CONTROLLING THE COMPLEMENT-SYSTEM IN INFLAMMATION

Inappropriate or excessive activation of the complement system can lea d to harmful, potentially life-threatening consequences due to severe inflammatory tissue destruction. These consequences are clinically man ifested in various disorders, including septic shock, multiple organ f ailure and hyperacute graft rejection. Genetic complement deficiencies or complement depletion have been proven to be beneficial in reducing tissue injury in a number of animal models of severe complement-depen dent inflammation. It is therefore believed that therapeutic inhibitio n of complement is likely to arrest the process of certain diseases. A ttempts to efficiently inhibit complement include the application of e ndogenous soluble complement inhibitors (C1-inhibitor, recombinant sol uble complement receptor 1-rsCR1), the administration of antibodies, e ither blocking key proteins of the cascade reaction (e.g. C3, C5), neu tralizing the action of the complement-derived anaphylatoxin C5a, or i nterfering with complement receptor 3 (CR3, CD18/11b)-mediated adhesio n of inflammatory cells to the vascular endothelium. In addition, inco rporation of membrane-bound complement regulators (DAF-CD55, MCP-CD46, CD59) has become possible by transfection of the correspondent cDNA i nto xenogeneic cells. Thereby, protection against complement-mediated inflammatory tissue damage could be achieved in various animal models of sepsis, myocardial as well as intestinal ischemia/reperfusion injur y, adult respiratory distress syndrome, nephritis and graft rejection. Supported by results from first clinical trials, complement inhibitio n appears to be a suitable therapeutic approach to control inflammatio n. Current strategies to specifically inhibit complement in inflammati on have been discussed at a recent meeting on the 'Immune Consequences of Trauma, Shock and Sepsis', held from March 4-8, 1997, in Munich, G ermany. The Congress (chairman: E. Faist, Munich, Germany), which was held in close cooperation with various national and international shoc k and trauma societies, was attended by about 2000 delegates from 40 c ountries. The major objective of the meeting was to provide an overvie w on the most state-of-the-art methods to prevent multiple organ dysfu nction syndrome (MODS)/multiple organ failure (MOF) following the syst emic inflammatory response (SIRS) to severe trauma. One of the largest symposia held within the Congress was devoted to current aspects of c ontrolling complement in inflammation (for abstracts see: Shock 1997, 7 Suppl., 71-75). After providing the audience with information on the scientific background by addressing the clinical relevance of complem ent activation (G.O. Till, Ann Arbor, MI, USA) and discussing recent d evelopments in modern complement diagnosis (J. Kohl, Hannover, Germany ), B.P. Morgan (Cardiff, UK) introduced the symposium's special issue by giving an overview on complement regulatory molecules. Selected top ics included overviews on the application of C1 inhibitor (C.E. Hack, Amsterdam, NL), sCR1 (U.S. Ryan, Needham, MA, USA), antibodies to C5 ( Y. Wang, New Haven CT, USA) and to the anaphylatoxin C5a (M. Oppermann , Gottingen, Germany), and a report on complement inhibition in cardio pulmonary bypass (T.E. Mollnes, Bodo, Norway). The growing interest of clinicians in complement-directed anti-inflammatory therapy, and the fact that only some of the various aspects of therapeutic complement i nhibition could be addressed on the meeting, has motivated the author to expand a Congress report into a short comprehensive review on recen t strategies to control complement in inflammation. (C) 1997 Elsevier Science B.V.