Elucidating the Mechanisms of Immune Dysfunction After Severe Burn Injury

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Project Summary/Abstract Burn injuries continue to be one of the leading causes of unintentional death and injury in the United States. Non-fatal burn injuries are a leading cause of morbidity with the most common complications being infectious related. Thermal injures result in massive fluctuations in the inflammatory and immune responses (e.g., plasma cytokines, cellular phenotypes, immune function, and soluble proteins) and these changes have been associated with mortality and infectious complications. However, the underlying mechanisms driving these dysfunctional responses is still largely unknown both systemically and locally. Our primary goal is to investigate the systemic and localized mechanisms of immune dysfunction following pediatric thermal injury to provide useful biomarkers to identify those at highest risk to develop subsequent infection with a goal to develop therapies to improve patient outcomes. Over the next five years we will pursue three integrated research plans that use both pediatric blood and tissue samples as well as an established juvenile murine model of burn injury and infection, to investigate the mechanisms of immune dysfunction after burn injury. Research Plan 1 will investigate the mechanisms underlying lymphocyte dysfunction after severe burn injury. In this work we will assess the cell surface expression of lymphocyte co-inhibitory molecules, examine apoptotic markers on isolated lymphocytes, and perform functional assays. This work will provide insight into the mechanisms surrounding lymphocyte dysfunction and guide future immunomodulatory therapies that can target these specific mechanisms. Research Plan 2 will evaluate the differentiation of systemic monocytes to tissue macrophages after severe burn injury and post-burn complications. In this work we will perform functional assays on isolated systemic monocyte populations and isolated tissue macrophages. This work will lead us to a more complete mechanistic understanding of the differentiation of systemic monocyte populations to the localized macrophages in the wound bed. This information will inform the best route of administration (systemic or topical) to apply immunomodulatory therapy to augment these macrophages and improve tissue level outcomes. Research Plan 3 will elucidate the potential benefits of FDA-approved immunomodulator therapies after severe burn injury to prevent post-burn complications. This work will use combination therapies, ex vivo in pediatric samples and in vivo in our murine burn model, to assess changes in immune function. The findings from this study will be important to advance the design of future immunostimulatory clinical trials in this population as well as other forms of surgical predisposition to sepsis such as trauma and major surgery. Moreover, this could serve as a model for other age groups of burn injuries. Together, these projects will provide an important building block for developing appropriate therapeutics in treating burn wounds that can simultaneously help control inflammation, prevent infection, and assist in wound healing, which is an absolute necessity for burn care research.