Skip to main content
NCBI home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;8(3):317–328. doi: 10.1111/j.1582-4934.2004.tb00321.x

Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease

Jannis Kountouras 1,✉, Christos Zavos 1, Dimitrios Chatzopoulos 1
PMCID: PMC6740145  PMID: 15491507

Abstract

Etiopathogenesis of mucosal inflammation in inflammatory bowel disease remains a complex and enigmatic field; various factors (genetic, environmental and microbial) trigger an event that activates intestinal immune and nonimmune systems cluminating in inflammation and tissue injury. Specifically, both innate and adaptive immune systems seem to play important roles in the pathophysiology of this disease. Cyclosporine A represents a macrolide immune modulator with primary inhibitory effects on T helper lymphocyte production of interleukin‐2, and other cytokines leading to altered T‐lymphocyte and B‐lymphocyte function. The diversity of its therapeutic outcome reported in inflammatory bowel disease may be due to the intricate immuno‐pathogenic profile of the disease and the variety of the applied dose‐dependent courses of therapy. Cyclosporine A exerts additional actions on other components of the inflammatory infiltrate, including neutrophils and mast cells, thereby appearing to be a multi‐dynamic therapeutic approach, although with potential drawbacks, that may be applied alone or combined with other immunomodulatory agents in inflammatory bowel disease patients. Because cyclosporine A induces apoptosis of T‐lymphocytes responsible for perpetuation of the chronic inflammatory process in the disease with potential tumorigenic effect, it may exert a further inhibitory effects on cancer development in inflammatory bowel disease patients, and can be combined with other relative agents, such as rapamycin, which also promotes T‐lymphocyte apoptosis. Therefore, recently established multifactorial action of cyclosporine A in relation to the pathogenesis of the disease can open new horizons for prospective, controlled trials in large cohorts, aiming to emphasize cyclosporine A's potential.

