CIUSSS Capitale nationale logo

Induction of protective immunity by vaccination with wild-type apo superoxide dismutase 1 in mutant SOD1 transgenic mice.

Publication Type:

Journal Article

Source:

J Neuropathol Exp Neurol, Volume 69, Issue 10, p.1044-56 (2010)

Keywords:

Amyotrophic Lateral Sclerosis, Analysis of Variance, Animals, Chromatography, Gel, Complement C1q, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Humans, Immunity, Immunoglobulin G, Interferon-gamma, Interleukin-4, Mice, Mice, Transgenic, Motor Neurons, Mutation, Signal Transduction, Spinal Cord, Spleen, Superoxide Dismutase, Th1 Cells, Th2 Cells, Vaccination

Abstract:

<p>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.</p>

Funding / Support / Partners

logo FRQ-S logo ctrn logo fci logo cihr irsc logo nserc logo MESISentinelle nord