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Efficacy and immunological mechanisms of type 1 interferon gene therapy in murine cytomegalovirus

Bartlett, Emmalene J. (2002) Efficacy and immunological mechanisms of type 1 interferon gene therapy in murine cytomegalovirus. PhD thesis, Murdoch University.

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      Abstract

      This thesis presents a comparative analysis of the type I Interferon (IFN) subtypes and an evaluation of their potential as DNA vaccines in a model of murine cytomegalovirus (MCMV) infection and disease. MCMV induces acute and chronic phases of myocarditis, a heart disease characterised by an inflammatory cell infiltrate, in susceptible BALB/c mice.

      The type I IFNs comprise 14 IFN alpha genes in the human and >10 IFN alpha genes in the mouse with a single IFN beta gene in both species, however, the purpose of their multiplicity has remained unclear to date. An extensive panel of murine type I IFN subtype genes, including IFNA1, A2, A4, A5, A6, A9 and B, were sub-cloned into the mammalian expression vector pkCMVint (Vical, Inc.) for expression in BALB/c mice. These DNA constructs express biologically active IFN both in vitro and in vivo with systemic, low level expression persisting in the mouse for up to 4 weeks. The individual type I IFN subtypes differentially affect the immune response to MCMV challenge. IFNA6 proved most efficacious, reducing viral replication and inflammation in the acute and chronic phase of disease. Data suggests this occurs via induction of a Th1-like cytokine and antibody response. Furthermore, IFNA6 inoculation after the acute phase was shown to protect mice from the onset of chronic myocarditis. Characterisation of the immune cell response in IFN-treated, MCMV-infected mice demonstrated that type I IFN subtypes modulate the type of immune cells infiltrating the myocardium during myocarditis. Notably, reduced CD8+ and CD4+ T cells and B cell numbers in the heart was associated with reduced chronic myocarditis. Finally, coadministration of type I IFNs, in particular, IFNA6 and IFNB, synergistically improved immunotherapy against MCMV infection and myocarditis.

      The findings detailed here highlight the potential for the type I IFNs as DNA vaccines and most importantly, demonstrate that the type I IFNs have differential antiviral and immunomodulatory efficacies in the MCMV model of infection and myocarditis.

      Publication Type: Thesis (PhD)
      Murdoch Affiliation: School of Veterinary Biology and Biomedical Science
      Supervisor: James, Cassandra
      URI: http://researchrepository.murdoch.edu.au/id/eprint/214
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