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

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.

List of scientific papers

I. Nguyen Hoang AT, Chen P, Juarez J, Sachamitr P, Billing B, Bosnjak L, et al. Dendritic cell functional properties in a three-dimensional tissue model of human lung mucosa. Am J Physiol Lung Cell Mol Physiol. 2012 Jan;302(2):226–37.
https://doi.org/10.1152/ajplung.00059.2011

II. Nguyen Hoang AT, Chen P, Björnfot S, Högstrand K, Lock JG, Grandien A, et al. Technical advance: live-imaging analysis of human dendritic cell migrating behavior under the influence of immune-stimulating reagents in an organotypic model of lung. J Leukoc Biol. 2014 Sep;96(3):481-9.
https://doi.org/10.1189/jlb.3TA0513-303R

III. Mairpady Shambat S, Chen P, Nguyen Hoang AT, Bergsten H, Vandenesch F, Siemens N, et al. Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology. Dis Model Mech. 2015 Nov;8(11):1413-25.
https://doi.org/10.1242/dmm.021923

IV. Mairpady Shambat S*, Chen P*, Barilla RM, Snäll J, Welin A, Cohen TS, et al. Alpha-toxin-elicited CX3CL1-release via ADAM10 in Staphylococcus aureus pneumonia impairs bactericidal function of human monocytes. *Equal contribution. [Manuscript]

V. Chen P, Svensson M. Immune-regulatory properties of human myeloid cells in a three-dimensional lung tumor model. [Manuscript]