39 Review Immune Cells in Animal Burn Models crucial to predicting and treating consequential complications effectively. There are several considerable (physiological) differences that make it difficult to convert treatment opportunities directly to patients. Rodents, unlike humans, have more lymphocytes than innate cells, and receptor binding and cytokine responses differ owing to evolution and distinct history of microbial exposure [51,52]. In addition, there are important genomic and evolutionary differences that cause mouse models to poorly reflect certain aspects of human disease [7]. Furthermore, the ultrahygienic environment of laboratory animals makes the immune system, in general, less tolerant [52,53]. Still, important aspects of the burn-induced human immune response were also present in our meta-analyses, exemplified by the response of thrombocytes, neutrophils, and monocytes [16,17]. Altogether, this review of the burn-induced immune response in animals using metaanalyses puts in perspective the uncontrolled, hyperactive response of immune cells that persists for weeks after burn trauma. Although numerous physiological processes are distinct, many aspects of the human immune response to burns were found in our meta-analyses, including the innate and lymphocyte response and the dynamics of mast cells and thrombocytes. We anticipate that this knowledge will guide the design of future experimental models while supporting the reduction, refinement, and replacement of animal experimentation. It will lead, to our knowledge, to previously unreported insights in clinical research on burn trauma that can ultimately improve burn care and outcome. MATERIALS AND METHODS Study protocol and eligibility criteria A review protocol was established beforehand and is registered at the International Prospective Register of Systematic Reviews (CRD42019136270; http://www.crd.york. ac.uk/PROSPERO/display_record.php?RecordID=136270). We amended this protocol once to further specify the meta-analyses. The 10-article requirement was changed to five to enable the inclusion of additional cell types. Search strategy The search was performed using PubMed and Embase [54] (Supplementary File 1), with a final update on August 6, 2021. Briefly, we searched for articles with primary data on the immune response in animals with burn injury (search components: burn wound, immune response, and animal). No language or publication date restrictions were applied. Search results were combined, and duplicates were removed using EndNote software (X9, Clarivate Analytics, London, United Kingdom). 2
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