Induction of hypersensitivity to endotoxin lethality in mice by treatment with trehalose 6,6 '-dimycolate but not with 2,3,6,6 '-tetraacyl trehalose 2 '-sulfate

The mechanism by which priming with trehalose 6,6'-dimycolate (TDM, cord fa ctor) induced hypersensitivity to endotoxin lethality was investigated. C57 BL/6 and BALB/c mice primed with TDM succumbed to endotoxin shock, but BALB /c IFN-gamma knock-out (IFN-gamma(-/-)) mice showed resistance to LPS letha lity. The levels of serum IFN-gamma peaked on day 4 after priming with TDM and kept significant Levels, indicating that IFN-gamma plays a. critical ro le for inducing hypersensitivity to LPS lethality. After challenge with LPS , TDM-primed mice produced higher amounts of serum TNF alpha and soluble CD 14. A sulfolipid (SL, 2,3,6,6'-tetraacyl trehalose 2'-sulfate) did not indu ce the hypersensitivity and, conversely, suppressed the activity of TDM whe n administered together. Administration of TDM induced infiltration of mono nuclear cells in liver, and apoptosis of cells present in the liver sinus w as observed after LPS challenge. These results suggest that the hypersensit ivity to LPS lethality is due to overproduction of cytokines and other mole cules.