title: Sustained suppression of peripheral blood immune functions by treatment with mycophenolate mofetil correlates with reduced severity of cardiac allograft rejection.
abstract: BACKGROUND
  We tested the hypothesis that sustained suppression of immune functions by mycophenolate mofetil (MMF) throughout the dosing interval reduces the severity of rejection.
  
  
  METHODS
  Four groups of rat heart allograft recipients were treated orally daily through Day 5 with either: "low-dose" MMF, 10 mg/kg once daily (QD) or 5 mg/kg twice daily (BID); or "high-dose" MMF, 20 mg/kg QD or 10 mg/kg BID. The following were determined for all animals on Day 6: pharmacokinetics (PK, using high-performance liquid chromatography) of mycophenolic acid (MPA); pharmacodynamics (PD, by flow cytometry quantitation of whole blood mitogen-stimulated lymphocyte proliferation and expression of diverse T-cell surface activation molecules); and histologic graft rejection scores (RS).
  
  
  RESULTS
  RS correlated with PD for suppression of both lymphocyte proliferation and transferrin receptor expression (r2 = 0.85 and 0.81, respectively) more highly than with MPA plasma levels (r2 = 0.45), which shows the validity of PD as surrogate markers of MMF efficacy. MMF 5 mg/kg BID produced greater (p < 0.001) suppression of lymphocyte proliferation (area under the PD effect-time curve, AUE = 2,010% inhibition. hour) and sustained trough (E0) PD effect (86% suppression) than MMF 10 mg/kg QD (AUE = 1,436% inhibition. hour, E0 = 55%). RS did not differ between the 20 mg/kg QD and 10 mg/kg BID "high-dose" groups, because PD was maximally suppressed.
  
  
  CONCLUSIONS
  PD were surrogate markers for MMF immunosuppressive efficacy. MMF 5 mg/kg BID produced more sustained suppression of both PD and rejection than MMF 10 mg/kg QD.
authors.affiliation: Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA. jochen.klupp@charite.de
authors.forename: Jochen
authors.initials: J
authors.lastname: Klupp
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.forename: Camille
authors.initials: C
authors.lastname: Dambrin
authors.forename: Jakub J
authors.initials: JJ
authors.lastname: Regieli
authors.forename: Katrin
authors.initials: K
authors.lastname: Boeke
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Billingham
authors.forename: Randall E
authors.initials: RE
authors.lastname: Morris
mesh_terms: D000818:Animals; D018845:CD11 Antigens / Q000378:metabolism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D018845:CD11 Antigens; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D018799:Intercellular Adhesion Molecule-1; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid