title: Llama heavy-chain antibody fragments efficiently remove toxic shock syndrome toxin 1 from plasma in vitro but not in experimental porcine septic shock.
abstract: Staphylococcus aureus produces the superantigen toxic shock syndrome toxin 1 (TSST-1). When the bacterium invades the human circulation, this toxin can induce life-threatening gram-positive sepsis. Current sepsis treatment does not remove bacterial toxins. Variable domains of llama heavy-chain antibodies (VHH) against toxic shock syndrome toxin 1 ([alpha]-TSST-1 VHH) were previously found to be effective in vitro. We hypothesized that removing TSST-1 with [alpha]-TSST-1 VHH hemofiltration filters would ameliorate experimental sepsis in pigs. After assessing in vitro whether timely removing TSST-1 interrupted TSST-1-induced mononuclear cell TNF-[alpha] production, VHH-coated filters were applied in a porcine sepsis model. Clinical course, survival, plasma interferon [gamma], and TSST-1 levels were similar with and without VHH-coated filters as were TSST-1 concentrations before and after the VHH filter. Plasma TSST-1 levels were much lower than anticipated from the distribution of the amount of infused TSST-1, suggesting compartmentalization to space or adhesion to surface not accessible to hemofiltration or pheresis techniques. Removing TSST-1 from plasma was feasible in vitro. However, the [alpha]-TSST-1 VHH adsorption filter-based technique was ineffective in vivo, indicating that improvement of VHH-based hemofiltration is required. Sequestration likely prevented the adequate removal of TSST-1. The latter warrants further investigation of TSST-1 distribution and clearance in vivo.
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Brummelhuis
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.forename: Jord C
authors.initials: JC
authors.lastname: Stam
authors.forename: Hendrik
authors.initials: H
authors.lastname: Adams
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Detmers
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Khattabi
authors.forename: Bram T
authors.initials: BT
authors.lastname: Maassen
authors.forename: C Theo
authors.initials: CT
authors.lastname: Verrips
authors.forename: Branko
authors.initials: B
authors.lastname: Braam
mesh_terms: D000818:Animals; D001427:Bacterial Toxins; D002161:Camelids, New World / Q000276:immunology; D002478:Cells, Cultured; D004768:Enterotoxins; D005260:Female; D006440:Hemofiltration / Q000379:methods; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010446:Peptide Fragments / Q000627:therapeutic use*; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control*; D018089:Superantigens; D034421:Sus scrofa
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; D007143:Immunoglobulin Heavy Chains; D010446:Peptide Fragments; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal