Al-Attiyah, Rajaa; (1991) The regulation of necrosis in mycobacterial lesions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tuberculosis is characterised by necrotic immunopathology in the lesions and tuberculin skin-test sites (Koch phenomenon), and persistence of the organisms. Previous work from this laboratory suggested that immunotherapy with killed M. vaccae can reduce this tissue damage, and that TNF plays a role in its pathogenesis. The purpose of this thesis was to study the mechanism of action of M. vaccae in man and in a rodent model. Sera from patients in Kuwait who received M.vaccae or saline were screened by immunoblotting and laser scanning to seek changes in the pattern of mycobacterial antigens recognised, and by an immunoassay for changes in levels of agalactosyl IgG (a correlate of T cell-dependent immunopathology). A fall in agalactosyl IgG and a selective increase in antibody to a 30kDa antigen was noted. This antigen was identified as the fibronectin-binding secreted protein, and was purified to homogeneity from culture filtrate by column chromatography. The increased antibody binding was confirmed by ELISA. A murine model of TNF-induced tissue damage in sites of T cell-mediated inflammation was then devised, to mimic aspects of the Koch phenomenon using the 30 KDa and the 65 KDa heat shock protein (hsp). This model allows simultaneous assessment of both swelling and haemorrhage caused by injection of TNF into delayed hypersensitivity (DTH) sites. It was found that some DTH responses evoked by mycobacterial antigens are as sensitive to subsequently injected TNF as are sites prepared by injection of LFS (local Shwartzman reaction) though for mycobacterial antigens CD8+ T cells are required. This phenomenon also involved CR3+ cells, phagocytic cells, complement, and perhaps IL-6, and could be diminished by PAF inhibitors and a prostaglandin analogue. However, by testing different immunisation schedules using M. vaccae, it was discovered that it is also possible to evoke DTH responses in which subsequent injection of TNF has no effect at all. The heat shock proteins may play a role in this effect. The implications of the existence of two qualitatively different types of DTH response and the consequences of neutralizing TNF, using an anti-murine TNF antibody, in a murine tuberculosis model are discussed in relation to the immunopathology of tuberculosis and autoimmune diseases such as rheumatoid arthritis where mycobacterial antigens, cytokines and T cell dependent inflammation are important.

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