Abstract
BackgroundVaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. This study focused on whether cytokine-neuroantigen (NAg) fusion proteins could inhibit disease in chronic murine models of experimental autoimmune encephalomyelitis (EAE) and thus serve as potential therapeutic modalities for multiple sclerosis.ResultsA fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE.ConclusionThese data indicated that fusion proteins containing GM-CSF coupled to myelin auto-antigens elicit tolerance rather than immunity.
Highlights
Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease
In vitro activities of GMCSF-myelin oligodendrocyte glycoprotein (MOG) The main question addressed in this study was whether murine GMCSF-NAg therapeutic vaccine (TTV) could block disease in murine models of chronic EAE, including the chronic progressive model of EAE in C57BL/6 mice and the relapsing-remitting model of EAE in SJL mice
Murine fusion proteins were derived which consisted of the murine granulocytemacrophage colony stimulating factor (GM-CSF) as the N-terminal domain and either the MOG35-55 epitope or the PLP139-151 epitope as the C-terminal domain
Summary
Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. Molecular mimicry may be mediated by chronic infectious agents such as viruses that exhibit prolonged latency but periodically reactivate and re-stimulate cross-reactive immunity. With each reactivation, these chronic infectious agents disease is postulated to reflect mechanisms of epitope spreading and erosion of regulatory T cell control. Monophasic, self-limiting models of EAE that feature spontaneous, enduring recovery may have more robust regulatory T cell responses compared to those operative in chronic models.
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