Donor treatment with mycophenolate mofetil: protection against ischemia-reperfusion injury in the rat
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Published on: April 2, 2017
J F Valentin1, J A Bruijn, L C Paul
1Department of Medicine, University of Toronto at St. Michael's Hospital, Ontario, Canada.
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.
Conclusion:
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.
Insights
Mycophenolate mofetil pretreatment of cardiac graft donors reduces leukocyte adhesion and improves graft survival after prolonged warm storage. This suggests a protective effect against ischemia-reperfusion injury by inhibiting cell adhesion molecule glycosylation.
Area of Science:
- Immunology
- Transplantation Biology
- Biochemistry
Background:
- Mycophenolic acid, the active metabolite of mycophenolate mofetil, inhibits glycoprotein glycosylation.
- This study investigates if inhibiting glycosylation reduces endothelial cell inflammation and immunogenicity post-transplant.
Purpose of the Study:
- To determine if mycophenolate mofetil pretreatment of donor rats affects leukocyte adhesion to cardiac tissue.
- To assess the impact of mycophenolate mofetil on heart graft survival after prolonged storage and transplantation.
Main Methods:
- Rat endothelial cells were stimulated with IL-1 and treated with mycophenolic acid, with mannose residue expression analyzed.
- Leukocyte adhesion to cardiac tissue sections from mycophenolate mofetil-treated or vehicle-treated donors was assessed in vitro.
- Heart grafts from treated or untreated donors were stored and transplanted into recipients, with survival monitored.
Main Results:
- Mycophenolic acid inhibited mannose residue expression on IL-1 stimulated endothelial cells.
- Leukocyte adhesion to cardiac tissue was significantly reduced in grafts from mycophenolate mofetil-treated donors.
- Mycophenolate mofetil pretreatment significantly improved heart graft survival after prolonged room temperature storage (9.4 days vs 1.2 days).
Conclusions:
- Donor pretreatment with mycophenolate mofetil protects cardiac grafts from primary nonfunction after extended warm storage.
- This protection is potentially mediated by the inhibition of glycosylation on cell adhesion molecules involved in ischemia-reperfusion injury.
