Abstract
Although corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) are widely used in the treatment of various systemic autoimmune diseases such as systemic lupus erythematosus (SLE), we often experience patients with systemic autoimmune diseases who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, is known to play a pivotal role in the acquisition of drug resistance to chemotherapy in malignancy. However, the relevance of MDR-1 and P-gp to resting and activated lymphocytes, which are the major target in the treatment of systemic autoimmune diseases, remains unclear. Studies from our laboratories found surface expression of P-gp on peripheral lymphocytes in patients with SLE and a significant correlation between the expression level and disease activity. Such expression is induced not only by genotoxic stresses but also by various stimuli including cytokines, resulting in active efflux of drugs from the cytoplasm of lymphocytes, resulting in drug-resistance and high disease activity. However, the use of both P-gp antagonists (e.g., cyclosporine) and inhibition of P-gp synthesis with intensive immunosuppressive therapy successfully reduces the efflux of corticosteroids from lymphocytes in vitro, suggesting that P-gp antagonists and P-gp synthesis inhibitors could be used to overcome drug-resistance in vivo and improve outcome. In conclusion, lymphocytes activated by various stimuli in patients with highly active disease apparently acquire MDR-1-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. The expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable target to combat drug resistance in patients with active systemic autoimmune diseases.
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Acknowledgments
The authors thank Ms. T. Adachi for the excellent technical assistance. This work was supported in part by research Grants-In-Aid for Scientific Research by the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan and University of Occupational and Environmental Health, Japan.
Conflict of interest
Dr. Tanaka has received consulting fees, speaking fees, and/or honoraria from Mitsubishi-Tanabe, Chugai, Eisai, Takeda, Astellas, and Abbott, and has received research grant support from Mitsubishi-Tanabe, Takeda, MSD, Pfizer, Astellas, Chugai, Abbott, and Eisai. Dr. Tsujimura declares no conflict of interest.
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Tsujimura, S., Tanaka, Y. Treatment strategy based on targeting P-glycoprotein on peripheral lymphocytes in patients with systemic autoimmune disease. Clin Exp Nephrol 16, 102–108 (2012). https://doi.org/10.1007/s10157-011-0520-3
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DOI: https://doi.org/10.1007/s10157-011-0520-3