Mechanisms of Endotoxin Tolerance

Sieved spleen cells (3 × 109) from rabbits immunized with a Biovin preparation of Escherichia coli endotoxin were capable of transferring significant “anamnestic” endotoxin-tolerant responses to non-inbred normal recipient animals. Thus, whereas the initial febrile responses of the primed spleen cell recipients to a standard dose of E. coli endotoxin remained unaltered, upon retesting 48 hr later significant reductions in febrile responses occurred in comparison with recipients given comparable numbers of spleen cells from non-immunized donors. Simple carry-over of free endotoxin by the primed spleen cells could not explain such transfer of “anamnesis” since frozen and thawed primed spleen cells were ineffective. The transferred “anamnestic” tolerance was partially specific for the endotoxin employed in immunizing the spleen cell donors, i.e., spleen cells from donors immunized with a Boivin preparation of Salmonella typhimurium transferred significantly less “anamnestic” tolerance to the standard E. coli endotoxin test preparation. These latter observations support the concept that antibodies directed against the specific “O” terminal polysaccharide side chains contribute significantly to pyrogenic tolerance to bacterial endotoxins. Despite the specificity of the transferred “anamnestic” tolerance to endotoxin, increments in circulating anti-“O” antibodies were not generally observed at 48 hr, suggesting that “O” protective antibodies at this time may be primarily cell-fixed. The smaller but nevertheless significant transfer of “anamnestic” tolerance to E. coli endotoxin conveyed by spleen cells from donors immunized with S. typhimurium endotoxin provides evidence that antibodies with broader specificity also participate in pyrogenic tolerance to bacterial endotoxin.