title: Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate.
abstract: BACKGROUND
  The triggering receptor expressed on myeloid cells-1 is an immunoreceptor that amplifies the inflammatory response mediated by toll-like receptors engagement. Triggering receptor expressed on myeloid cells-1 inhibitory peptides such LR12 have been shown to prevent hyperresponsiveness and death in several experimental models of septic shock.
  
  
  METHODS
  Twelve adult male Cynomolgus (Macaca fascicularis) monkeys exposed to an intravenous bolus of endotoxin (10 μg/kg) were randomized to receive LR12 or placebo (n = 6 per group) as an initial intravenous bolus followed by an 8-h continuous intravenous infusion. An additional group of four only received vehicle infusion. Vital signs were monitored for 8 h. Blood was sampled at H0, 1, 2, 4, and 8 for analysis of clinical chemistries, leukocyte count, coagulation parameters, and cytokine plasma concentration.
  
  
  RESULTS
  LR12 showed no effect on heart rate and body temperature. By contrast to the placebo group, which experienced a 25 to 40% blood pressure decrease after endotoxin administration, LR12-treated monkeys remained normotensive. Endotoxin induced leukopenia at 2 h (mean leukocyte count, 7.62 g/l vs. 21.1 at H0), which was attenuated by LR12. LR12 also attenuated cytokine production.
  
  
  CONCLUSIONS
  The triggering receptor expressed on myeloid cells-1 inhibitor LR12 is able to mitigate endotoxin-associated clinical and biological alterations, with no obvious side effects. This study paves the way for future phases Ia and Ib trials in humans.
authors.affiliation: From the INSERM UMR_S 1116, Université de Lorraine, Nancy, France (M.D., A.B., and S.G.); and Service de Réanimation Médicale, Hôpital Central, Nancy, France (S.G.).
authors.forename: Marc
authors.initials: M
authors.lastname: Derive
authors.forename: Amir
authors.initials: A
authors.lastname: Boufenzer
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gibot
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004731:Endotoxins / Q000097:blood; D007275:Injections, Intravenous; D007850:Lauric Acids / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D007970:Leukopenia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008252:Macaca fascicularis; D008297:Male; D022423:Myeloid Cells / Q000378:metabolism*; D009842:Oligopeptides; D011897:Random Allocation; D012235:Rhodamines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy*
chemical_list: D004731:Endotoxins; D007850:Lauric Acids; D009842:Oligopeptides; D012235:Rhodamines; C420324:nangibotide