Mechanisms of endotoxin tolerance with special reference to

In this review of the mechanisms underlying pyrogenic tolerance to bacterial endotoxins, two earlier concepts require modification. (l) Granulocytes are the major source of endogenous pyrogen release by endotoxin. (2) Pyrogenic toler-ance results simply from accelerated clearance of endotoxin by the reticuloendo-thelial system (RES), diverting the toxin from the granulocytes. Rather, it now appears that hepatic Kupffer cells are the major source of endogenous pyrogen release by endotoxin, and that pyrogenic tolerance results primarily from refrac-toriness of these cells to further release of endogenous pyrogen. Accelerated clear-ance by the RES appears to be an ancillary protective mechanism that brings toxin more rapidly to the refractory cells. Refractoriness to the release of endogenous pyrogen can be achieved both by direct cellular interaction with endotoxin and by antibodies to endotoxin. The direct cellular effect is transient and requires closely spaced injections of endotoxin for maximal maintenance; antibody-mediated protection is delayed but more enduring. The diverse, often conflicting observations on pyrogenic tolerance are explicable by the interplay of these pro-tective mechanisms. Assessment of the role of endotoxin in the patho-genesis of gram-negative bacterial infection of man requires an understanding of the mechanisms used by man to develop resistance to this toxin. In contrast to studies with animal models, how-ever, few critical studies exist on human mecha-nisms of acquisition of tolerance to endotoxin. Moreover, such studies in man are by necessity restricted to parameters (e.g., pyrogenicity) that pose minimal risk to the subjects. The following report presents a review, drawn from investiga-tions conducted in this and other laboratories, of the tolerant responses of man to bacterial endo-toxin. Our experience is based upon studies in These studies were supported by contract no. DA-49-193-MD-2867 from the United States Army Medical Research and Development Command and by researc