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Digestive Diseases and Sciences

, Volume 47, Issue 6, pp 1362–1368 | Cite as

Effect of Cyclosporine in a Murine Model of Experimental Colitis

  • Marko Banić
  • Branimir Anić
  • Tomislav Brkić
  • Neven Ljubicić
  • Sanja Plesko
  • Csaba Dohoczky
  • Damir Erceg
  • Mladen Petrovecki
  • Igor Stipancić
  • Ivo Rotkvić
Article

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.

inflammatory bowel disease experimental colitis inflammation cyclosporine A 

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REFERENCES

  1. 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, 1999PubMedGoogle Scholar
  2. 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, 1999PubMedGoogle Scholar
  3. 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, 1999PubMedGoogle Scholar
  4. 4.
    Brynskow J: Cyclosporine for inflammatory bowel disease: Mechanisms and possible actions. Scand J Gastroenterol 28:849–857, 1993PubMedGoogle Scholar
  5. 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 97–110Google Scholar
  6. 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, 1992PubMedGoogle Scholar
  7. 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, 1993PubMedGoogle Scholar
  8. 8.
    Shaw LM, Yatscoff RW, Bowers LD: Canadian consensus meeting on cyclosporine monitoring: report of the consensus panel. Clin Chem 36:1841–1846, 1990PubMedGoogle Scholar
  9. 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, 1984PubMedGoogle Scholar
  10. 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, 1990PubMedGoogle Scholar
  11. 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, 1995Google Scholar
  12. 12.
    Dawson-Saunders B, Trapp RG: Basic and Clinical Biostatistics. London, Prentice-Hall, 1994Google Scholar
  13. 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, 1991PubMedGoogle Scholar
  14. 14.
    Kim HS, Berstad A: Experimental colitis in animal models. Scand J Gastroenterol 27:529–537, 1992PubMedGoogle Scholar
  15. 15.
    Elson CO, Sartor RB, Tennyson GS, Riddell RH: Experimental models of inflammatory bowel disease. Gastroenterology 109:1344–1367, 1995PubMedGoogle Scholar
  16. 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 1007–1024Google Scholar
  17. 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, 1989PubMedGoogle Scholar
  18. 18.
    Higa A, McKnight GW, Wallace JL: Attenuation of epithelial injury in acute experimental colitis by immunomodulators 239:171–176, 1993Google Scholar
  19. 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, 1989PubMedGoogle Scholar
  20. 20.
    Suya H, Fujioka A, Pincelli C, Fukuyama K, Epstein WL: Skin granuloma in mice immunosupressed by cyclosporine. J Invest Dermatol 90:430–433, 1988PubMedGoogle Scholar
  21. 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 97–110Google Scholar
  22. 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, 1994PubMedGoogle Scholar
  23. 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, 1994PubMedGoogle Scholar
  24. 24.
    Sandborn WJ: A critical review of cyclosporine therapy in inflammatory bowel disease. Bowel Dis 1:48–63, 1995Google Scholar
  25. 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, 1986PubMedGoogle Scholar
  26. 26.
    Bucy PR, Xu XY, Li J, Huang GQ: Cyclosporine A-induced autoimmune disease in mice. J Immunol 151:1039–1050, 1993PubMedGoogle Scholar
  27. 27.
    Ottenhof THM: Selective modulation of T-cell responses in autoimmunitiy and cancer. Immunol Today 17:54–55, 1996PubMedGoogle Scholar
  28. 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, 1991PubMedGoogle Scholar
  29. 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, 1993PubMedGoogle Scholar
  30. 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 38Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Marko Banić
    • 1
  • Branimir Anić
    • 2
  • Tomislav Brkić
    • 2
  • Neven Ljubicić
    • 3
  • Sanja Plesko
    • 4
  • Csaba Dohoczky
    • 5
  • Damir Erceg
    • 5
  • Mladen Petrovecki
    • 6
  • Igor Stipancić
    • 1
  • Ivo Rotkvić
    • 2
  1. 1.Division of GastroenterologyUniversity Hospital “Dubrava,”ZagrebCroatia
  2. 2.Department of MedicineUniversity Hospital “Rebro,”ZagrebCroatia
  3. 3.Division of GastroenterologyUniversity Hospital “Sestre Milosrdnice,”ZagrebCroatia
  4. 4.Hospital of Infectious DiseasesZagrebCroatia
  5. 5.Biomedical Department“PLIVA” Research InstituteCroatia
  6. 6.Department of InformaticsRijeka School of MedicineRijekaCroatia

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