Donor treatment with mycophenolate mofetil: protection against ischemia-reperfusion injury in the rat.
BACKGROUND
Mycophenolic acid, the active metabolite of mycophenolate mofetil, inhibits the glycosylation of cell membrane glycoproteins. We hypothesized that impaired glycosylation of cell adhesion molecules on endothelial cells in vivo results in decreased susceptibility to inflammation or immunogenicity after allogeneic transplantation.


METHODS
The expression of mannose residues on cultured rat endothelial cells was examined after stimulation with interleukin 1 in the presence or absence of mycophenolic acid using labeled Galanthus nivalis agglutinin. The in vitro adhesion of blood leukocytes to heart tissue was examined using peripheral blood leukocytes of recipient origin and sections of donor heart tissue exposed to ischemia-reperfusion injury after pretreatment with vehicle or mycophenolic mofetil. (LEWxBN)F1 donor rats were treated with 20 or 60 mg/kg/day of mycophenolate mofetil for 1 or 2 weeks followed by transplantation of the heart into Lewis recipients after storage in heparin-containing normal saline for either 10 min at 4 degrees C or 120 min at room temperature.


RESULTS
Endothelial cells stimulated in vitro with interleukin 1 showed an increase in a population of strongly mannose-positive cells, which was prevented by the addition of mycophenolic acid during the culture. The in vitro adhesion of peripheral blood leukocytes to cardiac tissue sections exposed to prolonged storage and reperfusion was significantly less if the donor had been treated with mycophenolate mofetil. Treatment of cardiac graft donors with mycophenolate mofetil protected the graft against early graft failure after prolonged storage at room temperature, because the mean graft survival was 9.4+/-0.6 days for grafts that came from donors treated with mycophenolate mofetil versus 1.2+/-0.9 days (P<0.05) for grafts that came from vehicle-treated donors. Donor pretreatment with mycophenolate mofetil did not affect the survival time of heart grafts transplanted after 15 min of standard cold storage or the survival of grafts transplanted into presensitized recipients.


CONCLUSIONS
Donor treatment with mycophenolate mofetil protects cardiac grafts against primary nonfunction after prolonged tepid storage, which may be related to the inhibition of glycosylation of cell adhesion molecules involved in ischemia-reperfusion injury.
Valentin
J F
JF
Department of Medicine, University of Toronto at St. Michael's Hospital, Ontario, Canada.
Bruijn
J A
JA
Paul
L C
LC
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D027801:Galanthus; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007962:Leukocytes / Q000473:pathology; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D014019:Tissue Donors; D014181:Transplantation Immunology
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid