244 Chapter 8 and adaptive cell type that is able to convert its phenotype and change its functionality over time [99,100]. It has also been suggested that Tregs are able to parallel their effector counterparts (Th1/Th17) by mimicking their phenotype [101]. The exact mechanisms and the precise role of Tregs in wound healing are yet to be determined. Although we could not study the expression of chemokine receptors on T cells in burn tissue, because collagenase used for cell isolation cleaves off these receptors, the cytokine profile is likely to support a Th1 response, while Treg activity appeared limited. Overall, long-lasting high levels of pro-inflammatory cytokines and immune cells after burn injury and the lack of immunosuppression suggest that the immune system remains in a long-term inflammatory state instead of switching to a resolving state to support wound healing processes. To better understand the role of T cells during wound healing, research should include functional assays. Organotypic skin models with T cells have been produced to study pathogenesis and therapeutic interventions for skin diseases such as psoriasis and atopic dermatitis [102–104]. In this light, we developed burn skin models where pre-activated T cells were added to FSEs (Chapter 7). T cells actively migrated into these models and increased the production of inflammatory cytokines IFN-γ, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IP-10 and TGF-β1, demonstrating an interplay between T cells and skin cells. Both IP-10 and IL-10 were decreased when burn injury was applied to the models. In future experiments with these models, the effect of specific Th subsets on wound healing (re-epithelization, proliferation) can be studied. FUTURE OUTLOOK ON BURN CARE Research on the burn-induced immune response This thesis provides insights that are essential for the future of burn research and aids the development of improved treatment strategies. An important limitation of this thesis is the lack of information on functionality of the various immune cells. Also, we did not include markers to detect the presence of Th2 cells in patient blood. In the future, we would like to study T cell responses in more detail. Another limitation is that in several cases the sample size was too small to perform relevant subgroup analyses. Moreover, high variation between donors sometimes made it difficult to draw harsh conclusions. Small patient groups and variation amongst injuries and conditions are common in burn research and complicate studies in human. To advance burn research, we need to focus on hiatuses in our current understanding of the physiological responses to burn injury. Translation of animal data to the human situation and understanding how certain factors (e.g. aging, burn type and severity)
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