MUTLIDRUG RESISTANCE (PGP-170) EXPRESSION IN IBD

多药耐药基因(MDR-1)编码一种基于细胞膜的药物外排泵PGP-170，表达于外周血淋巴细胞(PBL)和肠上皮细胞(ECs)表面，是炎症性肠病(IBD)免疫抑制治疗的靶点。在MDR基因敲除小鼠中的研究表明，高表达MDR的T淋巴细胞和上皮细胞积极地将糖皮质激素和其他免疫抑制剂转运出靶细胞，从而将它们的细胞内浓度降低到亚治疗水平。我们以前的工作已经证明，内科治疗失败而需要直肠切除的溃疡性结肠炎患者和因难治性疾病而需要多次切除的克罗恩-S病患者的PBL mdr表达均显著高于疾病或正常对照组。我们还发现，PBL MDR的表达与结肠上皮内淋巴细胞(IEL)和上皮细胞MDR的表达有关，固有的高淋巴细胞和粘膜MDR表达可能在决定IBD患者对免疫抑制药物，特别是糖皮质激素的反应中发挥重要作用。如果这一假设是正确的，对MDR表达和功能的评估可能有助于加强IBD患者的药物治疗。在这个项目中，我们将专门研究人类T淋巴细胞和肠上皮细胞MDR依赖的糖皮质激素外流的调节，探索PGP-170在转运IBD治疗中心的其他免疫抑制剂中的作用，并评估MDR泵抑制剂的抗炎效果。

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.