Die Rolle von Zytokinen in der Pathogenese und Therapie chronisch-entzündlicher Darmerkrankungen

Crohn's disease and ulcerative colitis are chronic disorders of the gastrointestinal tract. Crohn`s disease is characterised by a transmural inflammation that can affect any part of the human gastrointestinal tract, whereas ulcerative colitis is restricted to the colon.Both diseases are disorders mediated by a pathogenic proinflammatory cytokine pattern produced by T-cells and macrophages. Inflammatory bowel diseases arise in individuals who are genetically susceptible as a result of a pathological immune response to mucosal bacterial antigens. In Crohn's disease, the interaction of macrophages and T-cells induces the production of proinflammatory cytokines, such as TNF-α, IL-12, IL-6 and IFN-γ. In the last decade these molecular mediators, their receptors and their mechanisms of action were characterised.Since then treatment has changed and new approaches based on the knowledge about cytokine interactions has been developed.One possibility to inhibit a proinflammatory cytokine response is to inhibit cell-cell interactions by blocking adhesion molecules (α4β1, α4β7) or costimulatory molecules (CD40L). The pathologic cytokine action in the inflamed gut can be counteracted in different ways. On the one hand clinical trials showed, that the function of proinflammatory cytokines can be neutralized by cytokine-antibodies (TNF-α, IL-12),by cytokine receptorantibodies (TNF-α, IL-6R) or by inhibiting the synthesis of proinflammatory cytokines by the application of antisense-oligonucleotides (TNF-α converting enzyme).On the other hand the application of protective antiinflammatory recombinant cytokines (IL-10, IL-11 and IFN-α) might protect individuals from an overwhelming proinflammatory immune response.The most effective cytokine antibody in the treatment of Crohn's disease so far is the anti-TNF-antibody infliximab,which may also cause serious side effects (e.g. tuberculosis reactivation).