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Effect of Cyclosporine in a Murine Model of Experimental Colitis

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Abstract

The use of immunosuppressive therapy may be associated with significant toxicity. The aim of this study was to investigate the effect of cyclosporine A (CsA) in murine model of experimental colitis. Experimental colitis was induced in NMRI mice using an enema of 0.2% solution of dinitrofluorobenzene, combined with skin sensitization. After inducing colitis, experimental groups of animals were treated with CsA (1, 3, 5, 10, 25, 50 mg/kg/day) intraperitoneally (i.p.) or intracolonically (i.c.), and control groups were treated with phosphate-buffered saline intraperitoneally or intracolonically, respectively. Colonic inflammatory changes were assessed using a histopathologic score of 0–30, and pooled whole blood samples were processed with monoclonal antibodies for cyclosporine concentration. In addition, two groups of animals with experimental colitis were treated intraperitoneally or intracolonically with 3 mg/kg/day of CsA, and the colons were also taken for immunohistochemistry for CD25. CsA diminished the extent of colitis in groups treated with 3, 5, 10, or 25 mg/kg intraperitoneally or intracolonically, and in groups treated with 1 and 50 mg/kg intracolonically (P < 0.05). The effect of intracolonic application of CsA was not related to whole blood cyclosporine concentrations. In addition, the effect of CsA at 3 mg/kg, applied intraperitoneally or intracolonically was, in part, expressed in decreasing the numbers of CD25+ cells within colonic mucosa/submucosa (P < 0.05). In conclusions, the results of this study indicate the possibility of intracolonic application of cyclosporine in order to widen the therapeutic window for effective, but possibly toxic drug, such as cyclosporine.

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REFERENCES

  1. Present DH, Rutgeerts P, Targan S, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ: Infliximab for treatment of fistulas in patients with Crohn's disease. N Engl J Med 340:1398–1405, 1999

    PubMed  Google Scholar 

  2. Ehrenpreis ED, Kane SV, Cohen LB, Cohen RD, Hanauer SB: Thalidomide therapy for patients with refractory Crohn's disease: An open label trial. Gastroenterology 117:1271–1277, 1999

    PubMed  Google Scholar 

  3. Vasiliauskas EA, Kam LY, Abreu-Martin MT, Hassard PV, Papadakis KA, Yang H, Zeldis JB, Targan SR. An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn's disease. Gastroenterology 117:1278–1287, 1999

    PubMed  Google Scholar 

  4. Brynskow J: Cyclosporine for inflammatory bowel disease: Mechanisms and possible actions. Scand J Gastroenterol 28:849–857, 1993

    PubMed  Google Scholar 

  5. Strober W, Ehrhardt RO, Ludviksson BR: Inflammatory bowel diseases: A breakdown of central and peripheral immunological homeostasis. In Inhibition and Modulation of gastrointestinal inflammation. Falk Symposium 104. A Stallmach, M Zeitz, W Strober, TT MacDonald, H Lochs (eds). Dordrecht, Kluwer Academic Publishers, 1998, pp 97–110

    Google Scholar 

  6. Brki? T, Bani? M, Ani? B, Grabarevi? Ž, Rotkvi? I, Artukovi? B, Duvnjak M, Sikiri? P, Troskot B, Hernandez DE: A model of inflammatory bowel disease induced by 2,4-dinitrofluorobenzene in previously sensitized BALB/c mice. Scand J Gastroenterol 27:184–188, 1992

    PubMed  Google Scholar 

  7. Bani? M, Brki? T, Ani? B, Rotkvi? I, Grabarevi? Ž, Duvnjak M, Troskot B, Mihatov Š: Effect of methylprednisolone on small bowel, spleen and liver changes in murine model of inflammatory bowel disease. Aliment Pharmacol Ther 7:201–206, 1993

    PubMed  Google Scholar 

  8. Shaw LM, Yatscoff RW, Bowers LD: Canadian consensus meeting on cyclosporine monitoring: report of the consensus panel. Clin Chem 36:1841–1846, 1990

    PubMed  Google Scholar 

  9. Selby WS, Janossy G, Boffil M, Jewell DP: Intestinal lymphocyte subpopulations in inflammatory bowel disease by immunohistochemical and cell isolation techniques. Gut 25:32–40, 1984

    PubMed  Google Scholar 

  10. Vilaseca J, Salas A, Guarner F, Rodrigez R, Martinez M, Malagelada J-R: Dietary fish oil reduces progression of chronic inflammatory lesions in a rat model of granulomatous colitis. Gut 31:539–544, 1990

    PubMed  Google Scholar 

  11. Velja?a M, Lesch CA, Pllana R, Sanchez B, Chan K, Guglieta A: BPC-15 reduces trinitrobenzene sulfonic acid-induced colonic damage in rats. JPET 272:417–422, 1995

    Google Scholar 

  12. Dawson-Saunders B, Trapp RG: Basic and Clinical Biostatistics. London, Prentice-Hall, 1994

    Google Scholar 

  13. Fukushima K, Masuda T, Ohtani H, Sasaki I, Funayama Y, Matsuno S, Nagura H: Immunohistochemical characterization, distribution and ultrastructure of lymphocyte bearing T-cell receptor gamma/delta in inflammatory bowel disease. Gastroenterology 101:670–678, 1991

