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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    • "In an ALS model, active immunization with a peptide epitope of mutant superoxide dismutase 1 (SOD1) in CFA induced a Th2-biased antibody response that delayed disease onset (Liu et al., 2012). Similarly, vaccination with Ribi, a Th2-biasing adjuvant, in the absence of antigen also generated a Th2-biased antibody response indicated by a high IgG1/ IgG2c ratio and increased IL-4/IFNγ ratio that positively correlated with lifespan (Takeuchi et al., 2010). Vaccination with Copolymer 1 (Cop-1), an APL designed to mimic MBP, has demonstrated protective effects in experimental models of AD, PD, HIV-1 encephalitis, glaucoma, and EAE (Benner et al., 2004; Butovsky et al., 2006; Gorantla et al., 2008; Kala et al., 2010; Schori et al., 2001). "
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    • "Frontiers in Cellular Neuroscience December 2013 | Volume 7 | Article 253 | 9 SOD1 G93A (Takeuchi et al., 2010 "
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    • "The finding that mutant SOD1 can be secreted and evidence of toxicity of extracellular mutant SOD112 provided a rationale for testing immunization approaches for ALS treatment. An active immunization approach with recombinant mutant or WT SOD1 as immunogen was found to delay disease onset and to increase life span of SOD1G37R mice and SOD1G93A mice expressing moderate levels of mutant SOD1.13,14 Similar results have been obtained with active immunization using an antigenic peptide that targets the dimer interface of SOD1 using SOD1G37R or SOD1G93A mice.15 "
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