The effect of CSA, FK506 and MMF on the expression of inducible cell adhesion molecules (iCAMs), transplant vasculopathy and leukocyte infiltration

Abstract

iCAMs play a critical role in mediating allograft recognition and rejection, leading to leukocyte attachment to graft endothelium and transendothelial migration into the myocardium. This process is a crucial step in the development of transplant vasculopathy (TVP). We investigated the effect of CSA, FK506 and MMF on ICAM-1, VCAM-1, PECAM-1 and P-Selectin expression, the resulting leukocyte infiltration and neointimal proliferation of arteries after cardiac transplantation in rats. 340 transplantations were performed (Lewis to Fisher), animals were divided into 4 groups: CSA 3mg/kg/d (n 74), MMF 40mg/kg/d (n 96), FK506 0.3mg/kg/d (n 96) and Control (no therapy, n 74). 3–4 animals of each group were sacri-ficed in intervals of 1–4 days up to day 60. Using immunohistochemistry we investigated quote, intensity and geometric distribution of ICAM-1, VCAM-1, PECAM and P-Selectin staining. We analysed the accumulation of leukocytes (CD4, CD8, CD11a, CD18, VLA4) in the perivascular space (pvs) of arteries. TVP in coronary arteries was expressed as mean vessel occlusion (mvo). In controls staining parameters of iCAMs, leukocyte accumulation and mvo rapidly increased and were reduced by all drugs compared to controls. We found significant correlations between staining parameters, infiltration of leukocytes and mvo. MMF was superior to CSA and FK506 in reducing TVP, leukocyte attachment, infiltration, and iCAMs expression, except VCAM-1 expression and VLA4 infiltration being significantly higher in MMF treated animals compared to CSA or FK506. The only difference between the calcineurin inhibitors was a further reduction of VCAM-1 expression and VLA4 leukocyte infiltration by FK506. Although MMF had no significant effect on VCAM-1/VLA4 mechanisms, it reduced the development of TVP significantly compared to calcineurin inhibitors. This effect was due to the reduction of ICAM-1, PECAM-1 and P-Selectin expression that correlates with the infiltration of leukocytes into the pvs of arteries.