title: Mycophenolate mofetil inhibits T-cell proliferation in kidney transplant recipients without lowering intracellular dGTP and GTP.
abstract: To study if mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), indeed inhibits T-cell proliferation in kidney transplant recipients by lowering intracellular deoxyguanosine triphosphate (dGTP) and guanosine triphosphate (GTP) levels. Blood was drawn from 11 kidney transplant recipients. Ex vivo T-cell proliferation was measured by stimulation with phytohemagglutin (PHA) and anti-CD3 monoclonal antibody (mAb). Plasma MPA levels and intracellular dGTP and GTP in peripheral blood mononuclear cells were measured. MMF induces a significant decrease in T-lymphocyte proliferation at all time points (i.e. 24 h, 10 days and 8 weeks) after stimulation with both PHA (P = 0.001, 0.002 and 0.013 respectively) and anti-CD3 mAb (P = 0.004, 0.004 and 0.005 respectively). There was no significant change in intracellular dGTP (P = 0.31, 0.16 and 0.35) or GTP levels (P = 0.99, 0.32 and 0.49) between baseline and day 1, day 10 or week 8. All MPA levels were above the minimal required concentration for the inhibition of lymphocyte proliferation. MMF inhibits T-lymphocyte proliferation in kidney transplant recipients without lowering intracellular dGTP or GTP levels. This suggests another mechanism underlying its immunosuppressive capacity.
authors.affiliation: Division of Infectious Diseases, Tropical Medicine and AIDS, Department of Internal Medicine, and Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands. s.u.sankatsing@amc.uva.nl
authors.forename: Sanjay U C
authors.initials: SU
authors.lastname: Sankatsing
authors.forename: Jan M
authors.initials: JM
authors.lastname: Prins
authors.forename: Si-La L
authors.initials: SL
authors.lastname: Yong
authors.forename: Jeroen
authors.initials: J
authors.lastname: Roelofsen
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Steve
authors.initials: S
authors.lastname: Kewn
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Frederike J
authors.initials: FJ
authors.lastname: Bemelman
authors.forename: Ineke J M
authors.initials: IJ
authors.lastname: ten Berge
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects*; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D005260:Female; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D003848:Deoxyguanine Nucleotides; D006160:Guanosine Triphosphate; C029603:deoxyguanosine triphosphate; D009173:Mycophenolic Acid