Studies on the Pathogenesis of Fever. I. The Presence of Transferable Pyrogen in the Blood Stream Following the Injection of Typhoid Vaccine

The rate of clearance of intravenously injected typhoid vaccine was studied in unsensitized, sensitized, and pyrogen-tolerant rabbits by means of a passive transfer technique. The blood of unsensitized rabbits which had not been previously exposed to bacterial pyrogen remained pyrogenic for normal recipients throughout a period of 2 hours following the injection. In contrast, rabbits sensitized by having received either one or two injections of the vaccine at least 3 weeks prior to the experiment cleared their blood of the test vaccine within 30 minutes despite the fact that they exhibit the same febrile response as unsensitized rabbits. After 1 hour, however, a transferable pyrogenic substance was again demonstrable in the sera of this group. Reasons are discussed for believing that this newly appearing substance may be of endogenous origin and may be the factor which directly affects the thermoregulatory centers of the brain. Rabbits which are made tolerant by repeated daily injections of vaccine have a characteristically depressed febrile response. Not only were the blood streams of such animals cleared of the injected vaccine within less than 5 minutes, but samples of their sera obtained 1 and 2 hours after the injection also failed to contain demonstrable quantities of the secondary pyrogen observed in sensitized animals. The latter observation is in keeping with the suggestion that the secondary pyrogen may play a critical role in the production of fever.