Abstract

Introduction: Bacterial DNA (CpG DNA) is a Toll-like receptor 9 (TLR9) agonist that is known to promote enhanced immunity by boosting Th1-type immune responses. This adjuvant activity of CpG DNA suggested to us that it might redirect the changes in immune function that occur after burn injury and protect mice from developing suppressed resistance to sepsis. Methods: Groups of male C57BL/6J mice were given CpG oligodeoxynucleotide (ODN) sequence 2336 (2ug/mouse) or saline by i.p. injection 1 day after sham or burn injury. The influence of CpG treatment on Th1-type responses was tested by measuring B-cell antibody isotype switching in mice immunized with TNP-haptenated ovalbumin (TNP-OVA). Spleen cells prepared at day 2 and 7 after injury were cultured for 48hours with or without anti-CD3 antibody, bacterial lipopolysaccharide (LPS), or bacterial lipopeptide (BLP) to measure changes in innate and adaptive cell responses. IFN-ã, TNFα, IL-6, IL-10 and MCP-1 were measured by cytometric bead arrays. Cecal ligation and puncture (CLP) was performed at day 7 after sham and burn injury in CpG- or saline-treated mice and mortality was followed for 10 days. Results: Burn injury caused a reduction in Th1- dependent antibody isotype, IgG2b, formation. However, CpG treatment fixed this burn-induced loss of Th1 reactivity. CpG treatment also reduced TNFα, IL-6, and MCP-1 production by LPS or BLP stimulated spleen cells from burn mice at day 2 and TNFα production remained lower at day 7. Most important, CpG ODN treatment significantly improved the survival outcome of CLP-challenged burn mice (10 day CLP survival - sham, 73%; sham CpG, 75%; burn, 5%; burn CpG, 35%, n=12-24mice per group) Conclusion: CpG treatment protects burn mice against polymicrobial sepsis suggesting that triggering the TLR9 pathway after injury might help to restore normal immune system function. Our findings suggest that CpG ODN may act by boosting Th1 immunity and by suppressing the enhanced inflammatory reactivity that occurs after injury.

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