Rapamycin decreases leukocyte migration in vivo and effectively reduces experimentally induced chronic colitis

Background: Immunosuppressive calcineurin inhibitors, like cyclosporine (CsA), can be used for the clinical management of severe ulcerative colitis. However, patients treated with CsA are at a risk for developing kidney failure and may be more susceptible to colon cancer. Furthermore, severe neurotoxicity and hypertension are common problems. To avoid the side effects of CsA, new immunosuppressive drugs to treat colitis are needed. The aim of the present study was to test the immunosuppressive mammalian target of rapamycin inhibitor rapamycin in an experimental model of chronic colitis and to compare its effectiveness with CsA. Methods: Chronic colitis was established in Balb/c mice after four feeding cycles of dextran sodium sulfate. Because leukocyte recruitment to sites of intestinal inflammation is crucial for the development of chronic colitis, intravital microscopy was used to study the effect of rapamycin and CsA on leukocyte-endothelium interactions and leukocyte extravasation. To assess the degree of colitis, histological sections were evaluated. Results: Both rapamycin and cyclosporine effectively reduced leukocyte sticking (> 60%) in submucosal venules, as compared to controls. Furthermore, rapamycin, but not CsA, reduced (> 35%) leukocyte extravasation in the mucosa. Both rapamycin and CsA treatments significantly improved the histologic inflammation score. Conclusion: Our in vivo results demonstrate that rapamycin reduces leukocyte sticking and extravasation during chronic colitis induction and proves to be as effective as CsA at reducing experimental chronic colitis. These results support the use of rapamycin in clinical trials to avoid serious side effects of CsA therapy in chronic colitis patients.