Modulation of the immune response by current and novel treatments for hepatitis C virus

Abstract

Hepatitis C virus (HCV) infection is a major global healthcare problem infecting 180 million people worldwide. Infection persists in 80% of patients and is thought to result from a failure to sustain an immune response to HCV. Current treatment with ribavirn and PEG-IFN? leads to a sustained viral clearance in 40-80% of patients. Despite its use for many years, the exact mechanisms of actions of ribavirin are poorly understood. These current treatments are poorly tolerated by many and therefore newer and more effective treatments are being investigated.
This thesis investigated how current and novel treatments were able to modulate the immune response looking at effects on the innate immune response including dendritic cells and NK cells and their ability to stimulate T cells and the adaptive immune response.
The aim of the work described in chapter 3 was to investigate the immunomodulatory effects of ribavirin on dendritic cell (DC) function. The results obtained suggest that ribavirin is able to modulate cytokine production from dendritic cells in response to maturation stimuli, in particular suppressing the production of IFN? from pDCS from both CHC and NHD patients but also TNF?, IL8 and IL10. In MoDCs from NHDs, ribavirin decreased CD40L-induced TNF? production but had no effect on other cytokines tested or on DC phenotype. These findings explain possible reasons behind the failure of monotherapy and dependence on co-administration of IFN? in treatment regimens.
The aim of the work in chapters 4 and 5 was to investigate the immunomodulatory effects of two novel treatments, a novel helminth protein, rOv-ASP-1 and a TLR7 agonist, SM-360320.
rOv-ASP-1 showed evidence of DC phenotypic maturation, based on up-regulation of phenotypic markers (CD40, HLA-DR, CD83 and CD86) and enhanced pro-inflammatory cytokine production (IL-6, IL-8 and TNF?). It was also shown to stimulate proliferation of allogeneic CD4+ T cells suggesting that the protein is able to enhance the accessory/antigen presentation by DCs. These findings suggest that this novel protein may be used as an effective immuno-stimulant to boost antigen specific responses or as a vaccine adjuvant.
SM-360320 was shown to enhance viral clearance and immune modulation with induction of 2’5’OAS gene expression, inhibition of replication of HCV replicons in Huh 7 cells, enhanced secretion of anti-viral and pro-inflammatory cytokines, up-regulation of NK cell activation. These findings suggest that SM-360320 might provide complementary and additional mechanisms of action to current HCV therapies making it a promising novel treatment.
Further investigation of these compounds is therefore warranted due to their potential widespread application in treating infectious diseases and immune mediated conditions

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