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Title: Immune responses to mycobacteria : the role of age and disease severity
Author: Whittaker, Elizabeth
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Investigating the immune mechanisms that predispose the development of TB disease is essential to expand our understanding of immune protection from TB. We hypothesized younger children would have a distinctly different immune response to mycobacteria than older children predisposing them to severe TB disease. We compared mycobacterial immune responses in healthy, BCG vaccinated children of increasing ages, focusing on CD4, γō and regulatory T cells and their related cytokines. Additionally we compared these responses in 4 groups of children; healthy controls, latent TB infection (LTBI), pulmonary TB (PTB) and extra-pulmonary TB (EPTB) both at diagnosis and after 6 months TB treatment. Our data demonstrates that healthy children of all ages have robust and comparable antigen specific effector and central memory immune responses to BCG. However, distinct differences between children < 1 yr of age and older children identified on analysis of secreted cytokine data supports further studies into potential age-related differences in the innate immune response to BCG. In addition we demonstrate a waning of proliferative T cell responses to BCG with increasing age which raises the question of benefit of re-vaccination with BCG in high endemic areas to protect children 2yrs and over from disseminated TB. All children with TB disease had suppressed mycobacterial immune responses at the time of disease. However these recovered and were of greater magnitude after 6 months than those of healthy controls, suggesting a boosting effect on the central memory compartment of the immune response. We report for the first time in children that regulatory T cells are increased in children with both TB infection and disease. Although at baseline our assays could not distinguish children with PTB from those with EPTB, after 6 months those with EPTB have lower effector and central memory responses, in association with differences in their secreted cytokine responses. This warrants further exploration to determine whether it is a function of timing, bacterial load or mycobacterial clearance, but may be primary evidence of an underlying susceptibility linked to immune profiles.
Supervisor: Kampmann, Beate Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available