A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis

Journal of Neuroinflammation

Moses Rodriguez²  Arthur E Warrington¹  Jens O Watzlawik¹  Aleksandar Denic¹  Bharath Wootla¹ 

[1] Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester 55905, MN, USA;Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester 55905, MN, USA

关键词: Axons;    Brainstem;    N-acetyl-aspartate;    MRS;    Theiler’s murine encephalomyelitis virus;    Multiple sclerosis;   

Others  :  1213713
DOI  :  10.1186/s12974-015-0303-y

 received in 2015-03-04, accepted in 2015-04-17,  发布年份 2015

【 摘 要 】

Background

Intracerebral infection of susceptible mouse strains with Theiler’s murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology.

Findings

¹H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12.

Conclusions

This study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials.

【 授权许可】

   
2015 Wootla et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

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