Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression

Sukh Singh, Dave Singh, John Alexander, Andrew Owen, Rana Rustom, Mike Bone, Abdel Hammad, Norman Roberts, Kevin Park, Munir Pirmohamed

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Background. Cyclosporine (CsA) is a substrate for the MDR-1 gene product P-glycoprotein (P-gp). CsA efficacy may be modulated by lymphocyte P-gp expression levels. In this study, CsA inhibition of lymphocyte proliferation in whole-blood cultures ex vivo has been related to (1) lymphocyte P-gp expression and (2) the C3435T polymorphism in the MDR-1 gene, which has been reported to alter P-gp function. Methods. In 30 renal-transplant recipients taking CsA monotherapy, P-gp expression was measured by flow cytometry. Whole-blood samples were stimulated with purified protein derivative (PPD) and phytohemagglutinin (PHA). CsA resistance ex vivo was defined as less than 10% reduction in proliferation with either PPD or PHA at 2 hours compared with 0 hours. Results. CsA resistance was associated with greater P-gp expression using either PPD (median expression, resistant 1.89 vs. sensitive 0.96, P=0.02) or PHA (1.66 vs. 0.96, respectively, P=0.02). Whole-blood CsA levels in resistant and sensitive patients were similar. The C3435T polymorphism did not affect inhibition of proliferation by CsA (P>0.05 for all between genotype group comparisons). Conclusions. Our results indicate that lymphocyte P-gp expression determines the degree of inhibition of proliferation by CsA ex vivo; whether this also affects CsA effectiveness in vivo and therefore graft survival requires further study.
    Original languageEnglish
    Pages (from-to)557-561
    Number of pages4
    JournalTransplantation
    Volume77
    Issue number4
    DOIs
    Publication statusPublished - 27 Feb 2004

    Keywords

    • Administration, Oral
    • Adult
    • Aged
    • drug effects: Cell Division
    • Cells, Cultured
    • administration & dosage: Cyclosporine
    • Cytosine
    • Drug Resistance
    • Female
    • genetics: Genes, MDR
    • Genotype
    • Heterozygote
    • Homozygote
    • Humans
    • administration & dosage: Immunosuppressive Agents
    • Kidney Transplantation
    • pathology: Lymphocytes
    • Male
    • Middle Aged
    • metabolism: P-Glycoprotein
    • pharmacology: Phytohemagglutinins
    • genetics: Polymorphism, Genetic
    • Thymine
    • pharmacology: Tuberculin

    Fingerprint

    Dive into the research topics of 'Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression'. Together they form a unique fingerprint.

    Cite this