The nature of endotoxin tolerance.

Certain of the mechanisms by which man develops pyrogenic tolerance to bacterial endotoxins have been considered. After an initial intravenous injection of toxin, two temporally distinct phases of tolerance can be discerned, early and late, each with very different characteristics. Early tolerance appears to be mediated by a non-antibody mechanism entailing a transiently occurring refractory state, apparently involving to a major degree decreased production of endogenous pyrogen by the macrophage system, particularly the hepatic macrophages. Late tolerance appears to be mediated by anti-endotoxin antibodies directed against both "O" and common core antigens which blunt the release of endogenous pyrogen from macrophages. The common core antigens are masked in the presence of the "O" antigenic side chains and become effective immunogens only when these "O" side chains are lacking. Accelerated reticuloendothelial system clearance of circulating endotoxin provides an ancillary protective mechanism in that it brings the toxin more efficiently into the macrophages that are refractory or protected by antibody. When endotoxin is administered repeatedly at closely spaced intervals, both the early phase (non-immune) and late phase (immune) mechanisms may become superimposed. In addition, a third mechanisms, enhanced detoxification capabilities of macrophages, also now appears to come into play. At any given time, it is the relative contribution of each mechanism, which in turn is dependent upon the immunization schedule, antigenicity of the endotoxin, dosage, and immunological competency of the host, that determines the expression of the endotoxin tolerant state.