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Title: Regulation of macrophage subpopulations and their relationship to T cell function in the pathogenesis of asthma
Author: Tormey, Vincent Joseph
ISNI:       0000 0001 3535 2995
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1999
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As monocytes differentiate into macrophages, subsets emerge that exhibit stimulatory, suppressive or phagocytic potential. These functionally distinct subsets can be discriminated using monoclonal antibodies RFDl and RFD7. The overall functional capacity of this pool depends on the relative balance of these subpopulations. Analysis of the immunopathology in bronchial biopsies from asthmatic subjects has revealed significantly reduced proportions of suppressive macrophages associated with chronic T cell mediated inflammation which is corrected by treatment with inhaled corticosteroids. This thesis investigates the effect of the T cell cytokines (IFNγ, 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 RFDl 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 IFNγ increased the proportion of RFD1+RFD7- inductive macrophages and stimulated T cell proliferation. IL-10 decreased the proportion of RFDl + RFD7-cells and concomitantly increased the proportion of RFD1-RFD7+ and RFDH-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 v^th a suppressive RFD1+RPD7+ phenotype was lower in asthmatics. Asthmatic monocytes had a greater effect in stimulating MLR than normal. The addition of IL10 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 vAth IL-10 being of therapeutic benefit.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine