Studies on the pathogenesis of fever with influenzal viruses. III. The relation of tolerance to the production of endogenous pyrogen.

Tolerance to the pyrogenic action of intravenously injected virus has been studied in rabbits given either PR8 strain of influenza A virus or Newcastle disease virus (NDV). The following findings suggest that the capacity of the animal to release an endogenous pyrogen is a critical factor. (a) Viruses produce fever by the release of endogenous pyrogen. (b) Tolerance to the pyrogenic effect of reinjected virus is associated with a decrease or absence of endogenous pyrogen production. (c) Tolerance to virus fever may be induced by the prior injection of endogenous pyrogen. (d) Cross-tolerance has been demonstrated between virus and bacterial endotoxin (typhoid vaccine), both of which cause the release of endogenous pyrogen. A difference has been noted in the mechanism of tolerance to successive injections of virus and of bacterial endotoxin. Repeated injections of endotoxins bring about an accelerated clearance of these substances from the blood stream with the result that there is a diminished stimulus to endogenous pyrogen production. Tolerance to virus, on the other hand, is unaccompanied by changes in the rate at which virus disappears from the circulation. It is postulated that circulating endogenous pyrogen, induced by the injection of a number of pyrogenic agents including viruses, temporarily suppresses the further release of endogenous pyrogen and thereby contributes to virus tolerance.