Selective immunomodulation in patients with inflammatory bowel disease--future therapy or reality?

Knowledge of the aetiology and pathogenesis of the inflammation in ulcerative colitis and Crohn's disease is still insufficient. It is thought that some antigen is the trigger which induces a chain of immune reactions but the origin of this antigen has not so far been elucidated. In theory, an antigen-presenting cell forms a complex with endotoxin-derived peptides as antigen. T-helper lymphocytes recognize this complex, are activated and start to produce cytokines. For inflammatory bowel diseases (IBD) the most important cytokines identified are interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), gamma-interferon (G-IFN), and tumor necrosis factor-alpha (TNF-alpha). Inhibition of these cytokines can be achieved by administration of cyclosporine, which inhibits the function of T-helper lymphocytes. Orally, intravenously, and locally administered cyclosporine is able to improve the disease activity in ulcerative colitis and Crohn's disease, but its use is limited because of side-effects. The novel immunosuppressant FK506 has comparable actions to cyclosporine in regulating cytokine production and may even be more effective than cyclosporine. The receptor antagonist of IL-1 (IL-1ra) competitively binds to the IL-1 receptor located on several lymphocytes. Treatment of animals with IL-1ra has been successful and clinical trials using recombinant IL-1ra are underway in IBD. Antibodies against alphaIL-2r have also been used successfully in animal studies. No experience with this substance has been obtained in man. The use of alpha-interferon seems to be effective in some patients with Crohn's disease. CD4 and CD8 molecules on lymphocytes are needed to form the interaction between antigen, antigen-presenting cell, and lymphocytes. Specific monoclonal antibodies against CD4 are successfully used in patients with active ulcerative colitis and Crohn's disease. TNF-alpha shares many of the proinflammatory activities of IL-1. In preliminary studies, especially in patients with Crohn's disease, the effects of the administration of antibodies to TNA-alpha were excellent.