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Title: Protection from hepatitis C : a study of potential immune mechanisms
Author: Warshow, U. M.
Awarding Body: Exeter and Plymouth Peninsula Medical School
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2012
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Abstract:
Hepatitis C virus (HCV) infection is common with more than 180 million people infected worldwide. The majority of individuals who acquire the virus develop chronic infection leading to chronic hepatitis, and are at risk of developing cirrhosis and hepatocellular carcinoma. In the minority who clear infection acutely, an effective adaptive immune response against the virus is paramount. There is presently no available preventative vaccine against HCV infection. In the developed world, injection drug use (IOU) of illicit substances is the dominant source of new infections with high rates of HCV transmission. Rates of HCV infection are particularly high in long term I DU who frequently share drug injecting equipment such as needles and syringes. Despite this there is a cohort of long term I DU with high risk injecting practises who remain negative for any markers of HCV infection when tested for by commercial assays. It is possible they are being exposed to HCV yet remain uninfected, and have been termed exposed uninfected (or EU). It is possible that they possess immune mechanisms of protection. Understanding these mechanisms could be important in developing preventative strategies against HCV infection. This thesis has set out work to identify the potential immune mechanisms that may underlie this resistance to HCV infection in this unique cohort of IOU. Earlier studies had demonstrated HCV specific T cell reactivity in up to 50% of this cohort. These responses were of low amplitude and thus did not entirely explain this apparent resistance. To further study these T cell responses, HCV specific T cell reactivity against recombinant HCV proteins and overlapping peptides spanning the entire HCV polyprotein were studied in EU subjects using the ELlSPOT assay. Multispecific T cell responses were confirmed in up to 50% EU subjects, however were still of comparatively lower amplitude when compared to those seen in spontaneous resolvers of HCV. A large panel of serum cytokines were analysed in 22 EU subjects and levels compared to those found in cases with spontaneous clearance of HCV and chronically infected patients. This demonstrated a distinct cytokine profile in EU with raised levels of innate immune cytokines and proinflammatory chemokines, particularly Interleukin-6 and interleukin-8. These findings suggested an upregulation of the innate immune system in these individuals. To investigate host innate immunogenetic factors possibly related to protection from HCV in this cohort, a functional single nucleotide polymorphism (SNP) in the promoter region of the IL-6 gene as well as the recently discovered IL-28B related SNPs, rs12979860 and rs8099917, were studied. No over-expression or association was demonstrated betvveen these variants and this cohort. As studies had demonstrated an association with EU and a NK cell receptor:HLA compound genotype that favours viral clearance, immunophenotyping of NK cells and dendritic cells was performed in EU cases. The predominantly cytotoxic NK cell subset, CD56dim NK cells, was found to be expanded in EU, suggesting a possible phenotypic alteration in NK cell subsets in this cohort. Further studies on NK cell cytotoxicity against NK-sensitive K562 cell line demonstrated enhanced I L-2 induced cytotoxicity in EU compared to chronic viraemics. Overall, the studies performed in this thesis demonstrated a distinct immune phenotype in EU SUbjects with low amplitude HCV specific T cell reactivity, upregulated innate immune cytokines and cytotoxic NK cell subsets with enhanced cytotoxicity, thus pointing to the initial innate immune responses as the predominant factor in preventing HCV infection in this cohort.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.565980  DOI: Not available
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