Christine K Ward

MedImmune, LLC, GAI, Maryland, United States

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Publications (3)10.29 Total impact

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    ABSTRACT: Emerging evidence suggests a link between innate immunity and development of type 2 diabetes mellitus (T2D); however, the molecular mechanisms linking them are not fully understood. Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that recognizes the double-stranded RNA of microbial or mammalian origin and contributes to immune responses in the context of infections and chronic inflammation. The objective of this study was to determine whether TLR3 activity impacts insulin sensitivity and lipid metabolism. Wild type (WT) and TLR3 knock-out (TLR3(-/-)) mice were fed a high fat diet (HFD) and submitted to glucose tolerance tests (GTTs) over a period of 33weeks. In another study, the same group of mice was treated with a neutralizing monoclonal antibody (mAb) against mouse TLR3. TLR3(-/-) mice fed an HFD developed obesity, although they exhibited improved glucose tolerance and lipid profiles compared with WT obese mice. In addition, the increase in liver weight and lipid content normally observed in WT mice on an HFD was significantly ameliorated in TLR3(-/-) mice. These changes were accompanied by up-regulation of genes involved in cholesterol efflux such as PPARδ, LXRα, and LXRα-targeting genes and down-regulation of pro-inflammatory cytokine and chemokine genes in obese TLR3(-/-) mice. Furthermore, global gene expression profiling in liver demonstrated TLR3-specific changes in both lipid biosynthesis and innate immune response pathways. TLR3 affects glucose and lipid metabolism as well as inflammatory mediators, and findings in this study reveal a new role for TLR3 in metabolic homeostasis. This suggests antagonizing TLR3 may be a beneficial therapeutic approach for the treatment of metabolic diseases.
    No preview · Article · May 2012 · Metabolism: clinical and experimental
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    ABSTRACT: Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log(10) CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log(10) CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log(10) CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.
    Full-text · Article · Feb 2011 · Antimicrobial Agents and Chemotherapy
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    ABSTRACT: Toll-like receptor 3 (TLR3) binds and signals in response to dsRNA and poly(I:C), a synthetic double stranded RNA analog. Activation of TLR3 triggers innate responses that may play a protective or detrimental role in viral infections or in immune-mediated inflammatory diseases through amplification of inflammation. Two monoclonal antibodies, CNTO4685 (rat anti-mouse TLR3) and CNTO5429 (CDRs from CNTO4685 grafted onto a mouse IgG1 scaffold) were generated and characterized. These mAbs bind the extracellular domain of mouse TLR3, inhibit poly(I:C)-induced activation of HEK293T cells transfected with mTLR3, and reduce poly(I:C)-induced production of CCL2 and CXCL10 by primary mouse embryonic fibroblasts. CNTO5429 decreased serum IL-6 and TNFα levels post-intraperitoneal poly(I:C) administration, demonstrating in vivo activity. In summary, specific anti-mTLR3 mAbs have been generated to assess TLR3 antagonism in mouse models of inflammation.
    No preview · Article · Jan 2011 · Cellular Immunology