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Prophylactic Treatment with Fms-Like Tyrosine Kinase-3 Ligand after Burn Injury Enhances Global Immune Responses to Infection¹

Julia Bohannon, Weihua Cui^*, Robert Cox^*,, Rene Przkora, Edward Sherwood^*, and Tracy Toliver-Kinsky^2,*,

^* Department of Anesthesiology, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, and Shriners Hospitals for Children, Galveston Burn Unit, Galveston, TX 77550

Severely burned patients are susceptible to infections with opportunistic organisms due to altered immune responses and frequent wound contamination. Immunomodulation to enhance systemic and local responses to wound infections may be protective after burn injury. We previously demonstrated that pretreatments with fms-like tyrosine kinase-3 (Flt3) ligand (Flt3L), a dendritic cell growth factor, increase the resistance of mice to a subsequent burn injury and wound infection by a dendritic cell-dependent mechanism. This study was designed to test the hypothesis that Flt3L administration after burn injury decreases susceptibility to wound infections by enhancing global immune cell activation. Mice were treated with Flt3L after burn injury and examined for survival, wound and systemic bacterial clearance, and immune cell activation after wound inoculation with Pseudomonas aeruginosa. To gain insight into the local effects of Flt3L at the burn wound, localization of Langerhans cells was examined. Mice treated with Flt3L had significantly greater numbers of CD25-expressing T cells and CD69-expressing T and B cells, neutrophils, and macrophages after, but not before, infection. Overall leukocyte apoptosis in response to infection was decreased with Flt3L treatment. Survival and local and systemic bacterial clearance were enhanced by Flt3L. Langerhans cells appeared in the dermis of skin bordering the burn wound, and further increased in response to wound infection. Flt3L augmented the appearance of Langerhans cells in response to both injury and infection. These data suggest that dendritic cell enhancement by Flt3L treatments after burn injury protects against opportunistic infections through promotion of local and systemic immune responses to infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research Grants R01 GM072810 from the National Institutes of Health and 8810 from the Shriners Hospitals for Children.

² Address correspondence and reprint requests to Dr. Tracy Toliver-Kinsky, Department of Anesthesiology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0591. E-mail address: ttoliver{at}utmb.edu

³ Abbreviations used in this paper: Flt3, fms-like tyrosine kinase-3; Flt3L, Flt3 ligand; DC, dendritic cell; HKPA, heat-killed P. aeruginosa.