Enhancement of Dendritic Cells After Burn Injury

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DESCRIPTION (provided by applicant): Patients with severe bums are at risk for the development of nosocomial infections that can prolong hospitalization and increase morbidity and mortality. This is due not only to loss of the skin as a protective barrier, but also to altered responses of most immune cells, including antigen-presenting cells and effector lymphocytes. Dendritic cells are antigen presenting cells that activate both innate and acquired immune responses. Dendritic cells produce cytokines that activate neutrophil, macrophage, and natural killer cell microbicidal functions. Dendritic cells interact with T cells to promote cell differentiation and activation, and promote the humoral response. Given the central role of dendritic cells in promoting immune responses, enhancement of dendritic cells in bum patients may increase their resistance to infections. Fms-like tyrosine kinase-3 ligand (Flt3L) is a hemopoietic cytokine that stimulates the production of dendritic cells from bone marrow-derived progenitor cells. Treatment with exogenous Flt3L dramatically enhances dendritic cell numbers in humans and rodents, increases the resistance of normal mice to infections that are typically lethal, and prevents bum-induced impairments in early IL-12 and IFN-gamma production after bacterial challenge. This proposal addresses the hypothesis that expansion of dendritic cells in burned mice by Flt3L treatments can increase their resistance to infections. This will be tested through the following aims: 1) To examine activation of acquired immunity in burned mice treated with Flt3L. Dendritic cell promotion of T cell differentiation, antigen-specific antibody production, and immunoglobulin isotype profiles will be examined; 2) To determine the ability of Flt3L to increase the resistance of mice to a progressive bum wound infection. Bacterial clearance, survival, and cytokine responses after burn wound infection will be examined; 3) To examine the contribution of dendritic cells to enhanced immunity in Flt3L-treated burned mice. We will both adoptively transfer dendritic cells into burned mice and deplete FltSL-treated burned mice of dendritic cells, and assess immune function as in aims 1 and 2. These studies will determine rf enhancement of dendritic cells after severe bums can increase resistance to bum wound infection, and will determine the contribution of dendritic cells to specific immune functions.