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Title: Characterization of IL-4Δ2 and assessment of its potential in immunotherapy for multi-drug resistant tuberculosis
Author: Diogo, Gil Reynolds
ISNI:       0000 0004 6057 6570
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2017
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Despite the availability of the Bacillus Calmette-Guerin (BCG) vaccine and current drug regimens, tuberculosis (TB) remains an ever growing global health burden, even more so with the emergence of new drug resistant strains. Therefore it is necessary to improve treatment regimens. Disproportionately high levels of the major Th2 cytokine, IL-4, have been linked to poor TB prognosis. However, T-lymphocytes also produce an alternative IL-4 variant (IL-4Δ2) which can antagonise its activity, and it is the ratio of IL-4 and its antagonist that has been associated with clinical status of Mycobacterium tuberculosis (MTB) infected individuals. This study aims to generate and characterise the mouse version of the IL-4Δ2 molecule and test its potential in vivo to modulate the Thl/Th2 immune response balance and inhibit MTB infection. The aim is to test the therapeutic potential of IL-4Δ2 in the context of the previously established ‘Combined Immunotherapy’ (CIT) utilising the human IgA antibody IgA2E9 and IFN-y. This treatment was shown previously to be protective against drug susceptible TB when administered intranasally to MTB-infected CD89-transgenic mice expressing human IgA receptor. However, the application of CIT would be more realistic in multi-drug resistant TB (MDR-TB) to increase treatment options, and therefore, one of the aims of this study is to test whether addition of IL-4Δ2 to CIT could be effective against MDR-TB. Murine IL-4Δ2 was able to inhibit IL-4 mediated cellular processes in macrophages, B, and T cells. IL-4Δ2 reversed IL-4 mediated inhibition of IFN-y induced nitric oxide release, and furthermore, it inhibited IL-4 mediated T cell proliferation and IgE synthesis by IL-4 treated B cells. In the present study IL-4Δ2 did not competitively bind to the IL-4Ra and did not interfere with the downstream STAT6 phosphorylation. Further studies are required to elucidate the antagonistic mechanism of this molecule. The combination immunotherapy significantly reduced the burden of infection in MDR-TB challenged CD89 positive transgenic mice, but IL-4Δ2 did not appear to enhance this effect.
Supervisor: Reljic, Rajko ; Macallan, Derek ; Drake, Pascal Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available