Keywords: cyclosporine, Crohn's, ulcerative colitis, inflammatory bowel disease

References

  • 1. Abreu M.T., Arditi M., Innate immunity and toll‐like receptors: clinical implications of basic science research, J. Pediatr., 144: 421–429, 2004. [DOI] [PubMed] [Google Scholar]
  • 2. Baert F., Rutgeerts P., Immunomodulator therapy of inflammatory bowel disease, Acta Clin. Belg., 52: 251–257, 1997. [DOI] [PubMed] [Google Scholar]
  • 3. Panes J., Granger D.N., Leukocyte‐endothelial cell interactions: molecular mechanisms and implications in gastrointestinal disease, Gastroenterology, 114: 1066–1090, 1998. [DOI] [PubMed] [Google Scholar]
  • 4. Kountouras J., Chatzopoulos D., Zavos C., Reactive oxygen metabolites and upper gastrointestinal diseases, Hepatogastroenterology, 48: 743–751, 2001. [PubMed] [Google Scholar]
  • 5. Fiocchi C., Inflammatory bowel disease: etiology and pathogenesis, Gastroenterology, 115: 182–205, 1998. [DOI] [PubMed] [Google Scholar]
  • 6. Sands B.E., Crohn's disease, In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 7th Edn, Philadelphia : Saunders, pp. 2005–2038, 2002. [Google Scholar]
  • 7. Sandborn W.J., Tremaine W.J., Cyclosporine treatment of inflammatory bowel disease, Mayo Clin. Proc., 67: 981–990, 1992. [DOI] [PubMed] [Google Scholar]
  • 8. Sandborn W.J., A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6‐mercaptopurine, cyclosporine, and methotrexate, Am. J. Gastroenterol., 91: 423–433, 1996. [PubMed] [Google Scholar]
  • 9. Aranda R., Horgan K., Immunosuppressive drugs in the treatment of inflammatory bowel disease, Semin. Gastrointest. Dis., 9: 2–9, 1998. [PubMed] [Google Scholar]
  • 10. van Assche G., D'Haens G., Noman M., Vermeire S., Hiele M., Asnong K., Arts J., D'Hoore A., Penninckx F., Rutgeerts P., Randomized, double‐blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis, Gastroenterology, 125: 1025–1031, 2003. [DOI] [PubMed] [Google Scholar]
  • 11. van Assche G., Dalle I., Noman M., Aerden I., Swijsen C., Asnong K., Maes B., Ceuppens J., Geboes K., Rutgeerts P., A pilot study on the use of the humanized anti‐interleukin‐2 receptor antibody daclizumab in active ulcerative colitis, Am. J. Gastroenterol., 98: 369–376, 2003. [DOI] [PubMed] [Google Scholar]
  • 12. Ying S., Khan L.N., Meng Q., Barnes N.C., Kay A.B., Cyclosporin A, apoptosis of BAL T cells and expression of Bcl‐2 in asthmatics, Eur. Respir. J., 22: 207–212, 2003. [DOI] [PubMed] [Google Scholar]
  • 13. Koenen H.J., Michielsen E.C., Verstappen J., Fasse E., Joosten I., Superior T‐cell suppression by rapamycin and FK506 over rapamycin and cyclosporine A because of abrogated cytotoxic T‐lymphocyte induction, impaired memory responses, and persistent apoptosis, Transplantation, 75: 1581–1590, 2003. [DOI] [PubMed] [Google Scholar]
  • 14. Kountouras J., Kouklakis G., Zavos C., Chatzopoulos D., Moschos J., Molyvas E., Zavos N., Apoptosis, inflammatory bowel disease and carcinogenesis: overview of international and Greek experiences, Can. J. Gastroenterol., 17: 249–258, 2003. [DOI] [PubMed] [Google Scholar]
  • 15. Aiko S., Conner E.M., Fuseler J.A., Grisham M.B., Effects of cyclosporine or FK506 in chronic colitis, J. Pharmacol. Exp. Ther., 280: 1075–1084, 1997. [PubMed] [Google Scholar]
  • 16. Rafiee P., Johnson C.P., Li M.S., Ogawa H., Heidemann J., Fisher P.J., Lamirand T.H., Otterson M.F., Wilson K.T., Binion D.G., Cyclosporine A enhances leukocyte binding by human intestinal microvascular endothelial cells through inhibition of p38 MAPK and iNOS. Paradoxical proinflammatory effect on the microvascular endothelium, J. Biol. Chem., 277: 35605–35615, 2002. [DOI] [PubMed] [Google Scholar]
  • 17. Brynskov J., Tvede N., Andersen C.B., Vilien M., Increased concentrations of interleukin 1 beta, interleukin‐2, and soluble interleukin‐2 receptors in endoscopical mucosal biopsy specimens with active inflammatory bowel disease, Gut, 33: 55–58, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Metcalf D., The molecular biology and functions of the granulocyte‐macrophage colony‐stimulating factors, Blood, 67: 257–267, 1986. [PubMed] [Google Scholar]
  • 19. Pullman W.E., Elsbury S., Kobayashi M., Hapel A.J., Doe W.F., Enhanced mucosal cytokine production in inflammatory bowel disease, Gastroenterology, 102: 529–537, 1992. [DOI] [PubMed] [Google Scholar]
  • 20. Breese E., Braegger C.P., Corrigan C.J., Walker‐Smith J.A., MacDonald T.T., Interleukin‐2‐ and interferongamma‐secreting T cells in normal and diseased human intestinal mucosa, Immunology, 78: 127–131, 1993. [PMC free article] [PubMed] [Google Scholar]
