Revealing the dynamics of immune cells in humans: mechanistic modelling of deuterium labelling data

Reliable estimates of lymphocyte turnover are important for understanding the immune response in health and disease. Deuterium labelling techniques have paved the way for the estimation of these parameters in vivo in humans. However, its interpretation has proven to be notoriously complicated. It seems that a complete understanding of this technique and its interpretation has been lacking so far. To address this issue I formulated the following question: Can the understanding of deuterium labelling data be enhanced by a physiological interpretation of the system of study? This thesis aims to tackle the former question by the use of mathematical modelling, a detailed interpretation of the biological system of interest, and the use of interdisciplinary approaches borrowed from pharmacometrics research. On doing this, the work presented here confirms the recently disputed short blood half-life of a neutrophil, estimates the average half-life of T cell immunological memory to be around two years in the absence of re-stimulation, confirms the proliferative capability of late-stage differentiated memory T cells, and rejects the hypothesis that pointed at issues in estimating the deuterium availability as the underlying reason for the reported discrepancies in T cell turnover estimates. Overall, this thesis provides a better understanding of the interpretation of deuterium labelling experiments and sets the framework for the implementation of more mechanistic models that may be parametrized by the combination of deuterium labelling data, other turnover markers, and data already available in the literature.Open Acces