Develop Therapy to Induce Longterm Endotoxin Tolerance

Bacterial Lipopolysaccharide (LPS) is a component of gram negative bacterial cell walls thatinduces endotoxic shock by stimulating secretion of toxic mediators by macrophages. Derivatives ofbacterial LPS with reduced toxicity and sublethal doses of native LPS protect against endotoxic shockif given prophylactically, since they both induce tolerance to subsequent LPS exposure at toxic levels.Most of these LPS derivatives do, however, exhibit some toxicity themselves, and the induced toleranceis transient (hours to a few days). The window of opportunity for use of this type of therapy, therefore,is small. Francisella tularensis is a gram negative bacterium with a unique LPS: this LPS is apparentlynon-toxic in animal models, nonreactive in vitro for stimulating cytokine production by macrophages, anda thousand times less reactive than Samonella LPS on a weight-for-weight basis in an amoebocyte lysisassay. Yet, Francisella infection in humans induces LPS hyporesponsiveness. Francisella's unique LPS,then, may induce endotoxin tolerance without toxicity. The general goal of this Phase I proposal is toexamine whether Francisella LPS will be a useful immunotherapeutic agent to protect againstendotoxemia or gram negative infection. The specific aims are to (1) produce Francisella LPS insufficient quantity to test its activity, (2) determine its toxicity and reactivity, and (3) assess in vivotolerance induction by Francisella LPS alone or incorporated into liposomes.