Rapamycin decreases leukocyte migration in vivo and effectively reduces experimentally induced chronic colitis
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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.
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.
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.
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.
KeywordsRapamycin Cyclosporine Experimental chronic colitis In vivo microscopy
Dextran sodium sulfate
- 4.Farkas S, Herfarth H, Rossle M, Schroeder J, Steinbauer M, Guba M, Beham A, Scholmerich J, Jauch KW, Anthuber M (2001) Quantification of mucosal leucocyte endothelial cell interaction by in vivo fluorescence microscopy in experimental colitis in mice. Clin Exp Immunol 126:250–258CrossRefPubMedGoogle Scholar
- 7.D’Haens G, Lemmens L, Geboes K, Vandeputte L, Van Acker F, Mortelmans L, Peeters M, Vermeire S, Penninckx F, Nevens F, Hiele M, Rutgeerts P (2001) Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology 120:1323–1329CrossRefPubMedGoogle Scholar
- 15.Fernandez-Banares F, Bertran X, Esteve-Comas M, Cabre E, Menacho M, Humbert P, Planas R, Gassull MA (1996) Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 91:2498–2499PubMedGoogle Scholar
- 28.Ciancio G, Burke GW, Gaynor JJ, Mattiazzi A, Roth D, Kupin W, Nicolas M, Ruiz P, Rosen A, Miller J (2004) A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Transplantation 77:252–258CrossRefPubMedGoogle Scholar
- 30.Sato T, Inagaki A, Uchida K, Ueki T, Goto N, Matsuoka S, Katayama A, Haba T, Tominaga Y, Okajima Y, Ohta K, Suga H, Taguchi S, Kakiya S, Itatsu T, Kobayashi T, Nakao A (2003) Diabetes mellitus after transplant: relationship to pretransplant glucose metabolism and tacrolimus or cyclosporine A-based therapy. Transplantation 76:1320–1326CrossRefPubMedGoogle Scholar
- 34.Kahan BD, Stepkowski SM, Napoli KL, Katz SM, Knight RJ, Van Buren C (2000) The development of sirolimus: The University of Texas-Houston experience. Clin Transpl 145–158Google Scholar
- 38.Obermeier F, Kojouharoff G, Hans W, Scholmerich J, Gross V, Falk W (1999) Interferon-gamma (IFN-gamma)- and tumour necrosis factor (TNF)-induced nitric oxide as toxic effector molecule in chronic dextran sulfate sodium (DSS)-induced colitis in mice. Clin Exp Immunol 116:238–245CrossRefPubMedGoogle Scholar
- 39.Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135CrossRefPubMedGoogle Scholar
- 48.Seeliger H, Guba M, Koehl GE, Doenecke A, Steinbauer M, Bruns CJ, Wagner C, Frank E, Jauch KW, Geissler EK (2004) Blockage of 2-deoxy-d-ribose-induced angiogenesis with rapamycin counteracts a thymidine phosphorylase-based escape mechanism available for colon cancer under 5-fluorouracil therapy. Clin Cancer Res 10:1843–1852CrossRefPubMedGoogle Scholar