Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody

Kazuhiro Kurosawa, Tatsuro Misu, Yoshiki Takai, Douglas Kazutoshi Sato, Toshiyuki Takahashi, Yoichiro Abe, Hiroko Iwanari, Ryo Ogawa, Ichiro Nakashima, Kazuo Fujihara, Takao Hamakubo, Masato Yasui, Masashi Aoki

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

INTRODUCTION: Neuromyelitis optica (NMO), an autoimmune astrocytopathic disease associated with anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions preferentially involving the optic nerves and spinal cord. However, previous in-vivo experimental models injecting human anti-AQP4 antibodies only resulted in mild spinal cord lesions compared to NMO autopsied cases. Here, we investigated whether the formation of severe NMO-like lesions occurs in Lewis rats in the context of experimental autoimmune encephalomyelitis (EAE), intraperitoneally injecting incremental doses of purified human immunoglobulin-G from a NMO patient (hIgGNMO) or a high affinity anti-AQP4 monoclonal antibody (E5415A), recognizing extracellular domain of AQP4 made by baculovirus display method.

RESULTS: NMO-like lesions were observed in the spinal cord, brainstem, and optic chiasm of EAE-rats with injection of pathogenic IgG (hIgGNMO and E5415A), but not in control EAE. Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG. Loss of AQP4 was observed both in EAE rats receiving hIgGNMO and E5415A in a dose dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50 % than those receiving low-dose E5415A or hIgGNMO less than 3 %. These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b-9, which is compatible with post mortem NMO pathology. In high dose E5415A rats, massive neutrophil infiltration was observed especially at the lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage. In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO.

CONCLUSIONS: In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models. Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages. (350/350).

Original languageEnglish
Pages (from-to)82
Number of pages1
JournalActa neuropathologica communications
Volume3
DOIs
Publication statusPublished - 2015 Dec 4

Fingerprint

Aquaporin 4
Neuromyelitis Optica
Monoclonal Antibodies
Immunoglobulin G
Autoimmune Experimental Encephalomyelitis
Spinal Cord
Antibodies
Complement Membrane Attack Complex
Optic Chiasm
Injections
Neutrophil Infiltration
Baculoviridae
Glial Fibrillary Acidic Protein
Demyelinating Diseases
Optic Nerve
Myelin Sheath
Autoimmune Diseases
Brain Stem
Rodentia
Neutrophils

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody. / Kurosawa, Kazuhiro; Misu, Tatsuro; Takai, Yoshiki; Sato, Douglas Kazutoshi; Takahashi, Toshiyuki; Abe, Yoichiro; Iwanari, Hiroko; Ogawa, Ryo; Nakashima, Ichiro; Fujihara, Kazuo; Hamakubo, Takao; Yasui, Masato; Aoki, Masashi.

In: Acta neuropathologica communications, Vol. 3, 04.12.2015, p. 82.

Research output: Contribution to journalArticle

Kurosawa, K, Misu, T, Takai, Y, Sato, DK, Takahashi, T, Abe, Y, Iwanari, H, Ogawa, R, Nakashima, I, Fujihara, K, Hamakubo, T, Yasui, M & Aoki, M 2015, 'Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody', Acta neuropathologica communications, vol. 3, pp. 82. https://doi.org/10.1186/s40478-015-0259-2
Kurosawa, Kazuhiro ; Misu, Tatsuro ; Takai, Yoshiki ; Sato, Douglas Kazutoshi ; Takahashi, Toshiyuki ; Abe, Yoichiro ; Iwanari, Hiroko ; Ogawa, Ryo ; Nakashima, Ichiro ; Fujihara, Kazuo ; Hamakubo, Takao ; Yasui, Masato ; Aoki, Masashi. / Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody. In: Acta neuropathologica communications. 2015 ; Vol. 3. pp. 82.
@article{24e77584a0ec468ca6a42d89d24baa51,
title = "Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody",
abstract = "INTRODUCTION: Neuromyelitis optica (NMO), an autoimmune astrocytopathic disease associated with anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions preferentially involving the optic nerves and spinal cord. However, previous in-vivo experimental models injecting human anti-AQP4 antibodies only resulted in mild spinal cord lesions compared to NMO autopsied cases. Here, we investigated whether the formation of severe NMO-like lesions occurs in Lewis rats in the context of experimental autoimmune encephalomyelitis (EAE), intraperitoneally injecting incremental doses of purified human immunoglobulin-G from a NMO patient (hIgGNMO) or a high affinity anti-AQP4 monoclonal antibody (E5415A), recognizing extracellular domain of AQP4 made by baculovirus display method.RESULTS: NMO-like lesions were observed in the spinal cord, brainstem, and optic chiasm of EAE-rats with injection of pathogenic IgG (hIgGNMO and E5415A), but not in control EAE. Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG. Loss of AQP4 was observed both in EAE rats receiving hIgGNMO and E5415A in a dose dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50 {\%} than those receiving low-dose E5415A or hIgGNMO less than 3 {\%}. These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b-9, which is compatible with post mortem NMO pathology. In high dose E5415A rats, massive neutrophil infiltration was observed especially at the lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage. In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO.CONCLUSIONS: In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models. Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages. (350/350).",
author = "Kazuhiro Kurosawa and Tatsuro Misu and Yoshiki Takai and Sato, {Douglas Kazutoshi} and Toshiyuki Takahashi and Yoichiro Abe and Hiroko Iwanari and Ryo Ogawa and Ichiro Nakashima and Kazuo Fujihara and Takao Hamakubo and Masato Yasui and Masashi Aoki",
year = "2015",
month = "12",
day = "4",
doi = "10.1186/s40478-015-0259-2",
language = "English",
volume = "3",
pages = "82",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody

