title: Inhibition of PHA induced mononuclear cell proliferation by FK506 in combination with cyclosporine, methylprednisolone, 6-mercaptopurine and mycophenolic acid.
abstract: In vitro inhibition of human peripheral blood mononuclear cell (PBMC) proliferation by immunosuppressive drugs has been shown to correlate with clinical outcomes in kidney transplant patients. The aim of our study was to analyse the degree of variability of in vitro interactions of FK506 (FK) with combinations of cyclosporin A (CyA), methylprednisolone (MP), 6-mercaptopurine (6ME), and mycophenolic acid (MPA) using phytohaemagglutinin (PHA) stimulated PBMCs. Our hypotheses were: that a wide range of interindividual variation would be detected; and that certain combinations of drugs would have a synergistic inhibitory effect on PHA stimulated PBMCs. Cells were cultured in supplemented RPMI 1640 for 65 hours at 37 degrees C in humidified 5% CO2 - 95% air and proliferative responses measured by 3H-thymidine incorporation over a further 24 hours. Inhibition of PBMC proliferation was assessed over 10 FK concentrations ranging from 1 x 10(-8) to 10 micrograms/ml using both volunteer controls (n = 51) and dialysis patients (n = 23). A wide range of interindividual variability of FK inhibition occurred throughout the range of FK concentrations tested, becoming less variable at the higher concentrations. The interactions of FK with CyA, MP, 6ME and MPA were assessed using PBMCs from 12 volunteer controls. For FK at 1 x 10(-8) micrograms/ml; CyA, MP, 6ME and MPA were used at 0.01 microgram/ml. For FK at 1 x 10(-7) micrograms/ml; CyA, MP, 6ME and MPA were used at 0.1 microgram/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Renal Medicine, Westmead Hospital, Sydney, NSW Australia.
authors.forename: M
authors.initials: M
authors.lastname: Hibbins
authors.forename: S
authors.initials: S
authors.lastname: Inutsuka
authors.forename: J R
authors.initials: JR
authors.lastname: Chapman
mesh_terms: D016572:Cyclosporine / Q000008:administration & dosage; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D016030:Kidney Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D015122:Mercaptopurine / Q000008:administration & dosage; D008775:Methylprednisolone / Q000008:administration & dosage; D009173:Mycophenolic Acid / Q000008:administration & dosage; D010835:Phytohemagglutinins / Q000494:pharmacology; D016559:Tacrolimus / Q000008:administration & dosage*; D014511:Uremia / Q000276:immunology
chemical_list: D010835:Phytohemagglutinins; D016572:Cyclosporine; D015122:Mercaptopurine; D009173:Mycophenolic Acid; D016559:Tacrolimus; D008775:Methylprednisolone