Induction of Protective Immunity by Vaccination With Wild-Type Apo Superoxide Dismutase 1 in Mutant SOD1 Transgenic Mice

Molecular Neuroscience Research Center, Shiga University of Medical Science
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 10/2010; 69(10):1044-56. DOI: 10.1097/NEN.0b013e3181f4a90a
Source: PubMed


Vaccinations targeting extracellular superoxide dismutase 1 (SOD1) mutants are beneficial in mouse models of amyotrophic lateral sclerosis (ALS). Because of its misfolded nature, wild-type nonmetallated SOD1 protein (WT-apo) may have therapeutic application for vaccination of various SOD1 mutants. We compared the effects of WT-apo to those of a G93A SOD1 vaccine in low-copy G93A SOD1 transgenic mice. Both SOD1 vaccines induced antibody against G93A SOD1 and significantly delayed disease onset compared with saline/adjuvant controls. WT-apo SOD1 significantly extended the life span of vaccinated mice. The vaccines potentiated TH2 deviation in the spinal cord as determined by the ratio of interleukin-4 to interferon-γ (IFNγ) or tumor necrosis factor and induced C1q deposition around motor neurons. Transgenic mice had abundant microglial expression of signal transducers and activators of transcription 4, an activator of transcription of IFNγ, in the spinal cord implicating IFNγ in the pathogenesis. On the other hand, the sera from G93A SOD1-vaccinated mice showed higher IFNγ or tumor necrosis factor and yielded a lower IgG1/IgG2c ratio than the sera from WT-apo-vaccinated mice. These results indicate that the TH1/TH2 milieu is affected by specific vaccinations and that antigenicity might counteract beneficial effects by enhancing TH1 immunity. Thus, because of its lower TH1 induction, WT-apo may be a therapeutic option and have broader application in ALS associated with diverse SOD1 mutations.

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Available from: Makoto Urushitani, Nov 20, 2014
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    • "This strategy delays disease onset and increases the life span of mSOD1 mice longer than other therapeutic methods [95]. A SOD1 vaccine was developed for the wild type protein and used on mSOD1 mice, also achieving a delay of disease onset [96,97]. A very promising strategy for ALS patients is vaccination with effector T cells against neural constituents during the symptomatic disease phase; which combined with autologous neural stem cell treatment , achieves neurologic improvements probably by establishment of self-tolerance against neural constituents [98]. "
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