Article

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: 4.37). 10/2010; 69(10):1044-56. DOI: 10.1097/NEN.0b013e3181f4a90a
Source: PubMed

ABSTRACT 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 www.frontiersin.org December 2013 | Volume 7 | Article 253 | 9 SOD1 G93A (Takeuchi et al., 2010 "
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    • "After determination of the optimal concentration of cystamine using WT C57BL/ 6 mice (60 mg/mL), the mSOD1 mice were treated at 30 weeks of age (i.e., the timing of clinical onset) (n = 8 for cystamine; n = 11 for the saline control). The therapeutic effects were evaluated by weekly measures of grip power and body weight and by life span, in which the inability of mice to turn around from the supine position within 30 s was used as the endpoint (Takeuchi et al. 2010). To investigate the effect of cystamine for SOD1 oligomers or neuroinflammation , mice were killed and total spinal cords were resected for western blotting 30 days after the pump installment. "
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