Tormey, Vincent Joseph;
(1999)
Regulation of macrophage subpopulations and their relationship to T cell function in the pathogenesis of asthma.
Doctoral thesis (Ph.D.), University College London.
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Abstract
This thesis investigates the effect of the T cell cytokines (IFN<IMG WIDTH=8 HEIGHT=14 ALIGN=MIDDLE SRC="/maths/gamma.gif">, IL-2, IL-4 and IL-10) on the differentiation of peripheral blood monocytes in a controlled in vitro environment. Mature macrophage phenotype was determined by double immunofluorescence using RFD1 and RFD7. Cytokine production in culture supernatants was determined by ELISA. Macrophage function was assessed by the capacity to stimulate T cell proliferation in a mixed leucocyte reaction. Both IL-4 and IFN<IMG WIDTH=8 HEIGHT=14 ALIGN=MIDDLE SRC="/maths/gamma.gif"> increased the proportion of RFD1+RFD7- inductive macrophages and stimulated T cell proliferation. IL-10 decreased the proportion of RFD1 + RFD7-cells and concomitantly increased the proportion of RFD1-RFD7+ and RFD1+RFD7+ suppressive cells which inhibited T cell proliferation. IL-2 showed no effect on monocytes. These initial observations were extended by investigating monocyte differentiation in atopic asthma. The proportion of maturing macrophages with a suppressive RFD1+RFD7+ phenotype was lower in asthmatics. Asthmatic monocytes had a greater effect in stimulating MLR than normal. The addition of IL-10 restored the imbalance within the macrophage subsets and reduced their ability to promote T cell proliferation. Corticosteroids (dexamethasone and fluticasone) had a similar effect to IL-10, decreasing the proportion of inductive macrophages, increasing suppressive macrophages and downregulating macrophage driven T cell proliferation. This thesis contributes to an understanding of the regulation of macrophage dysfunction and chronic inflammation in asthma. It describes a model system whereby monocyte differentiation can be tested in vitro. Further, it introduces a new mechanism by which fluticasone propionate is efficacious in asthma and raises the possibility of manipulation with IL-10 being of therapeutic benefit.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | Regulation of macrophage subpopulations and their relationship to T cell function in the pathogenesis of asthma. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10102304 |
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