title: Inhibition of C5a-induced inflammation with preserved C5b-9-mediated bactericidal activity in a human whole blood model of meningococcal sepsis.
abstract: The complement system plays an important role in the initial defense against Neisseria meningitidis. In contrast, uncontrolled activation in meningococcal sepsis contributes to the 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 (mAbs) blocking lectin and alternative pathways inhibited complement activation by N meningitidis and oxidative burst induced in granulocytes and monocytes. Oxidative burst was critically dependent on CD11b/CD18 (CR3) expression but not on Fc gamma-receptors. Specific inhibition of C5a using mAb 137-26 binding the C5a moiety of C5 before cleavage prohibited CR3 up-regulation, phagocytosis, and oxidative burst but had no effect on C5b-9 (TCC) formation, lysis, and bacterial killing. An 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 N meningitidis-induced C5a formation while preserving complement-mediated bacterial killing. We suggest that this may be an attractive approach for the treatment of meningococcal sepsis.
authors.affiliation: Department of General Internal Medicine, University Medical Centre St Radboud Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. t.sprong@aig.umcn.nl
authors.forename: Tom
authors.initials: T
authors.lastname: Sprong
authors.forename: Petter
authors.initials: P
authors.lastname: Brandtzaeg
authors.forename: Michael
authors.initials: M
authors.lastname: Fung
authors.forename: Anne M
authors.initials: AM
authors.lastname: Pharo
authors.forename: E Arne
authors.initials: EA
authors.lastname: Høiby
authors.forename: Terje E
authors.initials: TE
authors.lastname: Michaelsen
authors.forename: Audun
authors.initials: A
authors.lastname: Aase
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Marcel
authors.initials: M
authors.lastname: van Deuren
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001769:Blood / Q000382:microbiology; D003167:Complement Activation / Q000187:drug effects; D015936:Complement C5a / Q000037:antagonists & inhibitors*; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008589:Meningococcal Infections / Q000188:drug therapy / Q000276:immunology*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D009345:Neisseria meningitidis / Q000187:drug effects*; D011961:Receptors, Fc / Q000096:biosynthesis; D016897:Respiratory Burst / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015938:Complement Membrane Attack Complex; D016177:Macrophage-1 Antigen; D011961:Receptors, Fc; D015936:Complement C5a