PREVENTION OF ENDOTOXIN-INDUCED ACUTE LETHALITY IN PROPIONIBACTERIUM ACNES-PRIMED RABBITS BY AN ANTIBODY TO LEUKOCYTE INTEGRIN BETA(2) WITH CONCOMITANT REDUCTION OF CYTOKINE PRODUCTION

Acute lethality was induced in rabbits by the sequential injection of Propionibacterium acnes and lipopolysaccharide (LPS). P. acnes induced the infiltration of inflammatory cells into the liver lobules during the early phase, and LPS in the late phase caused death in association with pathological changes mimicking hepatocellular necrosis or degeneration around infiltrated mononuclear cells and fibrin deposition in the liver, lung, and kidney, suggestive of a systemic Schwartzman-like reaction. These pathological changes were accompanied by the elevation of plasma tumor necrosis factor (TNF) and interleukin-8 (IL-8) levels. A neutralizing antibody to a leukocyte adhesion molecule, integrin beta(2) (CD18), administered at the time of LPS challenge, prevented hepatocellular injury and fibrin deposition and improved the survival rates. Unexpectedly, the antibody reduced the elevation of plasma TNF and IL-8 levels, An anti-TNF alpha antibody but not an anti-IL-8 antibody prevented the acute lethality induced by P. acnes and LPS, confirming that TNF alpha is an essential mediator in this model. These results indicate that CD18 is critically involved in vivo in activating leukocytes to produce cytokines in response to LPS.