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-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. Design: Prospective, double-blind, randomized, controlled trial. Setting: Clinical research center. Patients: Forty-four healthy volunters. Intervention: In part 1 of the study, 29 volunters 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 μg/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. Measurements and Main Results: In part 1 of the study, subjective effects and increases in cytokine levels were not observed until a dose of 10 μg/kg of monophosphoryl lipid A was administered. Six volunters receiving a maximum dose of 20 μg/kg experienced mild-to-moderate symptoms that did not require therapy. Moderate increases in temperature, heart rate, and tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 release were observed. IL-1α and IL-1β 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-α 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. 692±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 volunters. 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