MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS* I . SPECIFICITY OF PYROGENIC TOLERANCE AND THE ROLE OF HYPERSENSITIVITY IN PYROGENICITY, LETHALITY, AND SKIN REACTIVITY BY DENNIS W. WATSON,$ ProD., AND YOON

The mechanism of tolerance to the pyrogenic activity of Gram-negative bacterial endotoxins is most often attributed to a non-specific increase in the activity of the reticuloendothelial system (RES) (1). Recently, it was shown that Group A streptococcal exotoxins produced biphasic fever responses in rabbits (2). In contrast to the non-specific tolerance induced by endotoxins, three distinct toxins were identified based on their ability to induce specific pyrogenic tolerance; in addition, the pyrogenic activity was neutralized specifically with antiserum. These observations suggested that, in addition to the non-specific RES activity, specific immune mechanisms may contribute to pyrogenic tolerance to Gram-negative bacterial endotoxins. Because endotoxins from organisms of different species and families induce non-specific pyrogenic tolerance, it is assumed that specific immunological mechanisms are not involved. If, however, there exist unsuspected common or cross-reactive antigens contributing to the pyrogenic activity, the non-specific nature of the mechanism would be more apparent than real. Our approach involved, therefore, an attempt to demonstrate specificity by the use of cross-tolerance tests as applied to the streptococcal pyrogenic toxins (2). Purified endotoxins were selected for this purpose on the basis of suspected chemical differences. In addition, there is evidence to implicate the immunological state of the host in many of the biological activities of endotoxins. From birth, animals are continually exposed to Gram-negative bacterial endotoxins derived from organisms growing in the gastrointestinal tract. Of particular interest is the enhanced susceptibility of animals to endotoxins after colonization with Gramnegative bacteria (3); here there was evidence of specificity because the induced susceptibility was greater when the endotoxin was derived from the