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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Case Western Reserve University
Internal Medicine/Medicine
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Greene, Jennifer A; DeVecchio, Jennifer L; Gould, Meetha P et al. (2006) In vivo and in vitro regulation of type I IFN synthesis by synergistic effects of CD40 and type II IFN. J Immunol 176:5995-6003
Gupta, Sameer; Gould, Meetha P; DeVecchio, Jennifer et al. (2006) CpG-induced IFNgamma expands TLR4-specific IL-18 responses in vivo. Cell Immunol 243:75-82
Yadavalli, Gopala K; Chien, Jason W; Wener, Kenneth M et al. (2005) Interleukin 12 and interferon-gamma synthetic deficiency is associated with dendritic cell cytopenia after cardiac surgery. Shock 24:26-33
Johnson, Angela C; Heinzel, Fred P; Diaconu, Eugenia et al. (2005) Activation of toll-like receptor (TLR)2, TLR4, and TLR9 in the mammalian cornea induces MyD88-dependent corneal inflammation. Invest Ophthalmol Vis Sci 46:589-95
Das, Lopamudra; DeVecchio, Jennifer; Heinzel, Frederick P (2005) Fms-like tyrosine kinase 3-based immunoprophylaxis against infection is improved by adjuvant treatment with anti-interleukin-10 antibody. J Infect Dis 192:693-702
Auletta, Jeffery J; Devecchio, Jennifer L; Ferrara, James L M et al. (2004) Distinct phases in recovery of reconstituted innate cellular-mediated immunity after murine syngeneic bone marrow transplantation. Biol Blood Marrow Transplant 10:834-47
Gould, Meetha P; Greene, Jennifer A; Bhoj, Vijay et al. (2004) Distinct modulatory effects of LPS and CpG on IL-18-dependent IFN-gamma synthesis. J Immunol 172:1754-62
Murray, Henry W; Brooks, Elaine B; DeVecchio, Jennifer L et al. (2003) Immunoenhancement combined with amphotericin B as treatment for experimental visceral leishmaniasis. Antimicrob Agents Chemother 47:2513-7
Garhart, Christine A; Nedrud, John G; Heinzel, Frederick P et al. (2003) Vaccine-induced protection against Helicobacter pylori in mice lacking both antibodies and interleukin-4. Infect Immun 71:3628-33
Murray, Henry W; Lu, Cristina M; Brooks, Elaine B et al. (2003) Modulation of T-cell costimulation as immunotherapy or immunochemotherapy in experimental visceral leishmaniasis. Infect Immun 71:6453-62

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