Reduction of MPO-ANCA epitopes in SCG/Kj mice by 15-deoxyspergualin treatment restricted by IgG2b associated with crescentic glomerulonephritis

Tomizawa, Kazuo; Nagao, Tomokazu; Kusunoki, Reina; Saiga, Kan; Oshima, Masamichi; Kobayashi, Kazuo; Nakayama, Toshinori; Tanokura, Masaru; Suzuki, Kazuo

doi:10.1093/rheumatology/keq087

Cited by 9 publications

(6 citation statements)

References 40 publications

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“…In particular, many kinds of MPO-ANCAs have a wide range of epitopes that exert pharmacological effects. 27,28 Alternatively, the pharmacological action of VasSF may be against an autoantibody to moesin. [29][30][31] Notably, however, the VasSF target antigen, VAP2, associates with AP1 to form high-density lipoprotein (HDL), which has anti-inflammatory action.…”

Section: Discussionmentioning

confidence: 99%

<p>Efficacy of a recombinant single-chain fragment variable region, VasSF, as a new drug for vasculitis</p>

Kameoka¹,

Kishi²,

Koura

et al. 2019

DDDT

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Background: Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis is a pauci-immune disease with the inflammation of the small blood vessels. The efficacies of antibody drugs for induction therapies of vasculitis vary among cases. Here, we developed a novel clone of a single chain Fv region (ScFv) with vasculitis-specific therapeutic potential. Materials and methods: The clone, termed VasSF, was selected from our Escherichia coli expression library of recombinant human ScFv based on the therapeutic efficacy in an SCG/ Kj mouse model of MPO-ANCA-associated vasculitis (MAAV), such as improvement of the urinary score and decreased crescent formation in glomeruli, granulomatous in lung, MPO-ANCA biomarkers, the anti-moesin antibody, and some cytokine levels. Results: We identified vasculitis-associated apolipoprotein A-II (VAP2) as a target molecule of the clone and confirmed the independently-established VAP2 antibodies were also therapeutic in SCG/Kj mice. In MAAV, MPO-ANCA and cytokines stimulate neutrophils by facilitating heterodimer formation of VAP2 with apolipoprotein A-I in HDL. Conclusion: VasSF would constitute a novel antibody drug for vasculitis by suppressing the heterodimer formation of the apolipoproteins.

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Section: Discussionmentioning

confidence: 99%

<p>Efficacy of a recombinant single-chain fragment variable region, VasSF, as a new drug for vasculitis</p>

Kameoka¹,

Kishi²,

Koura

et al. 2019

DDDT

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“…It has been reported that SCG/Kj mice have urinary abnormalities, crescent formation and increase in MPO–ANCA titers . Therefore, we first monitored urinary protein and hemoglobin in SCG/Kj mice from 5 to 14 weeks of age.…”

Section: Resultsmentioning

confidence: 99%

“…Because it has been reported that a spleen T cell subset expressing both CD3 and B220 in SCG/Kj and MRL/ lpr mice is caused by Fas mutation and leads to a defect in Fas‐mediated apoptosis, we further examined changes in the population of the CD3 + B220 + T cell subset with aging. FACS analysis of splenocytes showed that CD3 + B220 + T cells were rarely present in control C57BL/6 mice but their numbers were increased in SCG/Kj mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Correlation of interleukin‐6 and monocyte chemotactic protein‐1 concentrations with crescent formation and myeloperoxidase‐specific anti‐neutrophil cytoplasmic antibody titer in SCG/Kj mice by treatment with anti‐interleukin‐6 receptor antibody or mizoribine

Nagao

Kusunoki

Iwamura

et al. 2013

Microbiology and Immunology

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Myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) is associated with rapidly progressive glomerulonephritis (RPGN) and glomerular crescent formation. Pathogenic factors in RPGN were analyzed by using SCG/Kj mice, which spontaneously develop MPO-ANCA-associated RPGN. The serum concentration of soluble IL-6R was determined by using ELISA and those of another 23 cytokines and chemokines by Bio-Plex analysis. Sections of frozen kidney tissue were examined by fluorescence microscopy and the CD3 þ B220 þ T cell subset in the spleen determined by a flow cytometry. Concentrations of IL-6 and monocyte chemotactic protein-1 were significantly correlated with the percentages of crescent formation. Anti-IL-6R antibody, which has been effective in patients with rheumatoid arthritis, was administered to SCG/Kj mice to elucidate the role of IL-6 in the development of RPGN. MPO-ANCA titers decreased after administration of anti-IL-6R antibody, but not titers of mizoribine, which is effective in Kawasaki disease model mice. These results suggest that IL-6-mediated signaling is involved in the production of MPO-ANCA.

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“…Multiple genetic associations with MPO-ANCA development in SCG/Kj mice have been defined (141). This model has also been used to investigate possible treatments for ANCA-associated GN, including 15-deoxyspergualin (142,143) and omega-3 fatty acid eicosapentaenoic acid (EPA) (144). Dendritic cell transfer studies have implicated NETs in the development of autoimmunity to MPO and PR3 (59).…”

Section: Animalmentioning

confidence: 99%

Animal Models of ANCA Associated Vasculitis

2020

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Reduction of MPO-ANCA epitopes in SCG/Kj mice by 15-deoxyspergualin treatment restricted by IgG2b associated with crescentic glomerulonephritis

Abstract: These results strongly suggest that DSG treatment of SCG/Kj mice leads to the reduction of risk antibodies in IgG2b and normalization of B-cell clones accompanied by recovery of the cytokine and chemokine balance.

Cited by 9 publications

References 40 publications

<p>Efficacy of a recombinant single-chain fragment variable region, VasSF, as a new drug for vasculitis</p>

<p>Efficacy of a recombinant single-chain fragment variable region, VasSF, as a new drug for vasculitis</p>

Correlation of interleukin‐6 and monocyte chemotactic protein‐1 concentrations with crescent formation and myeloperoxidase‐specific anti‐neutrophil cytoplasmic antibody titer in SCG/Kj mice by treatment with anti‐interleukin‐6 receptor antibody or mizoribine

Animal Models of ANCA Associated Vasculitis

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