TOLERANCE TO BACTERIAL PYROGENS : I. FACTORS INFLUENCING ITS DEVELOPMENT.

In a study of the febrile responses of rabbits to repeated intravenous injections of pyrogenic substances from Eberthella typhosa, Serratia marcescens, and Pseudomonas aeruginosa, the following observations were made: 1. A characteristic pattern of response to daily injections of the same dose of pyrogenic material was noted. This consisted of a progressive diminution in febrile response during the 1st week or 10 days, after which an animal responded to each injection with approximately the same degree of fever, even when the injections were continued for several weeks. 2. Animals given injections of the same amount of pyrogenic material at semiweekly or weekly intervals showed some diminution in febrile reaction but the alteration was less pronounced than that in animals injected every day. 3. Pyrogen tolerance appeared to be lost quickly. Animals allowed to rest for approximately 3 weeks reacted to readministration of pyrogen with fever comparable with that which occurred after the first injection. 4. By gradually increasing the size of the daily dose of pyrogen a tolerance could be established such that a reduced, but still considerable, amount of pyrogen caused no fever whatever. 5. Rabbits that had been injected with S. marcescens or Ps. aeruginosa pyrogens showed a diminished febrile response to E. typhosa vaccine. 6. Passive transfer of the unresponsiveness to pyrogens could not be demonstrated. 7. Prevention of temperature elevations during the course of immunization by use of an antipyretic drug did not interfere with the development of tolerance to pyrogens. 8. A series of mechanically induced bouts of fever did not reduce the responsiveness to bacterial pyrogens.