[Multi-drug resistance in the treatments of autoimmune diseases].
Although corticosteroids and immunosuppressants are widely used for the treatments of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), we often experience patients who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, plays a pivotal role in the acquisition of drug resistance. However, the relevance of MDR-1 and P-gp to resting and activated lymphocyte, major targets of the treatments in autoimmune diseases, remains unclear. We found that peripheral lymphocytes in patients with SLE and RA express P-gp on the surface and its expression is highly correlated with disease activity. P-gp on lymphocytes is induced by activation with cytokines such as IL-2, IL-4 and TNF-alpha, resulting in active efflux of corticosteroids from cytoplasm of lymphocytes, which mechanisms could lead to drug-resistance and high disease activity. However, the addition of P-gp antagonists such as ciclosporin A and inhibitors of P-gp synthesis successfully reduce efflux of corticosteroids from lymphocytes in vitro and these results imply that P-gp antagonists and P-gp synthesis inhibitors could work in order to overcome drug-resistance in vivo. Therefore, we propose that measurement of P-gp on lymphocytes is useful marker to indicate drug resistance and requirement of antagonists and/or intensive treatments to overcome drug resistance in active SLE and RA patients.
Tanaka
Yoshiya
Y
Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.
Tsujimura
Shizuyo
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000328:Adult; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005260:Female; D019450:Genes, MDR; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy; D008214:Lymphocytes / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1