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dc.contributor.advisorvan den Hurk, Sylviaen_US
dc.creatorAtanley, Ethelen_US
dc.date.accessioned2013-09-14T12:00:11Z
dc.date.available2013-09-14T12:00:11Z
dc.date.created2013-08en_US
dc.date.issued2013-09-13en_US
dc.date.submittedAugust 2013en_US
dc.identifier.urihttp://hdl.handle.net/10388/ETD-2013-08-1192en_US
dc.description.abstractDendritic cells (DCs) function mainly as antigen presenting cells (APCs) and as such they play a significant role in activating the adaptive immune system. Dendritic cells express toll-like receptors (TLR), and when these receptors are engaged by their cognate agonists, they promote DC maturation, which is critical in the induction of potent T helper (Th) cell -1 responses. Due to the multifunctional abilities of DCs, they have been explored as vaccine carriers, largely in cancer immunotherapy and some infectious diseases including hepatitis C. Previous studies showed that DCs loaded with mRNA of hepatitis C virus (HCV) antigen(s) induced strong immune responses but immune protection was not complete. Therefore, I expected that adoptive transfer of DCs transfected with HCV NS3/4A and/or NS5A mRNA and further treated with TLR agonist(s) ex vivo would induce HCV-specific immunity in vivo. Bone marrow-derived DCs generated with Flt3L (FL-DCs) or GM-CSF (GM-DCs), and loaded with HCV NS3/4A and/or NS5A mRNA showed maturation characteristics and produced substantial amounts of IL-12 after ex vivo activation with CpG ODN or CpG ODN plus Poly I:C, when compared to their untreated counterparts. Treatment with a combination of CpG ODN and Poly I:C synergized to augment IL-12 production in comparison with stimulation with CpG ODN alone. IL-12 secretion by DCs is pivotal in directing immune responses towards a Th1-bias response, which is needed to eliminate HCV. However, the ex vivo responses of stimulated DCs bearing HCV antigen(s) were not efficiently translated in mice to potentiate vigorous antigen-specific T cell responses. This resulted in a lack of protection after challenge with recombinant vaccinia virus expressing HCV NS3/NS4/NS5 in immunized mice. In contrast, both antigen-specific humoral and cell-mediated immune responses were induced in mice vaccinated with HCV recombinant NS3 or NS5A protein co-formulated with CpG ODN, host defense peptide and polyphosphazene. These responses, however, did not mediate viral clearance, as vaccinated mice remained unprotected from infection with recombinant vaccinia virus expressing HCV antigens. Taken together, these results suggest HCV recombinant protein co-formulated with triple adjuvant to be a better vaccine candidate than the DC-based vaccine.en_US
dc.language.isoengen_US
dc.subjectDendritic cells, Hepatitis C virus, Toll-like receptors, GM-CSF, FLT3Len_US
dc.titleIMPACT OF NONSTRUCTURAL HEPATITIS C VIRUS ANTIGENS AND TOLL-LIKE RECEPTOR AGONISTS ON DENDRITIC CELL IMMUNOGENICITYen_US
thesis.degree.departmentMicrobiology and Immunologyen_US
thesis.degree.disciplineMicrobiology and Immunologyen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelMastersen_US
thesis.degree.nameMaster of Science (M.Sc.)en_US
dc.type.materialtexten_US
dc.type.genreThesisen_US
dc.contributor.committeeMemberWilson, Joyceen_US
dc.contributor.committeeMemberHavele, Calliopien_US
dc.contributor.committeeMemberHayes, Sidneyen_US


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