Modulation of gastrointestinal inflammation by chimeric proteins in experimental models

Summary

Conventional drug therapy in patients with chronic gastrointestinal inflammation is clinically effective in the majority of patients. However, in a relevant group of patients with highly active disease refractory to conventional drugs and for patients with severe side effects new therapeutic strategies are necessary. An advanced understanding of the immune mechanisms underlying chronic diseases resulted in the possibility to use chimeric proteins, in which the variable domains of an immunoglobulin are replaced by extracellular domains of cell surface molecules or cytokines for specific immunomodulation. The immunomodulating effects of chimeric proteins such as CTLA- 4-IgG, interleukin- 10-IgG, IL- 2-IgG or tumour necrosis factor (TNF)-receptor IgG have been proven beneficial in a variety of in vitro and in vivo models of chronic gastrointestinal inflammation and autoimmune diseases. It thus seems likely that genetically engineered fusion proteins targeting specific elements of the immune response may become an essential element in new clinical treatment protocols.

Key words: Cytokine Fusion Proteins - Inflammation - Inflammatory Bowel Disease

Modulation der gastrointestinalen Entzündung durch chimäre Proteine in experimentellen Modellen

Die me-dikamentöse Standardthe­rapie bei Patienten mit chronisch entzündlichen Darmerkrankungen ist in der Regel aus­reichend. Bei Patienten mit chronischer Krankheitsaktivität oder bei Patienten mit relevanten Nebenwirkungen der etablierten Medikamente sind jedoch neue therapeutische Strate­gien notwendig. Das bessere Verständnis der immunologischen Reaktionen bei chronischen Entzündungen führte in jüngster Zeit zur Entwicklung von chimären Proteinen, bei denen die variable Domäne eines Immunglobulins durch den extrazellulären Teil eines Zelloberflächenantigens oder durch funktionell-aktive Sequenzen von Zytokinen ersetzt wurden. Die immunmodulatorischen Effekte dieser Fusionsproteine, wie z. B. des CTLA- 4-IgG, des Interleukin- 10-IgG, des IL- 2-IgG oder des Tumor-Nekrose-Faktor (TNF)-Rezeptor-IgG sind erfolgreich in verschiedenen In-vitro- und In-vivo-Modellen getestet worden. Aufbauend auf diese Ergebnisse könnten genetisch her­gestellte Fusionsproteine zentrale Bestandteile zukünftiger klinischer Therapiestudien werden.

Schlüsselwörter: Zytokinfusionsproteine - Entzündung - Chronisch-entzündliche Darmerkrankung

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