The applicants propose to study the pathogenesis and biologic significance of injury-induced defects in the innate cellular immune response. These include studies of both experimental endotoxin tolerance in mice and clinical immune paralysis in cardiac surgery patients. Endotoxin tolerance is induced by repeated exposures to lipopolysaccharide (endotoxin) and results in reduced synthesis of pro-inflammatory cytokines to microbial stimuli. Immune paralysis is phenotypically similar, but is a clinical phenomenon induced by sepsis or trauma. They hypothesize that endotoxin tolerance and immune paralysis disrupt the interdependent production and synergistic anti-microbial activities of TNF-alpha, IL-12 and IFN-gamma that mediate the innate cellular immune response. Their first goal is to use the well-characterized mouse model of endotoxin tolerance to identify mechanisms that mediate the immune defects of endotoxin tolerance and enhance susceptibility to infection. They will then identify interventions that prevent or reverse these immune deficiencies. Preliminary data already indicate immune cell depletion is a mechanism for injury-induced cytokine deficiency and identify a 10- to 10,000-fold enhanced susceptibility to candidiasis during endotoxin tolerance. The applicants' second goal is to study the biologic basis and epidemiologic consequence of immune paralysis in cardiac surgery patients, with a long term goal of developing clinical interventions to prevent immune paralysis.
The specific aims of this proposal are: 1) Identify molecular and/or cellular defects in the innate immune response of endotoxin tolerant mice. 2) Determine if the defective innate immunity of endotoxin tolerance enhances susceptibility to common nosocomial pathogens. 3) Use these findings to rationally design drug or cytokine therapies that prevent the immune defects of endotoxin tolerance and thereby reduce susceptibility to nosocomial superinfection. 4) Characterize comparable cytokine and cellular defects in hospitalized patients following cardiac surgery and identify immune phenotypic markers predictive of post-operative infections. Studies of the immune pathogenesis of infectious susceptibility in endotoxin tolerant mice are likely to suggest cytokine- or anti-apoptosis-based therapies for clinical immune paralysis. This is a clinically desirable goal, as the preservation or enhancement of innate immunity against nosocomial infections in injured patients may significantly reduce hospital morbidity, costs, antibiotic use and the selection of antibiotic-resistant pathogens.
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