INDUCTION OF PULMONARY GRANULOMAS, MACROPHAGE PROCOAGULANT ACTIVITY, AND TUMOR-NECROSIS-FACTOR-ALPHA BY TREHALOSE GLYCOLIPIDS

Trehalose 6, 6' dimycolate (TDM), a mycobacterial glycolipid, induces granulomas and hemorrhagic toxic reactions when administered in oil bu t not as a suspension in saline. It was previously demonstrated by us that TDM forms highly structured layers at oil-water interfaces and th en postulated that its toxicity derives from the adhesive properties o f these layers. To test this hypothesis, an evaluation was made of the ability of TDM and two analogs, trehalose 6-monomycolate (TMM) and ga lactose-galactose 6, 6' dimycolate (GDM), to induce pulmonary granulom as and stimulate expression of procoagulant activity (PCA) and tumor n ecrosis factor-alpha (TNF-alpha). Intravenous injection in mice of oil -in-water emulsions of TDM produced more and larger pulmonary granulom as than injection of TMM or GDM. Similarly, TDM on the surface of bead s induced higher levels of PCA and TNF-alpha in human mononuclear cell s than the analogs. The correlation of these results with the structur e of surface layers of the glycolipids strengthens the hypothesis that the particular surface structure formed by TDM is necessary for its b iologic activity.