Byng-Maddick, Rachel; (2018) Differential effects of anti-TNF therapies for inflammatory arthritides on immune responses to Mycobacterium tuberculosis. Doctoral thesis (Ph.D), UCL (university College London).

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Abstract

Tumour necrosis factor (TNF) antagonists have revolutionised the management of rheumatoid arthritis (RA) and other inflammatory diseases. This success is partly tempered by substantially increased risk of granulomatous infectious diseases, particularly tuberculosis (TB). In this thesis I sought new insights into the mechanisms by which TNF blockade leads to an increased incidence of TB. In a new analysis of data collected by the British Society of Rheumatology Biologics Registry, I confirmed that anti-TNF therapy leads to reactivation of latent TB infection, rather than increasing the risk of new TB infection, consistent with published literature. I derived and validated four separate context-specific transcriptional modules representing TNF inducible gene expression in macrophages, keratinocytes and whole blood. I used these modules to quantify TNF bioactivity in clinical samples from RA patients responding to anti TNF therapies or treated with methotrexate only. As expected, anti-TNF therapy was associated with attenuated expression of the TNF modules in whole blood following ex vivo stimulation. However, anti-TNF therapy had no effect on TNF module expression and therefore TNF function, at the site of acute cell mediated immune responses in vivo, modelled by the tuberculin skin test. These data are consistent with a model in which anti-TNF therapies do not reach sufficient concentration within tissues to block TNF responses in an acute inflammatory challenge. Rather, my data suggest that anti TNF therapies mediate their therapeutic and adverse effects by regulating TNF activity at foci of chronic inflammation or by alternative non-canonical pathways. Finally I tested the hypothesis that anti-TNF therapy may inhibit cellular restriction of mycobacteria in human macrophage cultures. Using an in vitro model of human monocyte-derived macrophages, I established a new method to quantify fluorescent mycobacterial load both inside and outside cells, and showed that TNF blockade in this model did not have a significant impact on mycobacterial growth.

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