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The mechanisms underlying the pyrogenic refractory state which develops rapidly during a continuous intravenous infusion of bacterial endotoxin have been further explored. The findings demonstrate that: (a) rabbits rendered refractory to a continuous intravenous infusion of E. coli endotoxin at a standard rate (18 x 10–4 µg/min) become highly refractory to a single intravenous test bolus of endotoxin, but remain fully responsive to preformed endogenous pyrogen and to substances known to release endogenous pyrogen, i.e. influenza virus, old tuberculin in specifically sensitized rabbits, and staphylococcal enterotoxin; (b) administration of fresh whole blood from normal donors containing an average of 1.6 – 108 granulocytes fails to restore febrile responsiveness to the continuing E. coli endotoxin infusion; (c) refractory phase plasma and liver homogenates exhibit no enhanced capacity to inactivate E. coli endotoxin pyrogenicity; (d) splenectomized animals readily develop the pyrogenic refractory state during E. coli endotoxin infusions and exhibit diminished, rather than the increased inflammatory responses to intradermal endotoxin seen in sham-operated controls; (e) continuous intravenous infusions of gelatin-stabilized, heat-killed pneumococci produce sustained fevers; and (f) continuous intravenous infusions of old tuberculin into specifically sensitized animals rapidly elicit a pyrogenic refractory state. The present observations, considered together with those of other investigators, support the hypothesis that pyrogenic unresponsiveness to endotoxin involves two distinct immunologic mechanisms. In terms of this hypothesis, the rapid reduction in febrile responsiveness to endotoxin is mediated by desensitization at the cellular level. With small doses of endotoxin, such as those employed in the present studies, this desensitization is primarily specific; with larger doses, nonspecific mechanisms are superimposed. So long as the subsequent doses of endotoxin are closely spaced or continuously infused, optimal conditions are provided for cellular desensitization and pyrogenic unresponsiveness to a given quantity of endotoxin can be induced rapidly and maintained without the requirement for antibody. However, as the interval between endotoxin challenge is lengthened, cellular desensitization wanes and tolerance becomes increasingly dependent upon those antibodies directed against the common toxophore groupings responsible for endotoxin pyrogenicity which assist the reticuloendothelial system in the clearance and destruction of this molecule.
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