title: Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin: a prospective, double-blind, randomized, controlled trial.
abstract: OBJECTIVE
  Endotoxin is one of the principal mediators of Gram-negative septic shock. Pretreatment with monophosphoryl lipid A, a hydrolyzed derivative of endotoxin from Salmonella minnesota R595, induces endotoxin tolerance and nonspecific resistance to infection in experimental animals. The present clinical trial was undertaken to test the response to monophosphoryl lipid A in humans and the ability of monophosphoryl lipid A to attenuate the response of normal human volunteers to U.S. Reference Ec-5 endotoxin.
  
  
  METHODS
  Prospective, double-blind, randomized, controlled trial.
  
  
  METHODS
  Clinical research center.
  
  
  METHODS
  Forty-four healthy volunteers.
  
  
  METHODS
  In part 1 of the study, 29 volunteers were randomized in varying ratios to receive vehicle control or monophosphoryl lipid A intravenously in a double-blind dose escalation trial. In part 2 of the study, 12 volunteers were randomized to receive either monophosphoryl lipid A (20 micrograms/kg) or vehicle control and, 24 hrs later, all 12 volunteers were challenged with U.S. Reference Ec-5 endotoxin (20 units/kg intravenous, bolus injection). Systemic response to endotoxin challenge was evaluated and compared between the monophosphoryl lipid A and vehicle control-pretreated subjects.
  
  
  RESULTS
  In part 1 of the study, subjective effects and increases in cytokine levels were not observed until a dose of 10 micrograms/kg of monophosphoryl lipid A was administered. Six volunteers receiving a maximum dose of 20 micrograms/kg experienced mild-to-moderate symptoms that did not require therapy. Moderate increases in temperature, heart rate, and tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 release were observed. IL-1 alpha and IL-1 beta were not detected but a significant increase in IL-1 receptor antagonist was observed. In part 2 of the study, monophosphoryl lipid A pretreatment reduced the number of volunteers who experienced one or more subjective complaints after endotoxin administration (3/6 vs. 6/6; p = .09). The febrile response and tachycardic response to endotoxin were significantly reduced by pretreatment with monophosphoryl lipid A. Monophosphoryl lipid A-pretreated volunteers demonstrated significantly reduced concentrations of TNF-alpha after endotoxin challenge, as compared with subjects treated with vehicle control (84 +/- 76 vs. 244 +/- 128 pg/mL; p < .05). IL-6 concentrations (100 +/- 91 vs. 268 +/- 171 pg/ml; p < .05) and IL-8 concentrations (136 +/- 86 vs. 632 +/- 323 pg/mL; p < .05) elicited by endotoxin challenge were also significantly reduced by monophosphoryl lipid A pretreatment.
  
  
  CONCLUSIONS
  Data indicate that monophosphoryl lipid A, in a dose 10,000 times that of endotoxin, used in experimental pyrogenicity trials, is well tolerated in human volunteers. Pretreatment of normal human volunteers with monophosphoryl lipid A attenuated the systemic response to bacterial endotoxin. These data support further clinical testing of monophosphoryl lipid A for the prevention or amelioration of the severe sequelae of sepsis.
authors.affiliation: St. Vincent's Hospital and Medical Center of New York/New York Medical College, NY 10033.
authors.forename: M E
authors.initials: ME
authors.lastname: Astiz
authors.forename: E C
authors.initials: EC
authors.lastname: Rackow
authors.forename: J G
authors.initials: JG
authors.lastname: Still
authors.forename: S T
authors.initials: ST
authors.lastname: Howell
authors.forename: A
authors.initials: A
authors.lastname: Cato
authors.forename: K B
authors.initials: KB
authors.lastname: Von Eschen
authors.forename: J T
authors.initials: JT
authors.lastname: Ulrich
authors.forename: J A
authors.initials: JA
authors.lastname: Rudbach
authors.forename: G
authors.initials: G
authors.lastname: McMahon
authors.forename: R
authors.initials: R
authors.lastname: Vargas
mesh_terms: D000293:Adolescent; D000328:Adult; D001772:Blood Cell Count; D001831:Body Temperature; D002395:Catecholamines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D004731:Endotoxins / Q000276:immunology*; D004926:Escherichia coli; D006339:Heart Rate; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007108:Immune Tolerance / Q000187:drug effects; D007262:Infusions, Intravenous; D008050:Lipid A / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D011446:Prospective Studies; D018805:Sepsis / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D002395:Catecholamines; D016207:Cytokines; D004731:Endotoxins; D008050:Lipid A; C044101:endotoxin, Escherichia coli; C048436:monophosphoryl lipid A; D006854:Hydrocortisone