Mycophenolate mofetil significantly reduces leukocyte graft infiltration after heterotopic cardiac transplantation in a rat model: comparative study with cyclosporine and FK 506.
BACKGROUND
The purpose of the study was to evaluate the effects of cyclosporine (CsA), FK 506 and mycophenolate mofetil (MMF) on graft-infiltrating leukocytes (CD4, CD8, CD11a, CD18) after cardiac transplantation in rats.


METHODS
Three hundred forty animals were transplanted and randomly divided into 4 groups: CsA, 3 mg/kg/d (n = 74); MMF, 40 mg/kg/d (n = 96); FK 506, 0.3 mg/kg/d (n = 96); and a control group receiving no immunosuppressive therapy (n = 74). Three or 4 animals from each group were killed at intervals of 1 to 4 days up to Day 60. Immunohistochemistry was performed using monoclonal antibodies (MAb) against CD4, CD8, CD11a and CD18. Positively stained cells were analyzed in the perivascular space (PVS) of intra- and epicardial arteries. Statistical analysis was performed using area-under-the-curve assessment with an extended t-test.


RESULTS
CsA and FK 506 reduced the presence graft-infiltrating leukocytes (CD4, CD8, CD11a, CD18) in the PVS of intra- and epicardial arteries when compared with control animals. MMF therapy resulted in a further significant reduction in infiltrating leukocytes when compared with the 2 calcineurin inhibitors. MMF had a faster onset of action than the calcineurin inhibitors. CsA and FK 506 required 12 to 20 additional days to achieve the reducing effect of graft infiltration seen in MMF-treated animals.


CONCLUSIONS
MMF possesses potent infiltration-blocking properties and its application leads to a greater reduction of cellular infiltration in the course of transplant rejection when compared with calcineurin inhibitors.
Richter
Markus H C
MH
Department of Cardiac Surgery, Heart Center, University of Leipzig, Leipzig, Germany. drrichter@gmx.net
Zahn
Steffen
S
Kraus
Marion
M
Mohr
Friedrich Wilhelm
FW
Olbrich
Hans Georg
HG
D000818:Animals; D040881:CD11a Antigen / Q000276:immunology; D018821:CD18 Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D016572:Cyclosporine / Q000627:therapeutic use*; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007962:Leukocytes / Q000276:immunology / Q000502:physiology*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use*; D016042:Transplantation, Heterotopic
D040881:CD11a Antigen; D018821:CD18 Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus