Effects of the multidrug resistance-1 gene on drug resistance in primary immune thrombocytopenia

Abstract

Primary immune thrombocytopenia (ITP) is an autoimmune disorder that is characterized by low platelet count. Glucocorticoids (GCs) resistance is a great challenge in the treatment of ITP. P-glycoprotein (P-gp) is a widely studied protein, which is associated with drug resistance. However, in ITP, the functional activity and immune regulation mechanism of P-gp remain uncertain. In this study, we evaluated the expression and functional activity of P-gp in different lymphocyte subsets, explored the correlation between P-gp function and GCs resistance and investigated the role of P-gp in ITP pathogenesis. Results indicated that the functional activity and mRNA level of P-gp were significantly higher in GCs-nonresponsive patients than in GCs-responsive patients with ITP. However, these differences in P-gp were only significant in CD8⁺ T cells. P-gp function was related to disease activity rather than GCs therapy. P-gp was involved in secreting granzyme B and perforin, maintaining autoreactive lymphocytes survival and enhancing autologous platelets lysis in ITP. In conclusion, over-functional P-gp might play an important role in the pathogenesis of ITP and induce GCs resistance in nonresponsive ITP patients. The blockage of P-gp could be a promising therapeutic approach for GCs-resistant patients with ITP.

Keywords:

• P-glycoprotein
• drug resistance
• CD8⁺ T cells
• cytokine
• apoptosis

Acknowledgements

We are grateful to the patients and healthy individuals who made this study possible.

Declaration of interest

This study was supported in part by grants of National Natural Science Foundation of China (81270581, 81300385 and 81470286), Tianjin Municipal Science and Technology Commission (14JCZDJC35100), Peking Union Medical College Innovation Fund (10023-0710-1007) and Specialized Research Fund for the Doctoral Program of Higher Education (20131106120039).