The incidence of asthma is rising, posing a significant economic burden worldwide. Despite treatment advancements, some asthmatics remain unresponsive, highlighting the need for a deeper understanding of asthma pathogenesis. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine with a central role in the innate immune system and asthma development. A functional ‘CATT’ polymorphism controls MIF expression in the human population. The role of a high expressing CATT7 allele in asthma is currently unknown. Repetitive inhalation of airborne allergens such as house dust mite (HDM), damages the airway epithelium and trains the innate immune system over time, inducing epigenetic changes. The influence of the MIF polymorphism on innate immune training remains unexplored. Mesenchymal stromal cells (MSCs) can respond and communicate with their surrounding microenvironment. The impact of endogenous human MIF on MSC licensing and its functional role in MSC therapeutic efficacy is undocumented. Using novel humanised MIF mice, this study is the first to elucidate the role of the human MIF CATT7 allelic variant in a model of allergic airway inflammation. High expression of human MIF exacerbated HDM-induced asthma pathophysiology in CATT7 mice, identified by measuring changes in histology, Th2 cytokines and respiratory mechanics. MIF-licensed MSCs exhibited enhanced cytoprotective function, promoting airway epithelial wound closure in a VEGF-dependent manner. Moreover, this thesis illustrates the first evidence of innate training in macrophages from high human MIF expressing CATT7 mice, which was suppressed with MSC co-culture using transwell inserts. This research is of upmost clinical and translational importance, as the generation of this robust humanised MIF mouse model can facilitate the future development of treatments for MIFdependent diseases, like asthma. Furthermore, this cutting-edge research makes a substantial contribution to the field of cellular therapy, paving the way for MSC application in high MIFexpressing patients, where these cells can modulate an over-active immune response, suppressing excessive, pathogenic inflammation.