Given the prevalence and morbidity of pediatric thermal injury it is imperative that we completely understand and define all knowledge gaps related to this disease. The immunobiology of pediatric burn injury is not well defined and if understood can unlock the doors to novel therapeutic targets. My prior research training, current research advisory committee, strong mentorship and practice as a pediatric burn surgeon will allow me to obtain data and help close this knowledge gap. The overall objective of this proposal is to further develop my career into a surgeon-scientist whose focus is on the immunobiology of pediatric thermal injury with goals of using immunomodulation therapy to decrease adverse outcomes. Using methods validated in other forms of pediatric critical illness we will test our central hypothesis that upregulation of the PD-1 pathway is associated with immune suppression and adverse outcomes following pediatric burn injury; and that this immune suppression is reversible ex vivo through the use of PD-1 pathway inhibitors. Thermally injured children will undergo longitudinal blood sampling as well as tissue bed sampling at the time of debridement and grafting procedures. Leukocyte expression of PD-1/PD-L1/L2 will be quantified by flow cytometry. Innate and adaptive immune function will be measured by ex vivo stimulation assays and flow cytometry. Wound bed macrophage expression of PD-1/PD-L1/L2 will be measured along with pro- inflammatory and anti-inflammatory phenotypic markers using immunohistochemistry and laser capture microdissection with mRNA profiling. Furthermore, we will determine if the immune suppressive effects of thermal injury are reversible using ex vivo methods. We will co-incubate peripheral blood leukocytes from thermally injured children with inhibitors of the PD-1 pathway, GM-CSF or recombinant IL-7. Cells will then be evaluated for restoration of immune function via ex vivo stimulation assays and flow cytometry. This study will be the first to evaluate the role of the PD-1 pathway with respect to pediatric thermal injury. This is of particular importance given the clinical implications of immune checkpoint inhibitors in other forms of disease such as cancer and sepsis. This career development award will generate further preliminary data and also provide me with the tools necessary to successfully compete for future independent funding in areas of pediatric thermal injury.
Burn injury is one of the leading causes of morbidity and mortality in pediatric patients and its most common complications are infectious related. Many forms of pediatric critical illness, including sepsis and trauma, have demonstrated suppressed immune function however the immunobiology following pediatric thermal injury is poorly understood. This project seeks to be the first to evaluate the role of the immune checkpoint, programmed death 1 pathway, in relation to pediatric thermal injury and will test our central hypothesis that upregulation of the PD-1 pathway is associated with immune suppression and adverse outcomes following pediatric burn injury; and that this immune suppression is reversible ex vivo through the use of PD-1 pathway inhibitors.