  • 21. Monteleone G., Biancone L., Marasco R., Morrone G., Marasco O., Luzza F., Pallone F., Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells, Gastroenterology, 112: 1169–1178, 1997. [DOI] [PubMed] [Google Scholar]
  • 22. Bretscher P.A., Havele C., Cyclosporin A can switch the immune response induced by antigen from a humoral to a cell‐mediated mode, Eur. J. Immunol., 22: 349–355, 1992. [DOI] [PubMed] [Google Scholar]
  • 23. Neurath M.F., Finotto S., Fuss I., Boirivant M., Galle P.R., Strober W., Regulation of T‐cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question, Trends Immunol., 22: 21–26, 2001. [DOI] [PubMed] [Google Scholar]
  • 24. Bernstein C.N., Shanahan F., Cyclosporine and inflammatory bowel disease: still more questions, Gastroenterology, 108: 943–945, 1995. [PubMed] [Google Scholar]
  • 25. Egan L.J., Sandborn W.J., Tremaine W.J., Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn's disease with intravenous cyclosporine, Am. J. Gastroenterol., 93: 442–448, 1998. [DOI] [PubMed] [Google Scholar]
  • 26. Boura P., Kountouras J., Papadopoulou A., Zaharioudaki E., Anastasiadis N., Tsakiri I., Tsapas G., Peripheral blood and colonic T cell subsets and HLA‐DR expression before and after low dose cyclosporine treatment in patients with ulcerative colitis, Allergy Proceedings, 9: 324, 1988. [Google Scholar]
  • 27. Sandborn W.J., Tremaine W.J., Lawson G.M., Clinical response does not correlate with intestinal or blood cyclosporine concentrations in patients with Crohn's disease treated with high‐dose oral cyclosporine, Am. J. Gastroenterol., 91: 37–43, 1996. [PubMed] [Google Scholar]
  • 28. Stange E.F., Modigliani R., Pena A.S., Wood A.J., Feutren G., Smith P.R., European trial of cyclosporine in chronic active Crohn's disease: a 12‐month study. The European Study Group, Gastroenterology, 109: 774–782, 1995. [DOI] [PubMed] [Google Scholar]
  • 29. Loftus C.G., Loftus E.V. Jr., Sandborn W.J., Cyclosporin for refractory ulcerative colitis, Gut, 52: 172–173, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Navazo L., Salata H., Morales S., Dorta M.C., Perez F., de Las Casas D., Aviles J., Oral microemulsion cyclosporine in the treatment of steroid‐refractory attacks of ulcerative and indeterminate colitis, Scand. J. Gastroenterol., 36: 610–614, 2001. [DOI] [PubMed] [Google Scholar]
  • 31. Rolny P., Sadik R., Longer term outcome of steroid refractory ulcerative colitis treated with intravenous cyclosporine without subsequent oral cyclosporine maintenance therapy, Int. J. Colorectal Dis., 17: 67–69, 2002. [DOI] [PubMed] [Google Scholar]
  • 32. Okamura S., Aoki H., Ohashi S., Urano F., Shimodaira M., Kanamori S., Ishikawa H., Segawa K., Efficacy of cyclosporine with corticotropin for refractory ulcerative colitis, Hepatogastroenterology, 50: 91–94, 2003. [PubMed] [Google Scholar]
  • 33. Lichtiger S., Present D.H., 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. [DOI] [PubMed] [Google Scholar]
  • 34. 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., Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis, Gastroenterology, 120: 1323–1329, 2001. [DOI] [PubMed] [Google Scholar]
  • 35. Hawthorne A.B., Cyclosporin and refractory colitis, Eur. J. Gastroenterol. Hepatol., 15: 239–244, 2003. [DOI] [PubMed] [Google Scholar]
  • 36. Banic M., Anic B., Brkic T., Ljubicic N., Plesko S., Dohoczky C., Erceg D., Petrovecki M., Stipancic I., Rotkvic I., Effect of cyclosporine in a murine model of experimental colitis, Dig. Dis. Sci., 47: 1362–1368, 2002. [DOI] [PubMed] [Google Scholar]
  • 37. Weisdorf‐Schindele S., Lake J.R., Gastrointestinal complications of solid organ and hematopoietic cell transplantation, In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 7th Edn, Philadelphia : Saunders, pp. 473–486, 2002. [Google Scholar]
  • 38. Kountouras J., Zavos C., Chatzopoulos D., Apoptosis and apoptosis‐related proteins in inflammatory bowel disease, Apoptosis, 9: 657–658, 2004. [DOI] [PubMed] [Google Scholar]
  • 39. Morisaki T., Matsunaga H., Beppu K., Ihara E., Hirano K., Kanaide H., Mori M., Katano M., A combination of cyclosporine‐A (CsA) and interferongamma (INF‐gamma) induces apoptosis in human gastric carcinoma cells, Anticancer Res., 20: 3363–3373, 2000. [PubMed] [Google Scholar]
  • 40. Lim S.J., Simeone A.M., Kim C.K., Tari A.M., Cyclosporine A enhances the apoptotic effects of N‐(4‐hydroxyphenyl)retinamide in breast cancer cells, Int. J. Cancer, 101: 243–247, 2002. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES