ASSESSMENT OF THE EFFECT OF CANDIDATE ANTIINFLAMMATORY TREATMENTS ON THE INTERACTION BETWEEN MENINGOCOCCI AND INFLAMMATORY CELLS IN-VITRO IN A WHOLE-BLOOD MODEL

A wide range of immunomodulating agents are now available which may be of benefit in reducing inflammatory cell activation in meningococcal sepsis. In order to facilitate selection of candidate anti-inflammator y agents for clinical trials, we have used an in vitro whole blood mod el to evaluate the effects on meningococcal induced neutrophil and mon ocyte activation, of dexamethasone, prostacyclin, pentoxifylline and a human IgM anti-lipid A monoclonal antibody (HA-1A). Known concentrati ons of heat and penicillin killed meningococci were added to whole blo od and the time course of cellular activation was determined. Using el astase-alpha(1)-antitrypsin (elastase-alpha(1)-AT) and TNF alpha produ ction as markers of neutrophil and monocyte activation respectively, p lasma levels of elastase-alpha(1)-AT and TNF alpha were found to incre ase in a dose-dependant manner. Elastase-alpha(1)-AT was detected earl y, with most release occurring between 15-30 min whereas TNF alpha was detected later, between 120-180 min. Dexamethasone, prostacyclin and pentoxifylline caused a dose dependant inhibition of TNF alpha release but had no effect on elastase release. HA-1A had no effect on either TNF alpha or elastase release. This model may be useful in determining the sequence of inflammatory cell activation and in selecting candida te anti-inflammatory agents for evaluation in clinical trials.