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Tuberculosis, anti-glucocorticoids and the immune system

Al-Hajoj, Sahal Abdulaziz Mohammad; (1998) Tuberculosis, anti-glucocorticoids and the immune system. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

According to a recent estimate by the World Health Organisation, by the year 2000 tuberculosis (TB) will kill 4 million people a year. This dramatic increase, from 3 million in 1992 to 4 million by year 2000, is an alarming signal for health workers. Endocrinological abnormalities have been observed in TB that may explain the tendency for patients to develop an inappropriate TH2 response to M. tuberculosis. These abnormalities include a fall in the ratio of antiglucocorticoid hormones (dehydroepiandrosterone; DHEA) to glucocorticoid, and a marked decrease in conversion of the major glucocorticoid cortisol to inactive cortisone. This project was designed to investigate the significance for human tuberculosis of these two endocrine changes. Three approaches were used. 1) The antiglucocorticoid properties of DHEA and some of its metabolites, were tested in order to select the optimum metabolite and schedule for in vivo experiments in tuberculosis in mice. 2) The ability of live M. tuberculosis to convert DHEA sulphate (present in human serum at up to 4 µg/ml) into active metabolites was examined; 3) The hypothesis that the enzyme that interconverts cortisol and cortisone in the lung is susceptible to local regulation by cytokines was tested. Antiglucocorticoid effects of DHEA and a series of its metabolites were tested in vivo for their ability to protect the thymus from apoptosis induced by corticosterone, and to block the effects of glucocorticoid on non-specific inflammation. The metabolite 3 β,17β-androstenediol (AED) proved most active. The optimum dose level was identified and has since proved strongly protective in a model of murine tuberculosis that is used by collaborators in Mexico. These metabolites were then tested in vitro for their effects on proliferation and cytokine production by murine and human lymphocytes, alone or in the presence of glucocorticoid. DHEA and AED increased the production of IFNy by murine splenocytes, and antagonised the inhibitory effects of cortisol on IFNỿ production by human T cells. The in vivo model has subsequently confirmed that AED upregulates TH1 and proinflammatory cytokines, while downregulating TH2 cytokine release. Mycobacterium tuberculosis cleaved DHEA to a number of metabolites, visualised by thin layer chromatography, including AED and reduced forms of AED that were identified by gas chromatography and mass spectrometry. 11β-HSD activity was measured in different organs at different intervals after intravenous challenge with live BGC. On day three conversion to cortisone in the lung was reduced in the BCG group compared to normal mice, indicating that the activity of 11β-HSD was mainly dehydrogenase. However 10 days later the activity shifted towards reductase since conversion to cortisone was markedly increased not only in lung but also in spleen and thymus. The equilibrium point (i.e. the ratio of cortisol to cortisone) did not change in liver or kidney. These results suggest that 11β-HSD is regulated during the inflammatory response induced by live BCG. The above data are discussed in relation to the immunological abnormalities that accompany human tuberculosis, and the effects of manipulating the AED/corticosterone balance in the murine tuberculosis model. They help to explain the changing pattern of immunopathology in human tuberculosis of different ages, and correlation of these disease patterns with age-related changes in DHEAS levels.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Tuberculosis, anti-glucocorticoids and the immune system
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Bacteriology; Immune system; Tuberculosis
URI: https://discovery.ucl.ac.uk/id/eprint/10104618
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