dc.contributor.author | Gill, Upkar, S. | |
dc.date.accessioned | 2018-12-10T17:14:06Z | |
dc.date.available | 2018-12-10T17:14:06Z | |
dc.date.issued | 31/10/2018 | |
dc.date.submitted | 2018-12-10T15:54:09.958Z | |
dc.identifier.citation | Gill, U.S. 2018. HARNESSING THE IMMUNE RESPONSE TO OPTIMISE TREATMENT STRATEGIES IN CHRONIC HEPATITIS B. Queen Mary University of London | en_US |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/53580 | |
dc.description | PhD | en_US |
dc.description.abstract | Chronic Hepatitis B (CHB) related cirrhosis and hepatocellular carcinoma (HCC) account for
more than 750,000 deaths per year. Current therapies for CHB are limited in achieving
HBsAg decline/loss and thus there remains a pressing need for curative treatment strategies.
Although, Pegylated Interferon-α (Peg-IFNα) may be used, the majority of patients progress
to nucleos(t)ide analogue (NUC) therapy due to treatment failure. Peg-IFNα and NUCs used
in isolation act differentially on the immune response; Peg-IFNα induces NK cell activation
and NUC therapy may partially restore T cell function. NK cells are important antiviral
effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in
persistent viral infections. Here we examined the NK cell pool in HBeAg-positive CHB
patients treated with Peg-IFNα and whether changes in the NK cell repertoire are induced
when patients are ‘primed’ with Peg-IFNα and importantly, whether these changes are
sustained or further modulated long-term after switching to sequential NUC therapy. The
cumulative expansion of CD56bright NK cells driven by 48-weeks of Peg-IFNα was maintained
at higher than baseline levels throughout the subsequent 9 months of sequential NUCs. Peg-
IFNα-expanded NK cells showed further augmentation in their expression of the activating
NK cell receptors during sequential NUCs. The expansion in proliferating, functional NK cells
and HBsAg reduction was greater and more pronounced following sequential NUCs than in
patients treated with de novo NUCs. This highlights the potential benefit of Peg-IFNα-
priming, providing mechanistic insights for the further optimisation of treatment strategies to
achieve sustained responses. Sustained boosting of NK cells on sequential NUCs following
Peg-IFNα-priming has not previously been described raising the potential of ‘long-lived’ NK
cell populations in keeping with their emerging adaptive features. These findings provide a
mechanistic and immunological rationale to explore combination/sequential treatment
strategies for CHB, including on-treatment immune responses in the liver, whilst awaiting the
emergence of new therapies in the field. | en_US |
dc.description.sponsorship | Wellcome Trust | |
dc.language.iso | en | en_US |
dc.publisher | Queen Mary University of London | |
dc.subject | Mathematical Sciences | en_US |
dc.subject | Complex networks | en_US |
dc.title | HARNESSING THE IMMUNE RESPONSE TO OPTIMISE TREATMENT STRATEGIES IN CHRONIC HEPATITIS B | en_US |
dc.type | Thesis | en_US |
dc.rights.holder | The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author | |