Tuberculosis Clinical Trial
Official title:
Doxycycline and the Modulation of Host Immunopathology in Human Pulmonary Tuberculosis: A Pilot Study
Pulmonary cavitation, a hallmark of tuberculosis (TB), is the site of high mycobacterial
burden leading to disease transmission. The cause of tissue destruction leading to cavitation
in TB is primarily due to the host inflammatory response. A matrix degrading phenotype
develops in TB, in which the activity of host proteolytic enzymes, specifically matrix
metalloproteinases (MMPs) is unopposed by their specific Tissue Inhibitors of
Metalloproteinases (TIMPs), thus driving tissue destruction and cavitation in TB. This tissue
destruction causes morbidity and mortality. MMP inhibition with doxycycline has shown to
improve lung function in patients with chronic lung diseases but its use in TB is unclear.
We hypothesise that the MMP inhibitor doxycycline will reduce tissue destruction in human
pulmonary tuberculosis.
Specific aims:
- To investigate the MMP and TIMP secretion and gene expression in M. tuberculosis (M.tb)
- infected primary neutrophils and monocytes from healthy volunteers taking doxycycline.
- To investigate the intracellular signaling pathways modulated by doxycycline
- To investigate the effects doxycycline has on biological markers of tissue destruction
in TB patients
- To assess the tolerability and side effects of doxycycline with concurrent standard TB
therapy
All TB patients are to keep to their standard anti-tuberculous treatment. A standardized
questionnaire of symptoms, side-effects and weight shall be recorded. Induced sputum and
plasma samples from all TB patients shall be analysed for MMPs and TIMPs before and after the
administration of doxycycline for two weeks. In addition, neutrophils and mononuclear cells
from TB patients and these shall be stimulated with live, virulent M. tuberculosis in a
Biosafety Level 3 laboratory. The supernatants from these cells shall be analysed for MMPs
and TIMPs.
Healthy volunteers shall be recruited and administered doxycycline for 2 weeks. Neutrophils
and mononuclear cells will be isolated from blood prior to treatment, at weeks 2 and 8 and
infected with M.tb. Cell culture supernatants and nucleic acids will be harvested. MMP and
TIMP expression will be analysed using luminex array and real-time polymerase chain reaction.
Intracellular signaling pathways will be examined with a human phospho-kinase array. Matrix
destruction will be assessed using collagen quantitative fluorescent assays.
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