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Title: Mathematical modelling of inflammatory cytokine networks
Author: Stevens, Michael
ISNI:       0000 0001 3482 1761
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2003
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The cytokines regulate a number of cellular effects which give rise to a coordinated immune response. Many of these effects are an indirect consequence of the ability of most cytokines to regulate the production of other cytokines. This thesis approaches the problem of trying to understand how the network of interactions between the three inflammation-related cytokines interleukins (ILs)-l and -10 and tumour necrosis factor (TNF) determines their dynamical behaviour. Dynamical behaviours such as multistability and periodicity depend upon the topology of the cytokine network, and previous theoretical work based on the current understanding of the topology among TNF, IL-1 and IL-10 has suggested that such behaviours may arise in the in vitro monocyte system (Henderson et al., 1998; Seymour & Henderson, 2001). Topological results are presented from experiments in which cells were stimulated with recombinant cytokine, and response measured by intracellular staining and ELISA, which largely confirm the current picture of this network. However, evidence is also presented demonstrating that the topology of the network changes substantially within the time frame over which a typical experiment is conducted, limiting its utility as a model system in which to study dynamical network behaviours. Ultrasensitivity in the dose-response relationships between cytokines is another critical feature determining the existence of dynamical behaviours such as multistability and periodicity. This thesis presents novel measurements of the sensitivity of a number of the dose-response relationships in the TNF/IL-l/IL-10 network, and finds most of them to have non-ultrasensitive, hyperbolic relationships, providing further evidence that this experimental system is not a suitable model for investigating multistability and periodicity. The parameters of the response functions measured may be of use in future attempts to model networks involving these cytokines.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available