Mechanisms of Endotoxin Tolerance

Healthy male volunteers were rendered tolerant to the pyrogenic and toxic activities of bacterial endotoxin by daily intravenous injections. Five subjects were given 0.5 microg Salmonella typhosa endotoxin for 7 days; four subjects were given Pseudomonas endotoxin, increasing over a period of 30 days from 25 to 250 microg. Reticuloendothelial system (RES) phagocytic activity was assessed by serial measurements of the clearance of I(131)-labeled aggregated human serum albumin. In no subject was an increase in RES phagocytic activity detectable. Such negative findings could not be attributed to decreased RES blood flow.-Additional studies on the pyrogenic responses of man to various schedules of endotoxin administration revealed: (a) Hyperreactivity of some subjects to a second injection of endotoxin administered 24 hours after the initial dose; (b) prevention of such hyperreactivity by plasma from donors tolerant to a heterologous endotoxin, but not from normal donors; (c) reduced reactivity to a second injection of endotoxin given 7 days after the initial dose; (d) reversal of induced tolerance by administration of half the dose of endotoxin followed 2 hours later by the second half; (e) reversal of induced tolerance 24 hours after administration of a heterologous endotoxin; (f) enhanced dermal reactivity to endotoxin induced inflammation during tolerance. The observations are consistent with the hypothesis that tolerance to the pyrogenic activity of endotoxin in man is not based upon generalized enhancement of RES phagocytic activity or exhaustion of host reactivity but rather involves the participation of specific antibody which assists the RES in the clearance and inactivation of the endotoxin molecule.