title: Teasing apart structural determinants of 'toxicity' and 'adjuvanticity': implications for meningococcal vaccine development.
abstract: The use of lipopolysaccharide (LPS) as an adjuvant is limited by its high endotoxic activity. In particular, the fatty-acyl pattern of the lipid A part of LPS has been demonstrated to determine its biological activity. By genetic modification of the lipid A biosynthesis pathway in Neisseria meningitidis, a panel of recombinant strains with specific alterations in the lipid A acylation pattern, as well as a strain completely lacking LPS were isolated. Whereas all variations in the fatty-acyl pattern resulted in reduced endotoxic activity, as measured by TNF-alpha induction in the human macrophage cell line MM6, the adjuvant activity of the modified LPS was, in most cases, barely affected. The in vivo adjuvant properties of N. meningitidis wild-type and mutant LPS was found to correlate with induction of co-stimulatory molecules, in particular CD80 and CD40, and with IL-12 production by LPS-stimulated bone marrow-derived BALB/c dendritic cells in vitro. Our results suggest that the ability of LPS to stimulate pro-inflammatory cytokine induction is not necessarily linked to its adjuvant activity. The availability of this novel set of lipid A variants with improved pharmacological properties will be of great importance for the improvement of future outer membrane vesicle vaccines against N. meningitidis.
authors.affiliation: Laboratory of Immunotherapy, Department of Immunology, University Medical Centre Utrecht, The Netherlands. l.steeghs@lab.azu.nl
authors.forename: Liana
authors.initials: L
authors.lastname: Steeghs
authors.forename: Jan
authors.initials: J
authors.lastname: Tommassen
authors.forename: Jeanette H W
authors.initials: JH
authors.lastname: Leusen
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Peter
authors.initials: P
authors.lastname: van der Ley
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects; D008050:Lipid A / Q000633:toxicity; D008070:Lipopolysaccharides / Q000737:chemistry / Q000633:toxicity; D022401:Meningococcal Vaccines / Q000737:chemistry* / Q000633:toxicity*; D009345:Neisseria meningitidis / Q000276:immunology
chemical_list: D008050:Lipid A; D008070:Lipopolysaccharides; D022401:Meningococcal Vaccines