Z Gastroenterol 2005; 43 - 113
DOI: 10.1055/s-2005-869760

Assessment of MDR1/MRP1 transporter function in lymphocyte-subpopulations of inflammatory bowel disease

E Schäfer 3, I Peták 2, T Micsik 1, K Illés 3, O Szokolóczi 1, B Bránné Németh 1, A Gelley 4, R Vernes 1, T Gyökeres 3, Á Pap 3 R Schwab 1,
  • 1Rational Drug Design Labs CRC, Semmelweis University
  • 21st Institute of Pathology and Experimental Cancer Research, Semmelweis University
  • 3Department of Gastroenterology, MÁV Hospital, Budapest
  • 4Polyclinic of the Hospitaller Brothers of St. John of God in Budapest

Background: Most current drugs to treat inflammatory bowel disease (IBD) including corticosteroids, azathioprin (AZA), cyclosporine are substrates of ABC-MDR transporters. These proteins significantly alter intracellular drug availability and thus efficacy. Our aim was to determine the CD markers of choice to monitor induction of ABC-transporter proteins in IBD patients.

Patients & Methods: 50 patients were included in the study: 35 pts had Crohn's disease and 15 pts had ulcerative colitis. 24% (12/50) of pts were non-responsive to conventional pharmacotherapy, 22% (11/50) of them were currently on steroids. 33% were in remission with steroids at the time of testing (3/10). Functional MDR assays were performed based on the Calcein-AM method. Lymphocytes were labeled by anti-human CD3, CD4, CD8, CD19, CD45 and monocytes by anti-human CD14 antibodies. In all cases MDR1 and MRP1 activity was assessed as described in the original assay (http://www.solvobiotech.com).

Results: Both MDR1 and MRP1 activity was within normal limits in CD4, CD14 and CD19 positive lymphocyte-subpopulation. In contrast, MRP1 activity of CD8 positive (cytotoxic) T cells was significantly elevated in patients, who had previously been treated with steroids/AZA (MAF=33,9/34,0). No statistically significant difference was seen between Ulcerative Colitis and Crohn's Disease patients in this respect. Total (MDR1 and MRP1 related) resistance values were significantly elevated in both CD3 and CD8 positive cells compared to the rest of the lymphocyte-subsets.

Conclusion: CD3 and CD8 positive lymphocyte-subsets seem to express ABC-MDR transporters. Based on our findings, MRP1 activity of CD8 positive (cytotoxic) T cells may confer resistance to conventional drugs like steroids and AZA. Prospective trials have to address the role of this phenomenon in clinical resistance.