Inflammatory diseases such as autoimmune and atopic diseases are a common problem worldwide. Although there have been substantial advances in medical therapies, current treatments are not able to cure these conditions. In order to develop more specific, individually targeted and efficient treatments, a better understanding of the cells, mediators and mechanisms that lead to pathology are necessary. Macrophages and T cells are major players in the human immune system. Despite the abundance of macrophages at inflammatory sites and their secretion of T cell polarising cytokines, their roles as antigen presenting cells has been overlooked until now. This PhD project aimed to determine, firstly, the contribution of differentially activated human macrophages in the regulation of adaptive immune responses in inflammation with the main focus on the pro‐inflammatory T cell subset Th17, secondly, how macrophage functions could be modified to alter T cell polarisation and thirdly, how novel alternative mechanisms using electric fields can alter T cell responses. I demonstrate for the first time that macrophages can efficiently induce T cell polarisation and Th17 differentiation in response to recall and primary antigens and that the specific macrophage activation state is essential to drive Th17 responses. This suggests that macrophages are an important stimulus contributing to pathogenic T cell responses in human inflammatory diseases. Importantly, both memory and naïve T cells gave rise to Th17 cells following culture with antigen‐loaded activated macrophages, where non‐specific effects of mitogenic activation were avoided. Targeting human macrophage signalling pathways through SOCS3, reduced their pro‐inflammatory potential and Th17 polarising ability, pointing to SOCS3 as an effective therapeutic target. As an alternative approach, I demonstrate here that small electric fields of physiological strength strongly influence immune responses and significantly dampen Th17 differentiation. This suggests that EFs have the potential to facilitate healing processes or support conventional therapies for inflammatory diseases. Overall, these data present a strong basis for the development novel treatment possibilities for inflammatory diseases that are distinct from the currently used conventional therapies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:553806 |
| Date | January 2012 |
| Creators | Kluge, Christina |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=185639 |
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