MULTIDRUG TRANSPORTER P-GLYCOPROTEIN-170 AS A DIFFERENTIATION ANTIGENON NORMAL HUMAN-LYMPHOCYTES AND THYMOCYTES - MODULATION WITH DIFFERENTIATION STAGE AND DURING AGING

P-glycoprotein 170 (P-gp), the multidrug transport pump, excludes drug s from the interior of cells and is inhibited by agents such as cyclos porin A (CsA), verapamil, and FK-506, which are also substrates for th e P-gp pump, This work documents the age- and differentiation-related changes in P-gp on T and B lymphocytes from human blood or spleen, and its absence on most thymus and bone marrow cells, Analysis of rhodami ne 123 (Rh123) dye efflux, and its inhibition by cyclosporin A, was us ed as a quantitative measure of functional P-gp, and reactivity with M RK-16 was used as a measure of P-gp surface expression, The dye efflux and phenotypic expression of P-gp(+) PBMC appeared equivalent to that of a moderately drug-resistant cell line, although efflux is prolonge d. The sensitivity to inhibition by CsA, cyclosporin G (CsG), and PSC8 33 of P-gp on PBMC, thymocytes, or T-cell lines varied with apparent c ell-type specificity, Normal blood and splenic T- or a-cells included 50-80% of cells with surface P-gp (MRK-16(+)), which mediated CsA-sens itive dye export, The proportion of P-gp(+) T- and B-cells was lowest among children under age 10 years, increased in adulthood, and decreas ed after age 60, Thymus included 30% of P-gp(+) cells mediating CsA-se nsitive dye export, including CD3(-)4(-)8(-) progenitors and mature CD 3(hl) CD4(+)8(-) or CD4(-)8(+) thymocytes. Mature T-cells in cord or a dult blood, spleen, and bone marrow included a large proportion (50-60 %) with efficient CsA-sensitive dye export, preferentially among the C D45RA(+) subset. Monocytes from all tissue sources, and most bone marr ow cells, expressed surface P-gp but retained Rh123, suggesting the ab sence of a functional dye export mechanism. In vitro mitogen-stimulate d PBMC T and a lymphocytes lost P-gp function within 4-24 hr, consiste nt with the observation that P-gp was reduced on antigen-experienced C D45R0(+) T-cells in vivo. Drug export by P-gp may protect lymphocytes from toxic effects of CsA, and may contribute to the immunosuppressive effects of such drugs. The developmentally regulated expression of P- gp function on lymphocytes, and its modulation on activated T- or B-ce lls, suggest an important role in normal immune development. (C) 1995 Wiley-Liss, Inc.