Quantitative Studies of Febrile Tolerance and Levels of Specific Antibody Evoked by Bacterial Endotoxin*

Abstract

Febrile tolerance was induced in rabbits by a series of a daily intravenous injections of Salmonella enteritidis endotoxin, and at varying intervals thereafter the animals were tested quantitatively for resistance to the pyrogenic activity of this bacterial polysaccharide. Utilizing a 1,000-fold range of challenge doses, the refractoriness to the least amount of endotoxin (0.25[mu]g) persisted for more than 8 weeks, and tolerance to endotoxin in increasing amounts was of progressively shorter duration. During the period of diminished febrile response, there was no consistent correlation with the levels of circulating antibody as measured by 5 different techniques. In animals whose resistance had diminished, tolerance was "reactivated" within 24 hours by a single injection, from which no increase in antibody was discernible. The immune response to the tolerance schedule of multiple injections of endotoxin involved the development and persistence of substantial levels of macroglobulin antibody; however, after 3 weeks or more, small amounts of 7 S antibody appeared. A single injection of endotoxin evoked within 24 hours pyrogenic tolerance of a magnitude similar to that following multiple injections; this tolerance persisted at diminished levels for at least 34 days. Specific antibody was not detected before 72 hours. Maximum antibody production occured in 5 days and declined thereafter.