Endogenous production of TNF in mice long after BCG sensitization

The effect of tuberculin-antigen protein (PPD: purified protein derivatives) on the priming of tumor necrosis factor (TNF) a long time after sensitization with bacillus Calmette-Guérin (BCG) was investigated in mice. Mice were infected intravenously (i.v.) with 4 X 10(7) colony-forming units (CFU) of BCG per mouse, and the TNF activity triggered by 15 micrograms lipopolysaccharide (LPS) was assayed with time using L-929 cells. The activity was maximal 4 weeks after sensitization and decreased to the control level after 10 weeks. The i.v. injection of 10 micrograms of PPD per mouse enhanced the TNF production triggered by LPS in mice even 10-20 weeks after sensitization. This enhancement was unexpectedly quite transient, being maximal 3 h after PPD treatment. The activity was comparable to that in mice 4 weeks after sensitization of BCG (without PPD). The enhancing effect of PPD was observed in the dose range of 0.1-10 micrograms/mouse, and 10 micrograms of PPD significantly enhanced the TNF activity triggered by even 0.6 microgram LPS. These findings indicate that priming of sensitized animals with some antigens followed by triggering with LPS induces a significant endogenous production of TNF even a long time after antigen sensitization. The possible application of these findings for inducing endogenous production of TNF in human patients by use of tuberculin allergy is discussed.