Mechanisms of Endotoxin Tolerance

By serial quantitation of tolerance following a single intravenous injection of a Boivin-prepared Escherichia coli endotoxin into rabbits, pyrogenic tolerance could be readily separated into two distinct phases, early (waning within 48 hr) and late (increasing after 48 hr). The early phase of tolerance a) exhibited no inter-endotoxin specificity, b) was not associated with detectable increments in circulating anti-“O” antibody and c) within the sensitive dose-response range was directly proportional to the intensity of the initial pyrogenic response. It was not, however, a generalized refractory state since full responsiveness persisted to an unrelated pyrogen, staphylococcal enterotoxin B. In contrast, the late phase of pyrogenic tolerance a) exhibited a high degree of inter-endotoxin specificity, b) coincided with the appearance of detectable increments in circulating anti-“O” antibody, and c) within the sensitive dose-response range bore no direct relationship to the initial pyrogenic response. This latter characteristic was also demonstrated in man. The specificity of late tolerance was not demonstrable if the initial immunizing endotoxin preparation possessed poor “O” antigenicity (highly purified Westphal preparations), or if the endotoxin preparation employed for testing tolerance was derived from mutant strains lacking “O” specific terminal polysaccharide side chains. These findings support the concept that the pyrogenic tolerant state following intravenous endotoxin administration is mediated by two distinct mechanisms, an early transient cellular refractory state and a later production of antibody which assists the reticuloendothelial system with clearance and destruction of the molecule. “O” specific antibodies appear to play the major role in mediating the late phase of pyrogenic tolerance following a single intravenous injection of endotoxin.