title: Antilipid a monoclonal antibody HA-1A: immune complex clearance of endotoxin reduces TNF-alpha, IL-1 beta and IL-6 production.
abstract: HA-1A is a human monoclonal IgM antibody which recognizes the lipid A component of lipopolysaccharide (LPS). This antibody has reduced mortality in the septic shock syndrome resulting from Gram negative bacteria, in which many of the manifestations are considered to be due to cellular activation and secretion of cytokines, most notably TNF-alpha. However HA-1A does not directly neutralize LPS effectively in vitro, and studies reported to date have not defined its mechanism of action. Here we demonstrate that HA-1A, which in the presence of complement promotes immune adherence, may inhibit LPS action by facilitating its sequestration on red blood cells and clearance to an extent that cytokine production is reduced. Incubation of LPS at clinically significant (pg/ml) does with HA-1A at therapeutic levels (e.g. 10 micrograms/ml) and complement resulted in LPS association with erythrocyte CR1 receptors. This reduced the ability of the residual, free LPS by 50-70% to induce the secretion of TNF-alpha, IL-1 beta and IL-6 from normal blood mononuclear cells. This mechanism is likely to be operative in vivo, and could account for the protective effect of HA-1A, and its reduction of TNF-alpha production in vivo.
authors.affiliation: Kennedy Institute of Rheumatology, Sunley Division, Hammersmith, London.
authors.forename: P
authors.initials: P
authors.lastname: Katsikis
authors.forename: G
authors.initials: G
authors.lastname: Harris
authors.forename: T
authors.initials: T
authors.lastname: Page
authors.forename: E
authors.initials: E
authors.lastname: Paleolog
authors.forename: M
authors.initials: M
authors.lastname: Feldman
authors.forename: M R
authors.initials: MR
authors.lastname: Dalesandro
authors.forename: C S
authors.initials: CS
authors.lastname: Kinney
authors.forename: S A
authors.initials: SA
authors.lastname: Siegel
authors.forename: J N
authors.initials: JN
authors.lastname: Woody
authors.forename: P E
authors.initials: PE
authors.lastname: Daddona
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism*; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D006090:Gram-Negative Bacteria; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008050:Lipid A / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D007075:Immunoglobulin M; D007375:Interleukin-1; D015850:Interleukin-6; D008050:Lipid A; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha