Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica

Kana Harada; Yuki Fujita; Tatsusada Okuno; Shogo Tanabe; Yoshihisa Koyama; Hideki Mochizuki; Toshihide Yamashita

doi:10.1038/s41598-017-18362-2

Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica

Sci Rep. 2018 Jan 8;8(1):34. doi: 10.1038/s41598-017-18362-2.

Authors

Kana Harada¹, Yuki Fujita^{2

3}, Tatsusada Okuno^{4

5}, Shogo Tanabe⁶, Yoshihisa Koyama⁷, Hideki Mochizuki⁵, Toshihide Yamashita^{8

9

10}

Affiliations

¹ Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
² Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. yuki-fujita@molneu.med.osaka-u.ac.jp.
³ WPI Immunology Frontier Research Center, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. yuki-fujita@molneu.med.osaka-u.ac.jp.
⁴ Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁵ Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁶ WPI Immunology Frontier Research Center, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁷ Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁸ Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. yamashita@molneu.med.osaka-u.ac.jp.
⁹ WPI Immunology Frontier Research Center, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. yamashita@molneu.med.osaka-u.ac.jp.
¹⁰ Graduate School of Frontier Biosciences, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. yamashita@molneu.med.osaka-u.ac.jp.

Abstract

Neuromyelitis optica (NMO) is an autoimmune disease associated with NMO immunoglobulin G (NMO-IgG), an antibody that selectively binds to the aquaporin-4. Here, we established a localized NMO model by injecting NMO-IgG into the spinal cord, and assessed the efficacy of treating its NMO-like symptoms by blocking repulsive guidance molecule-a (RGMa), an axon growth inhibitor. The model showed pathological features consistent with NMO. Systemic administration of humanized monoclonal anti-RGMa antibody delayed the onset and attenuated the severity of clinical symptoms. Further, it preserved astrocytes and reduced inflammatory-cell infiltration and axonal damage, suggesting that targeting RGMa is effective in treating NMO.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aquaporin 4 / genetics
Aquaporin 4 / metabolism
Astrocytes / metabolism
Autoimmunity
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Disease Models, Animal
GPI-Linked Proteins
Gene Expression
Glial Fibrillary Acidic Protein / genetics
Glial Fibrillary Acidic Protein / metabolism
Humans
Immunoglobulin G / immunology*
Immunoglobulin G / pharmacology
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / immunology*
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / immunology*
Neuromyelitis Optica / diagnosis
Neuromyelitis Optica / drug therapy
Neuromyelitis Optica / immunology*
Neuromyelitis Optica / metabolism
Neurons / immunology
Neurons / metabolism
Rats
Severity of Illness Index
Spinal Cord / immunology
Spinal Cord / metabolism
Spinal Cord / pathology
Th17 Cells / immunology
Th17 Cells / metabolism

Substances

Aquaporin 4
GFAP protein, rat
GPI-Linked Proteins
Glial Fibrillary Acidic Protein
Immunoglobulin G
Membrane Proteins
Nerve Tissue Proteins
RGMA protein, rat