leukocytes in the PVS of arteries and the myocardium correlated with expression of ICAM-1 on graft endothelium. The severity of TVP in arteries correlated with the accumulation of LFA-1-positive leukocytes in PVS. All immunosuppressive drugs significantly reduced ICAM-1 expression, LFA-1 accumulation and extent of TVP, compared with controls. In MMF-treated animals, we also found a significant reduction of ICAM-1 expression, LFA-1 accumulation and extent of TVP compared with the groups treated with CsA and FK 506 (P < 0.005). Conclusion: These data support an essential role of LFA-1/ICAM-1 interaction in the genesis of TVP that may be abrogated, especially by the use of MMF. Copyright (C) 2004 by the International Society for Heart and Lung Transplantation.