P‐glycoprotein (P‐gp) Is Upregulated in Peripheral T‐Cell Subsets from Solid Organ Transplant Recipients

Immunosuppressive agents such ascyclosporine, tacrolimus, sirolimus, and corticosteroids are substrates for the transmembrane multidrug resistance pump P‐glycoprotein (P‐gp). Experience in oncology has suggested that chronic exposure to P‐gp substrates induces upregulation of P‐gp activity, which could result in resistance to immunosuppressive drugs. The authors investigated P‐gp function in CD4+ and CD8+ T cells from the peripheral blood of solid organ transplant recipients (SOTX). Subjects included 14 stable SOTX (10 liver, 4 lung) and 16 healthy controls. Four‐color flow cytometry was used to simultaneously measure intracellular concentration of the fluorescent P‐gp substrate Rhodamine 123 (Rh123) and surface expression of CD45RO (nominal memory/effector), CD45RA (naive), and either CD4 or CD8. P‐glycoprotein function was measured by a dye efflux assay in which activity was inferred from a decrease in Rh123 fluorescence. CD4+ and CD8+ T cells from patients and control subjects eliminated Rh123, and this activity was inhibited by verapamil, a known P‐gp substrate. CD8+ T cells had greater P‐gp activity than CD4+ cells, and naive and transitional T cells displayed greater activity than memory T cells. Activity wasbimodalin CD8+ CD45RO+ T cells, with a subset of these cells expressing the greatest P‐gp activity. Patient CD8+ naive and transitional T cells had upregulated P‐gp activity compared to control subjects. We conclude that (1) P‐gp activity is significantly upregulated in specific T‐cell subsets (CD8+/CD45RA+) in the peripheral blood of SOTX, and (2) the bimodal nature of P‐gp response in CD8+ T cells complicates analysis of the effect of chronic administration of P‐gp substrates to SOTX.