AU - Kurosawa, Kazuhiro

AU - Misu, Tatsuro

AU - Takai, Yoshiki

AU - Sato, Douglas Kazutoshi

AU - Takahashi, Toshiyuki

AU - Abe, Yoichiro

AU - Iwanari, Hiroko

AU - Ogawa, Ryo

AU - Nakashima, Ichiro

AU - Fujihara, Kazuo

AU - Hamakubo, Takao

AU - Yasui, Masato

AU - Aoki, Masashi

PY - 2015/12/4

Y1 - 2015/12/4

N2 - INTRODUCTION: Neuromyelitis optica (NMO), an autoimmune astrocytopathic disease associated with anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions preferentially involving the optic nerves and spinal cord. However, previous in-vivo experimental models injecting human anti-AQP4 antibodies only resulted in mild spinal cord lesions compared to NMO autopsied cases. Here, we investigated whether the formation of severe NMO-like lesions occurs in Lewis rats in the context of experimental autoimmune encephalomyelitis (EAE), intraperitoneally injecting incremental doses of purified human immunoglobulin-G from a NMO patient (hIgGNMO) or a high affinity anti-AQP4 monoclonal antibody (E5415A), recognizing extracellular domain of AQP4 made by baculovirus display method.RESULTS: NMO-like lesions were observed in the spinal cord, brainstem, and optic chiasm of EAE-rats with injection of pathogenic IgG (hIgGNMO and E5415A), but not in control EAE. Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG. Loss of AQP4 was observed both in EAE rats receiving hIgGNMO and E5415A in a dose dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50 % than those receiving low-dose E5415A or hIgGNMO less than 3 %. These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b-9, which is compatible with post mortem NMO pathology. In high dose E5415A rats, massive neutrophil infiltration was observed especially at the lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage. In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO.CONCLUSIONS: In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models. Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages. (350/350).

AB - INTRODUCTION: Neuromyelitis optica (NMO), an autoimmune astrocytopathic disease associated with anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions preferentially involving the optic nerves and spinal cord. However, previous in-vivo experimental models injecting human anti-AQP4 antibodies only resulted in mild spinal cord lesions compared to NMO autopsied cases. Here, we investigated whether the formation of severe NMO-like lesions occurs in Lewis rats in the context of experimental autoimmune encephalomyelitis (EAE), intraperitoneally injecting incremental doses of purified human immunoglobulin-G from a NMO patient (hIgGNMO) or a high affinity anti-AQP4 monoclonal antibody (E5415A), recognizing extracellular domain of AQP4 made by baculovirus display method.RESULTS: NMO-like lesions were observed in the spinal cord, brainstem, and optic chiasm of EAE-rats with injection of pathogenic IgG (hIgGNMO and E5415A), but not in control EAE. Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG. Loss of AQP4 was observed both in EAE rats receiving hIgGNMO and E5415A in a dose dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50 % than those receiving low-dose E5415A or hIgGNMO less than 3 %. These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b-9, which is compatible with post mortem NMO pathology. In high dose E5415A rats, massive neutrophil infiltration was observed especially at the lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage. In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO.CONCLUSIONS: In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models. Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages. (350/350).

UR - http://www.scopus.com/inward/record.url?scp=85010073324&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010073324&partnerID=8YFLogxK

U2 - 10.1186/s40478-015-0259-2

DO - 10.1186/s40478-015-0259-2

M3 - Article

C2 - 26637322

AN - SCOPUS:85010073324

VL - 3

SP - 82

JO - Acta neuropathologica communications

JF - Acta neuropathologica communications

SN - 2051-5960

ER -