Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.693864
Title: Dissection of the immunomodulatory effects of human immunodeficiency virus and Mycobacterium tuberculosis on cellular immunity
Author: Pollock, Katrina Mary
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Abstract:
Mycobacterium tuberculosis (MTB) is a significant infectious cause of morbidity and mortality in the HIV-infected population. Despite this, the impact of HIV and active TB on MTB-specific cell mediated immunity (CMI) is incompletely understood. MTB-specific cellular immunity, at defined stages of TB infection (latent and active TB) in those with and without HIV co-infection, was therefore studied and compared with responses to cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Candida albicans. Results from screening 225 participants with a next generation MTB IFN-? ELISpot were used to stratify participants into predefined subgroups. In those fulfilling study criteria, polychromatic flow cytometry was used to measure CD4+ and CD8+ interferon-gamma (IFN-?), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-?) responses and markers of cellular memory (CD45RA and CCR7), survival (CD127) and exhaustion (CD279/PD-1). MTB IFN-? ELISpot responses indicated that current UK guidance for LTBI screening in HIV-infected individuals would fail to detect 50% of cases. The frequency and phenotype of antigen-specific functional subsets varied by pathogen, particularly expression of PD-1, in the flow cytometry assay. The frequency of CD4+ MTB-specific IFN-? and IL-2-dual-secreting cells was reduced in HIV co-infection, with a similar although less profound effect on viral and fungal-specific responses. In active TB, HIV was associated with increased expression of PD-1 on MTB-specific IFN-?-secreting functional subsets. In LTBI, HIV was associated with a unique cytokine signature with increased secretion of IL-17 and IL-6. In active TB, there was an increased frequency of MTB-specific CD4+ and CD8+ effectors (secreting IFN-?, TNF-? or both), CD4+ functional subsets were more differentiated and there was a reduced frequency of viral and fungal-specific tri-functional CD4+ cells. Combined measurement of CD4+ MTB-specific frequency and phenotype yielded a highly discriminatory biomarker of active and latent TB infection with potentially significant clinical impact.
Supervisor: Lalvani, Ajit ; Taylor, Graham Sponsor: British Lung Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.693864  DOI: Not available
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