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Journal of Neuroinflammation

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Open Access 01-12-2015 | Short Report

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

Authors: Bharath Wootla, Aleksandar Denic, Jens O Watzlawik, Arthur E Warrington, Moses Rodriguez

Published in: Journal of Neuroinflammation | Issue 1/2015

Abstract

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.

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Warrington AE, Bieber AJ, Van Keulen V, Ciric B, Pease LR, Rodriguez M. Neuron-binding human monoclonal antibodies support central nervous system neurite extension. J Neuropathol Exp Neurol. 2004;63:461–73.PubMed

Acorda Therapeutics Inc. An intravenous infusion study of rHIgM22 in patients with multiple sclerosis. Clinical trials identifier - NCT01803867. Weblink - http://1.usa.gov/1N2gsHJ. 2015.

Rodriguez M, Warrington AE, Pease LR. Human natural autoantibodies in the treatment of neurologic disease. Neurology. 2009;72:1269–76.CrossRefPubMedCentralPubMed

Wright BR, Warrington AE, Edberg DD, Rodriguez M. Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies. Arch Neurol. 2009;66:1456–9.CrossRefPubMedCentralPubMed

Denic A, Macura SI, Warrington AE, Pirko I, Grossardt BR, Pease LR, et al. A single dose of neuron-binding human monoclonal antibody improves spontaneous activity in a murine model of demyelination. PLoS ONE. 2011;6, e26001.CrossRefPubMedCentralPubMed

Clark JB. N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci. 1998;20:271–6.CrossRefPubMed

Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol. 2000;48:893–901.CrossRefPubMed

Suhy J, Rooney WD, Goodkin DE, Capizzano AA, Soher BJ, Maudsley AA, et al. 1H MRSI comparison of white matter and lesions in primary progressive and relapsing-remitting MS. Mult Scler. 2000;6:148–55.PubMedCentralPubMed

Henning A, Schar M, Kollias SS, Boesiger P, Dydak U. Quantitative magnetic resonance spectroscopy in the entire human cervical spinal cord and beyond at 3 T. Magn Reson Med. 2008;59:1250–8.CrossRefPubMed

10.

Qian J, Herrera JJ, Narayana PA. Neuronal and axonal degeneration in experimental spinal cord injury: in vivo proton magnetic resonance spectroscopy and histology. J Neurotrauma. 2010;27:599–610.CrossRefPubMedCentralPubMed

11.

Kendi AT, Tan FU, Kendi M, Yilmaz S, Huvaj S, Tellioglu S. MR spectroscopy of cervical spinal cord in patients with multiple sclerosis. Neuroradiology. 2004;46:764–9.CrossRefPubMed

12.

Denic A, Bieber A, Warrington A, Mishra PK, Macura S, Rodriguez M. Brainstem 1H nuclear magnetic resonance (NMR) spectroscopy: marker of demyelination and repair in spinal cord. Ann Neurol. 2009;66:559–64.CrossRefPubMedCentralPubMed

13.

Warrington AE, Bieber AJ, Ciric B, Pease LR, Van Keulen V, Rodriguez M. A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res. 2007;85:967–76.CrossRefPubMed

14.

Dal Canto MC, Lipton HL. A new model of persistent viral infection with primary demyelination. Neurol Neurocir Psiquiatr. 1977;18:455–67.PubMed

15.

McGavern DB, Murray PD, Rodriguez M. Quantitation of spinal cord demyelination, remyelination, atrophy, and axonal loss in a model of progressive neurologic injury. J Neurosci Res. 1999;58:492–504.CrossRefPubMed

16.

Howe CL, Adelson JD, Rodriguez M. Absence of perforin expression confers axonal protection despite demyelination. Neurobiol Dis. 2007;25:354–9.CrossRefPubMedCentralPubMed

17.

Pavelko KD, Howe CL, Drescher KM, Gamez JD, Johnson AJ, Wei T, et al. Interleukin-6 protects anterior horn neurons from lethal virus-induced injury. J Neurosci. 2003;23:481–92.PubMed

18.

Sidman RL, Angevine JB, Pierce ET. Atlas of the mouse brain and spinal cord. Cambridge: Harvard Univ Press; 1971.

19.

Bieber AJ, Warrington A, Asakura K, Ciric B, Kaveri SV, Pease LR, et al. Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice. Glia. 2002;37:241–9.CrossRefPubMed

20.

Warrington AE, Asakura K, Bieber AJ, Ciric B, Van Keulen V, Kaveri SV, et al. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci U S A. 2000;97:6820–5.CrossRefPubMedCentralPubMed

21.

Ure D, Rodriguez M. Extensive injury of descending neurons demonstrated by retrograde labeling in a virus-induced murine model of chronic inflammatory demyelination. J Neuropathol Exp Neurol. 2000;59:664–78.PubMed

22.

Denic A, Pirko I, Wootla B, Bieber A, Macura S, Rodriguez M. Deletion of beta-2-microglobulin ameliorates spinal cord lesion load and promotes recovery of brainstem NAA levels in a murine model of multiple sclerosis. Brain Pathol. 2012;22:698–708.CrossRefPubMedCentralPubMed

23.

Denic A, Zoecklein L, Kerkvliet J, Papke L, Edukulla R, Warrington A, et al. Transgenic expression of viral capsid proteins predisposes to axonal injury in a murine model of multiple sclerosis. Brain Pathol. 2011;21:501–15.PubMedCentralPubMed

24.

Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler. 2003;9:323–31.CrossRefPubMed

25.

Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50:389–400.CrossRefPubMed

26.

De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML, et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology. 2003;60:1157–62.CrossRefPubMed

27.

Huizinga R, Gerritsen W, Heijmans N, Amor S. Axonal loss and gray matter pathology as a direct result of autoimmunity to neurofilaments. Neurobiol Dis. 2008;32:461–70.CrossRefPubMed

28.

Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science. 1998;280:1610–3.CrossRefPubMed

Title: 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
Authors: Bharath Wootla
Aleksandar Denic
Jens O Watzlawik
Arthur E Warrington
Moses Rodriguez
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-015-0303-y

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Findings

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Findings

Conclusions

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