    PubMed  Google Scholar 

  14. Kim HS, Berstad A: Experimental colitis in animal models. Scand J Gastroenterol 27:529–537, 1992

    PubMed  Google Scholar 

  15. Elson CO, Sartor RB, Tennyson GS, Riddell RH: Experimental models of inflammatory bowel disease. Gastroenterology 109:1344–1367, 1995

    PubMed  Google Scholar 

  16. Elson CO: Experimental models of intestinal inflammation. New insights into mechanisms of mucosal homeostasis: In PL Ogra, J Mestecky, ME Lamm, W Strober, J Bienenstock, JR McGhee (eds). Mucosal Immunology. San Diego, Academic Press, 1999, pp 1007–1024

    Google Scholar 

  17. Wallace JL, MacNaughton WK, Morris GP, Beck PL: Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease. Gastroenterology 96:29–36, 1989

    PubMed  Google Scholar 

  18. Higa A, McKnight GW, Wallace JL: Attenuation of epithelial injury in acute experimental colitis by immunomodulators 239:171–176, 1993

    Google Scholar 

  19. Morris, GP, Beck PL, Herridge MS, Depew WT, Sewczuk MR, Wallace JL: Hapten-induced model of chronic inflammation and ulceration in rat colon. Gastroenterology 96:795–803, 1989

    PubMed  Google Scholar 

  20. Suya H, Fujioka A, Pincelli C, Fukuyama K, Epstein WL: Skin granuloma in mice immunosupressed by cyclosporine. J Invest Dermatol 90:430–433, 1988

    PubMed  Google Scholar 

  21. Braunstein J, Autschbach F, Sido B, Nebl G, Schroeder A, Samstag Y, Meuer SC: Insensitivity towards inhibition by cyclosporine A, rapamycin and tacrolimus in human intestinal lamina propria T-lymphocytes. In Inhibition and Modulation of Gastrointestinal Inflammation. Falk Symposium 104. A Stallmach, M Zeitz, W Strober, TT MacDonald, H Lochs (eds). Dordrecht, Kluwer Academic Publishers, 1998, pp 97–110

    Google Scholar 

  22. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 330:1841–1845, 1994

    PubMed  Google Scholar 

  23. Feagan BG, McDonald JWD, Rochon J, Laupacis A, Fedorak RN, Kinnear D, Saibil F, Groll A, Archambault A, Gillies R, Valberg B, Irvine J, for Canadian Crohn's Relapse Prevention Trial Investigators: Low-dose cyclosporine for the treatment of Crohn's disease. N Engl J Med 330:1846–1851, 1994

    PubMed  Google Scholar 

  24. Sandborn WJ: A critical review of cyclosporine therapy in inflammatory bowel disease. Bowel Dis 1:48–63, 1995

    Google Scholar 

  25. Sorokin R, Kimura H, Schroeder K, Wilson DH, Wilson DB: Cyclosporine-induced autoimmunity. Conditions for expressing disease, requirement for intact thymus and potency estimates of autoimmune lymphocytes in drug treated rats. J Exp Med 164:1615–1625, 1986

    PubMed  Google Scholar 

  26. Bucy PR, Xu XY, Li J, Huang GQ: Cyclosporine A-induced autoimmune disease in mice. J Immunol 151:1039–1050, 1993

    PubMed  Google Scholar 

  27. Ottenhof THM: Selective modulation of T-cell responses in autoimmunitiy and cancer. Immunol Today 17:54–55, 1996

    PubMed  Google Scholar 

  28. Sandborn WJ, Stron RM, Forland SC, Chase RE, Cutler RE: The pharmacokinetics and colon tissue concentrations of cyclosporine after IV, oral and enema administration. J Clin Pharmacol 31:76–80, 1991

    PubMed  Google Scholar 

  29. Gurbindo C, Russo P, Sabbah S, Lohoues MJ, Seisman E: Interleukin-2 activity of colonic lamina propria mononuclear cells in a rat model of experimental colitis. Gastroenterology 104:964–972, 1993

    PubMed  Google Scholar 

  30. Brynskow J: Cyclosporine/Tacrolimus in Crohn's disease: acute and chronic. Falk symposium 119. Immunosuppression in inflammatory bowel disease—standards—new developments—future trends. Abstract Book, 2000, p 38

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Authors and Affiliations

  1. Division of Gastroenterology, University Hospital “Dubrava,”, Zagreb, Croatia

    Marko Banić & Igor Stipancić

  2. Department of Medicine, University Hospital “Rebro,”, Zagreb, Croatia

    Branimir Anić, Tomislav Brkić & Ivo Rotkvić

  3. Division of Gastroenterology, University Hospital “Sestre Milosrdnice,”, Zagreb, Croatia

    Neven Ljubicić

  4. Hospital of Infectious Diseases, Zagreb, Croatia

    Sanja Plesko

  5. Biomedical Department, “PLIVA” Research Institute, Croatia

    Csaba Dohoczky & Damir Erceg

  6. Department of Informatics, Rijeka School of Medicine, Rijeka, Croatia

    Mladen Petrovecki

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  1. Marko Banić
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  2. Branimir Anić
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Banić, M., Anić, B., Brkić, T. et al. Effect of Cyclosporine in a Murine Model of Experimental Colitis. Dig Dis Sci 47, 1362–1368 (2002). https://doi.org/10.1023/A:1015339018181

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