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Prepublished online as a Blood First Edition Paper on July 24, 2003; DOI 10.1182/blood-2003-03-0703. This Article Full Text (PDF) All Versions of this Article: 2003-03-0703v1 102/10/3702    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sprong, T. Articles by Mollnes, T. E. Search for Related Content PubMed PubMed Citation Articles by Sprong, T. Articles by Mollnes, T. E. Social Bookmarking                   What's this? Submitted March 7, 2003 Accepted July 14, 2003 Inhibition of C5a-induced inflammation with preserved C5b-9-mediated bactericidal activity in a human whole blood model of meningococcal sepsis Tom Sprong*, Petter Brandtzaeg, Michael Fung, Anne M Pharo, E Arne Hoiby, Terje E Michaelsen, Audun Aase, Jos W M van der Meer, Marcel van Deuren, and Tom Eirik Mollnes Department of General Internal Medicine, University Medical Centre St Radboud, Nijmegen, The Netherlands Department of Pediatrics, Ullevaal University Hospital, Oslo, Norway Tanox Inc., Houston, TX, USA Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway Norwegian Institute of Public Health, Oslo, Norway Department of Pharmacognosy, Institute of Pharmacy, University of Oslo, Oslo, Norway * Corresponding author; email: tsprong{at}aig.umcn.nl. The complement system plays an important role in the initial defence against Neisseria meningitidis. In contrast, uncontrolled activation in meningococcal sepsis contributes to development of tissue damage and shock. In a novel human whole blood model of meningococcal sepsis we studied the effect of complement inhibition on inflammation and bacterial killing. Monoclonal antibodies (mAb) blocking lectin and/or alternative pathways inhibited complement activation by Neisseria meningitidis and oxidative burst induced in granulocytes and monocytes. Oxidative burst was critically dependent on CD11b/CD18 (CR3) expression, but not on Fc-receptors. Specific inhibition of C5a using mAb 137-26 binding the C5a moiety of C5 before cleavage, prohibited CR3 upregulation, phagocytosis and oxidative burst, but had no effect on C5b-9 (TCC) formation, lysis and bacterial killing. A mAb blocking cleavage of C5, preventing C5a and TCC formation, showed the same effect on CR3, phagocytosis and oxidative burst as the anti-C5a mAb, but additionally inhibited TCC formation, lysis and bacterial killing, consistent with a C5b-9 dependent killing mechanism. In conclusion, the anti-C5a mAb 137-26 inhibits the potentially harmful effects of Neisseria meningitidis-induced C5a formation while preserving complement-mediated bacterial killing. We suggest that this may be an attractive approach for treatment of meningococcal sepsis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. S. Plested, J. A. Welsch, and D. M. Granoff Ex Vivo Model of Meningococcal Bacteremia Using Human Blood for Measuring Vaccine-Induced Serum Passive Protective Activity Clin. Vaccine Immunol., June 1, 2009; 16(6): 785 - 791. [Abstract] [Full Text] [PDF] E. B. Thorgersen, A. Pharo, K. Haverson, A. K. Axelsen, P. Gaustad, G. J. Kotwal, G. Sfyroera, and T. E. Mollnes Inhibition of Complement and CD14 Attenuates the Escherichia coli-Induced Inflammatory Response in Porcine Whole Blood Infect. Immun., February 1, 2009; 77(2): 725 - 732. [Abstract] [Full Text] [PDF] M. A. Flierl, D. Rittirsch, B. A. Nadeau, D. E. Day, F. S. Zetoune, J. V. Sarma, M. S. Huber-Lang, and P. A. Ward Functions of the complement components C3 and C5 during sepsis FASEB J, October 1, 2008; 22(10): 3483 - 3490. [Abstract] [Full Text] [PDF] J. A. Welsch and D. Granoff Immunity to Neisseria meningitidis Group B in Adults despite Lack of Serum Bactericidal Antibody Clin. Vaccine Immunol., December 1, 2007; 14(12): 1596 - 1602. [Abstract] [Full Text] [PDF] O.-L. Brekke, D. Christiansen, H. Fure, M. Fung, and T. E. Mollnes The role of complement C3 opsonization, C5a receptor, and CD14 in E. coli-induced up-regulation of granulocyte and monocyte CD11b/CD18 (CR3), phagocytosis, and oxidative burst in human whole blood J. Leukoc. Biol., June 1, 2007; 81(6): 1404 - 1413. [Abstract] [Full Text] [PDF] T. Sprong, D. Roos, C. Weemaes, C. Neeleman, C. L. M. Geesing, T. E. Mollnes, and M. van Deuren Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections Blood, June 15, 2006; 107(12): 4865 - 4870. [Abstract] [Full Text] [PDF] L. Plant, H. Wan, and A.-B. Jonsson MyD88-Dependent Signaling Affects the Development of Meningococcal Sepsis by Nonlipooligosaccharide Ligands. Infect. Immun., June 1, 2006; 74(6): 3538 - 3546. [Abstract] [Full Text] [PDF] T. Sprong, A.-S. W. Moller, A. Bjerre, E. Wedege, P. Kierulf, J. W. M. van der Meer, P. Brandtzaeg, M. van Deuren, and T. E. Mollnes Complement Activation and Complement-Dependent Inflammation by Neisseria meningitidis Are Independent of Lipopolysaccharide Infect. Immun., June 1, 2004; 72(6): 3344 - 3349. [Abstract] [Full Text] [PDF]

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