Tuberculosis, caused by infection with the intracellular pathogen Mycobacterium tuberculosis, remains a major global threat to humanity. BCG remains the only prophylactic vaccine against tuberculosis but gives variable protection against pulmonary disease. While it is unclear what determines an effective immune response against Mycobacterium tuberculosis infection, the generation of host Th1 responses is accepted to be a major mechanism of protection; and promoting earlier and enhanced Th1 responses may increase the efficacy of tuberculosis vaccines. Early production of interleukin-17 in the lungs following Mycobacterium tuberculosis challenge of previously vaccinated mice has been shown to be required for efficient Th1 cell recruitment. Interleukin-10 is an immunosuppressive cytokine that regulates various processes involved in the generation of both Th1 and Th17 responses. The investigations within this thesis extend on previous studies showing interleukin-10 negatively regulates the immune response to primary Mycobacterium tuberculosis infection. Firstly, these investigations show that interleukin-10 signalling inhibits host control of infection with virulent and hypervirulent Mycobacterium tuberculosis strains, in both Mycobacterium tuberculosis-resistant C57BL/6 mice, and Mycobacterium tuberculosis-susceptible CBA/J mice. Furthermore, inhibition of interleukin-10 signalling specifically during BCG vaccination enhanced host-generated antigen-specific interferon-γ and interleukin-17 responses, and this regime gave significantly greater protection against aerogenic Mycobacterium tuberculosis challenge in both mouse strains. In susceptible CBA/J mice, antibody blockade of interleukin-10 receptor specifically during BCG vaccination resulted in an unprecedented 1-Log10 further protection against Mycobacterium tuberculosis challenge as compared to BCG-vaccination alone. This robust protection was sustained during the course of Mycobacterium tuberculosis infection, and correlated with superior lung Th1 and Th17 responses, and enhanced interferon-γ and interleukin-17 production from innate lymphoid cells. In summary, interleukin-10 inhibits both host-mediated protection against primary Mycobacterium tuberculosis infection, and optimal BCG-elicited protection. Antagonists of interleukin-10 may therefore be greatly beneficial as adjuncts to tuberculosis therapy, and as adjuvants in preventive vaccination against tuberculosis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625924 |
| Date | January 2012 |
| Creators | Pitt, J. M. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1365866/ |
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