The Multidrug Resistance gene (MDR-1) encodes a cell membrane based drug efflux pump Pgp-170 expressed on the surface of peripheral blood lymphocytes (PBLs) and intestinal epithelial cells (ECs), the putative targets of immunosuppressant therapy in inflammatory bowel disease (IBD). Studies in mdr-knockout mice, indicate that high MDR expressing T-lymphocytes and epithelial cells actively transports glucocorticoids, and other immunosuppressants out of target cells thereby lowering their intracellular concentrations to subtherapeutic levels. Previous work by us has demonstrated that ulcerative colitis patients requiring proctocolectomy for failed medical therapy and Crohn s disease patients requiring multiple resections for refractory disease both showed significantly elevated PBL MDR expression compared to either disease or normal controls. We have also shown that PBL MDR expression correlates with both colonic intraepithelial lymphocyte (IEL) and epithelial cell MDR expression and that constitutively high lymphocyte and mucosal MDR expression may play an important role in determining the response of IBD patients to immunosuppressant therapy, particularly glucocorticoids. If this hypothesis is correct, evaluation of MDR expression and function may be useful in enhancing pharmacotherapy of patients with IBD. In this project we will specifically examine the regulation of MDR-dependent glucocorticoid efflux from human T-lymphocytes and intestinal epithelial cells, explore the role of Pgp-170 in transporting other immunosuppressants central to IBD therapy, and assess the anti-inflammatory efficacy of MDR pump inhibitors.
| Farrell, R J; Menconi, M J; Keates, A C et al. (2002) P-glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes. Aliment Pharmacol Ther 16:1021-31 |
