MECHANISMS OF ENDOTOXIN TOLERANCE

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Abstract
Healthy male volunteers were rendered tolerant to bacterial endotoxins. 5 were given 0.5 [mu]g Salmonella typhosa endotoxin for 7 days; 4 were given Pseudomonas endotoxin, increasing over a period of 30 days from 25 to 250 [mu]g. Reticuloendothelial (RES) phagocytic activity was assessed by serial measurements of clearance of I131 labeled aggregated human serum albumin. In no subject was an increase in RES phagocytic activity detectable. Further studies revealed hyper-reactivity of some subjects to a second injection of endotoxin 24 hours after the initial dose; plasma from tolerant but not from normal donors prevented such hyperreactivity. Tolerance was also found to be reversed by administration of half the dose of endotoxin followed 2 hours later by the second half or by administration of a heterologous endotoxin. The data are consistent with the hypothesis that tolerance to endotoxin pyrogenicity in man is not based upon generalized enhancement of RES phagocytic activity or exhaustion of host reactivity but upon immunologic mechanisms.