PRETREATMENT OF NORMAL HUMANS WITH MONOPHOSPHORYL LIPID-A INDUCES TOLERANCE TO ENDOTOXIN - A PROSPECTIVE, DOUBLE-BLIND, RANDOMIZED, CONTROLLED TRIAL

Objectives: Endotoxin is one of the principal mediators of Gram-negati ve septic shock. Pre-treatment with monophosphoryl lipid A, a hydrolyz ed derivative of endotoxin from Salmonella minnesota R595, induces end otoxin tolerance and nonspecific resistance to infection in experiment al animals. The present clinical trial was undertaken to test the resp onse to monophosphoryl lipid A in humans and the ability of monophosph oryl lipid A to attenuate the response of normal human volunteers to U .S. Reference Ec-5 endotoxin. Design: Prospective, double-blind, rando mized, controlled trial. Setting: Clinical research center. Patients: Forty-four healthy volunteers. Interventions: In part 1 of the study, 29 volunteers were randomized in varying ratios to receive vehicle con trol or monophosphoryl Lipid A intravenously in a double-blind dose es calation trial. In part 2 of the study, 12 volunteers were randomized to receive either monophosphoryl lipid A (20 mu g/kg) or vehicle contr ol and, 24 hrs later, all 12 volunteers were challenged with U.S. Refe rence Ec-5 endotoxin (20 units/kg intravenous, bolus injection). Syste mic response to endotoxin challenge was evaluated and compared between the monophosphoryl lipid A and vehicle control-pretreated subjects. M easurements and Main Results: In part 1 of the study, subjective effec ts and increases in cytokine levels were not observed until a dose of 10 mu g/kg of monophosphoryl lipid A was administered. Six volunteers receiving a maximum dose of 20 mu g/kg experienced mild-to-moderate sy mptoms 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 d etected but a significant increase in IL-1 receptor antagonist was obs erved. In part 2 of the study, monophosphoryl lipid A pretreatment red uced the number of volunteers who experienced one or more subjective c omplaints after endotoxin administration (316 vs. 6/ 6; p = .09). The febrile response and tachycardic response to endotoxin were significan tly reduced by pretreatment with monophosphoryl lipid A. Monophosphory l lipid A-pretreated volunteers demonstrated significantly reduced con centrations of TNF-alpha after endotoxin challenge, as compared with s ubjects 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 < .0 5) elicited by endotoxin challenge were also significantly reduced by monophosphoryl lipid A pretreatment. Conclusions: Data indicate that m onophosphoryl Lipid A, in a dose 10,000 times that of endotoxin, used in experimental pyrogenicity trials, is well tolerated in human volunt eers. Pretreatment of normal human volunteers with monophosphoryl lipi d A attenuated the systemic response to bacterial endotoxin. These dat a support further clinical testing of monophosphoryl lipid A for the p revention or amelioration of the severe sequelae of sepsis.