Models of the lung tissue microenvironment for studies of human myeloid cell function

Sammanfattning: Studies of the immune system requires knowledge concerning not only the perturbating event itself, i.e. specific microorganisms, and how it interacts with immune cells but also how it functions in its natural environment – tissues. The non-hematopoietic component of tissues contributes immensely to all immune responses and acknowledging its contribution have been central to immunological research during the last decade. The work in this thesis focuses on the use of a three-dimensional organotypic lung tissue model, which recapitulates many aspects of its in vivo correlate. Study I describe the properties of the organotypic tissue model and implanted monocyte-derived dendritic cells. In Study II we show how the organotypic tissue model can be used to study, not only secreted factors influenced by dendritic cells, but also a key functional property of dendritic cells – cell migration. In Study III, we used the tissue model to model a staphylococcus aureus infection, and in particular how derived toxins such as alpha-toxin and Panton-Valentine Leukocidin (PVL) contribute to tissue pathology. Immunological downstream effects of staphylococcal toxins are further explored in Study IV, where we investigate the role of ADAM10 and CX3CL1 (fractalkine) in alpha-toxin mediated pathology. In Study V, the goal was to set up a model system in which it is possible to study the interaction between immune cells, tissue model and tumor cells, analogous to Study III and IV. The studies here provide a framework for how complex, multicellular in vitro systems can be used in immunological studies in context to inflammation-driven pathologies. The validity of the model system remains to be studied, and the role for organotypic tissue models in medical research is yet to be determined. However, it is becoming increasingly clear that the study of disease mechanisms relating to inflammation will benefit from added complexity and acknowledgement that cells such as epithelial cells and fibroblast are active contributors to immune responses and tissue pathology.