title: Treatment by mycophenolate mofetil of advanced graft vascular disease in non-human primate recipients of orthotopic aortic allografts.
abstract: Failure to control chronic graft dysfunction [e.g. graft vascular disease (GVD)] is the primary cause of immunologic graft failure. This is the first study of mycophenolate mofetil (MMF) for the treatment of GVD in non-human primate recipients of aortic allografts. Abdominal aortic allografts were exchanged between mixed leukocyte reaction (MLR) -mismatched, blood-group-compatible cynomolgus monkeys. Six control recipients were untreated. Individualized treatment with frequent dose adjustments of MMF insured that treatment was close to the maximum tolerated dose (mean 99.2 mg/kg/day). Immune-mediated injury proceeded unhindered until day 45, after which MMF treatment began. Changes in intimal volume (IV) were quantified by intravascular ultrasound (IVUS) and compared to histology on day 105. Serial IVUS measurements of IV (mm(3)) in controls showed progressive GVD. In four out of six animals, MMF was well tolerated, thus enabling optimum treatment; in all these animals, IV was significantly less than in the control animals (p = 0.02). In the two remaining animals, high doses were not tolerated; at day 105, there was no significant difference in IV between them and the controls. We found a significant correlation between the mean MMF tolerated dose and the inhibition of progression of IV (r = -0.88, p = 0.015). When high MMF doses were tolerated, MMF slowed progression of GVD.
authors.affiliation: Transplantation Immunology, Department of Cardiothoracic Surgery, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5407, USA. jochen.klupp@charite.de
authors.forename: Jochen
authors.initials: J
authors.lastname: Klupp
authors.forename: Camille
authors.initials: C
authors.lastname: Dambrin
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hibi
authors.forename: Jorge
authors.initials: J
authors.lastname: Luna
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Bernard
authors.initials: B
authors.lastname: Hausen
authors.forename: Tudor
authors.initials: T
authors.lastname: Birsan
authors.forename: Teun
authors.initials: T
authors.lastname: Van Gelder
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fitzgerald
authors.forename: Gerald
authors.initials: G
authors.lastname: Berry
authors.forename: Randall E
authors.initials: RE
authors.lastname: Morris
mesh_terms: D000818:Animals; D001011:Aorta / Q000637:transplantation*; D001012:Aorta, Abdominal / Q000637:transplantation; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006083:Graft Occlusion, Vascular / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D008252:Macaca fascicularis; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid