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Inflammatory bowel diseases (IBD), characterised by a chronic inflammation of the gut wall, develop as consequence of an overreacting immune response to commensal bacteria, caused by a combination of genetic and environmental conditions. Large inter-individual differences in the outcome of currently available therapies complicate the decision for the best option for an individual patient. Predicting the prospects of therapeutic success for an individual patient is currently only possible to a limited extent; for this, a better understanding of possible differences between responders and non-responders is needed.
In this thesis, we have developed a mathematical model describing the most important processes of the gut mucosal immune system on the cellular level. The model is based on literature data, which were on the one hand used (qualitatively) to choose which cell types and processes to incorporate and to derive the model structure, and on the other hand (quantitatively) to derive the parameter values. Using ordinary differential equations, it describes the concentration-time course of neutrophils, macrophages, dendritic cells, T cells and bacteria, each subdivided into different cell types and activation states, in the lamina propria and mesenteric lymph nodes. We evaluate the model by means of simulations of the healthy immune response to salmonella infection and mucosal injury.
A virtual population includes IBD patients, which we define through their initially asymptomatic, but after a trigger chronically inflamed gut wall. We demonstrate the model's usefulness in different analyses: (i) The comparison of virtual IBD patients with virtual healthy individuals shows that the disease is elicited by many small or fewer large changes, and allows to make hypotheses about dispositions relevant for development of the disease. (ii) We simulate the effects of different therapeutic targets and make predictions about the therapeutic outcome based on the pre-treatment state. (iii) From the analysis of differences between virtual responders and non-responders, we derive hypotheses about reasons for the inter-individual variability in treatment outcome. (iv) For the example of anti-TNF-alpha therapy, we analyse, which alternative therapies are most promising in case of therapeutic failure, and which therapies are most suited for combination therapies: For drugs also directly targeting the cytokine levels or inhibiting the recruitment of innate immune cells, we predict a low probability of success when used as alternative treatment, but a large gain when used in a combination treatment. For drugs with direct effects on T cells, via modulation of the sphingosine-1-phosphate receptor or inhibition of T cell proliferation, we predict a considerably larger probability of success when used as alternative treatment, but only a small additional gain when used in a combination therapy.
Gene flow is an important factor determining the evolution of a species, since it directly affects population structure and species’ adaptation. Here, we investigated population structure, population history, and migration among populations covering the entire distribution of the geographically isolated South-West European common lizard (Zootoca vivipara louislantzi) using 34 newly developed polymorphic microsatellite markers. The analyses unravelled the presence of isolation by distance, inbreeding, recent bottlenecks, genetic differentiation, and low levels of migration among most populations, suggesting that Z. vivipara louislantzi is threatened. The results point to discontinuous populations and are in line with physical barriers hindering longitudinal migration south to the central Pyrenean cordillera and latitudinal migration in the central Pyrenees. In contrast, evidence for longitudinal migration exists from the lowlands north to the central Pyrenean cordillera and the Cantabrian Mountains. The locations of the populations south to the central Pyrenean cordillera were identified as the first to be affected by global warming; thus, management actions aimed at avoiding population declines should start in this area.