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Anästhesiol Intensivmed Notfallmed Schmerzther 2000; 35(4): 207-213
DOI: 10.1055/s-2000-7982
ÜBERSICHT
Georg Thieme Verlag Stuttgart ·New York

Das Komplementsystem: Alter Hut oder Ziel neuer Therapieansätze?

The complement system: An old story or target of new therapeutic approaches?A. Heller, Thea Koch
  • Klinik und Poliklinik für Anaesthesiologie und Intensivmedizin Universitätsklinikum Carl Gustav CarusTechnische Universität Dresden(Direktor: Prof. Dr. med. D. M. Albrecht)
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Publication History

Publication Date:
10 January 2005 (online)

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Zusammenfassung.

Das Komplementsystem ist ein multifaktorielles Proteinkaskadensystem das im Zentrum der unspezifischen frühen Immunantwort steht. Seine wesentliche Aufgabe ist die Aktivierung zellulärer Abwehrmechanismen, die Opsonierung von Fremdkörpern und die Zerstörung entsprechender Zielzellen. Die Bedeutung der einzelnen Komplementkomponenten für die Bakterienelimination in der Sepsis wird jedoch immer noch kontrovers diskutiert. Trotz oder gerade wegen der effizienten zytotoxischen Wirkung kann die überschießende Aktivierung der Komplementkaskade im Organismus zu schweren lebensbedrohlichen Gewebeschäden führen. Eine Reihe von tierexperimentellen Studien hat gezeigt, daß genetische Komplementdefekte oder Komplement- Depletion den Verlauf von schweren Entzündungsvorgängen günstig beeinflussen und Organschäden reduzieren können. Versuche die Aktivierung der Komplementkaskade zu supprimieren sind einerseits die Applikation endogener Komplementinhibitoren z. B. C1-Inhibitor (C1-INH) oder rekombinanter Komplementrezeptoren wie des löslichen Komplementrezeptors 1 (rsCR1). Andererseits stellt die Gabe von Antikörpern gegen Schlüsselproteine (C3 oder C5), deren Aktivierungsprodukte (C5a) oder gegen die Komplementrezeptor 3 (CR3, CD18/ 11b) -mediierte Adhäsion von Entzündungszellen an das vaskuläre Endothel effektive Möglichkeiten der Komplementmodulation dar. Darüber hinaus wird derzeit zur Vermeidung Komplement-vermittelter Abstoßungsreaktionen bei Xenotransplantation der Einbau von membranständigen Komplementregulatoren in das Spenderorgan (DAF- CD55, MCP- CD46 oder CD59) untersucht. Die beschriebenen Interventionen schützten in einer Vielzahl von tierexperimentellen Modellen von Sepsis, bei myokardialem und intestinalem Ischämie-/Reperfusionsschaden, ARDS, Nephritis und Transplantatabstoßung vor Komplement-mediierten Gewebeschäden. Gestützt auf neue klinische Daten könnte die Komplementinhibition eine geeignete therapeutische Strategie darstellen, überschießende Entzündungsvorgänge zu dämpfen. Eigene Untersuchungen zeigten in einem Modell Komplement-induzierter Lungenschädigung die Effizienz einer Modulation der Komplementkaskade durch die Komplementregulatoren C1-Inhibitor und löslichem Komplementrezeptor 1. Hingegen muß im Hinblick auf eine suffiziente Erregerabwehr der Einsatz von Komplementinhibitoren kritisch abgewogen werden.

The complement system is a multifactorial protein cascade system which is essentially involved in the early unspecific immune response. Its major function is the activation of cellular defense mechanisms, opsonisation of foreign particles and the destruction of target cells. While the impact of the different complement components for bacterial elimination still remains controversial, overwhelming activation of the complement cascade, however, can induce life threatening tissue damage due to the effective cytotoxic properties. In the last years a variety of studies demonstrated beneficial, organ protective effects of complement modulation in models of severe inflammation. Attempts to control the complement system include the application of endogenous complement inhibitors e.g. C1-inhibitior (C1-INH) or the administration of recombinant complement receptors such as the soluble complement receptor 1 (rsCR1). Moreover antibodies against key proteins (C3, C5), against their activation products (C5a) or against complement receptor 3 (CR3, CD18/ 11b) mediated adhesion of leukocytes to the vascular endothelium, represent effective options of complement modulation. Besides this, insertion of membrane bound human complement regulators (DAF- CD55, MCP- CD46 or CD59) into xenogenic donor organs has proven effectiveness to prevent xenograft rejection. The described interventions protected from severe organ damage in various animal models of sepsis, myocardial and intestinal ischaemia-reperfusion injury, ARDS, nephritis, and xenograft rejection. With respect to recent clinical data, complement inhibition could represent a useful therapeutic strategy to control overwhelming inflammation. Own experiments demonstrated protective effects of complement modulation with C1 INH and rsCR1 in a model of complement induced pulmonary injury. With respect to sufficient host defense, however, the use of complement inhibitors must be considered carefully.

Schlüsselwörter:

Komplement - Anaphylatoxine - terminaler Komplement-Komplex - C-1INH - SCR-1 - MOF - SIRS

Key words:

Complement - anaphylatoxins - terminal complement complex - C-1INH - SCR-1 - ARDS - MOF - SIRS

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Dr. Axel Heller

Klinik und Poliklink für Anaesthesiologie und Intensivmedizin Universitätsklinikum Carl Gustav Carus Technische Universität Dresden

Fetscherstraße 74

01307 Dresden

Email: heller-a@rcs.urz.tu-dresden.de

URL: WEB: http://www.tu-dresden.de/medkai/

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