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).


CONCLUSIONS
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.
Richter
Markus
M
Department of Cardiac Surgery, Heart Center, University of Leipzig, Leipzig, Germany. drichter@gmx.net
Zahn
Steffen
S
Richter
Heike
H
Mohr
Friedrich Wilhelm
FW
Olbrich
Hans Georg
HG
D000818:Animals; D040881:CD11a Antigen / Q000032:analysis; D023921:Coronary Stenosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D003331:Coronary Vessels / Q000473:pathology*; D016572:Cyclosporine / Q000494:pharmacology; D016027:Heart Transplantation / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis*; D007962:Leukocytes / Q000737:chemistry* / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology
D040881:CD11a Antigen; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus