Medium-to-small vessel vasculitis induced by NKT cells that react with vascular endothelial cells

• Project/Area Number: 24659171
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Experimental pathology
• Research Institution: Hokkaido University
• Principal Investigator: ISHIZU Akihiro 北海道大学, 保健科学研究院, 教授 (60321957)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 血管炎 / 血管内皮細胞 / 自己免疫 / NKT細胞 / 自己反応性

Research Abstract

A T cell clone reactive with rat vascular endothelial cells (REC) was established from the rat model of medium-to-small vessel vasculitis and named VASC-1. Intravenous injection of VASC-1 induced small vessel vasculitis (SVV) in normal recipients. After interaction with REC, several cytokines were produced from VASC-1, which was inhibited by blocking of CD1d on the REC surface. The collective findings indicated VASC-1 as an NKT cell clone. NKT cells are classified into type I and II. Type I NKT cells are characterized by expression of semi-invariant TCRs and potential to bind to marine sponge-derived alpha-galactosylceramide (a-GalCer) loaded on CD1d; whereas, type II NKT cells do not manifest the characteristics. VASC-1 exhibited a usage of TCR other than the type I invariant TCR and did not bind to a-GalCer-loaded CD1d; therefore, it was regarded as a type II NKT cell clone. These evidences suggested that REC-reactive type II NKT cells could be involved in the pathogenesis of SVV.

Research Products

• [Journal Article] Enhanced formation and disordered regulation of NETs in MPO-ANCA-associated microscopic polyangiitis (2014)
  • Author(s): Nakazawa D, Shida H, Tomaru U, Yoshida M, Nishio S, Atsumi T, Ishizu A.
  • Journal Title: Journal of the American Society of Nephrology Volume: Epub Issue: 5 Pages: 990-997
  • DOI: 10.1681/asn.2013060606
  • Peer Reviewed / Open Access
• [Journal Article] Ag and IL-2 immune complexes efficiently expand Ag-specific Treg cells that migrate in response to chemokines and reduce localized immune responses. (2014)
  • Author(s): Hamano R, Baba T, Sasaki S, Tomaru U, Ishizu A, Kawano M, Yamagishi M, Mukaida N
  • Journal Title: Eur J Immunol Volume: 44 Issue: 4 Pages: 1005-1015
  • DOI: 10.1002/eji.201343434
  • Peer Reviewed / Open Access
• [Journal Article] Possible linkage between microscopic polyangiitis and thrombosis via neutrophil extracellular traps (2014)
  • Author(s): Imamoto T, Nakazawa D, Shida H, Suzuki A, Otsuka N, Tomaru U, Ishizu A.
  • Journal Title: Clin Exp Rheumatol Volume: 32(1) Pages: 149-150
  • NAID: 120005397871
  • URL: http://www.clinexprheumatol.org/pubmed/find-pii.asp?pii=24321560
  • Peer Reviewed
• [Journal Article] Possible linkage between microscopic polyangiitis and thrombosis via neutrophil extracellular traps. (2014)
  • Author(s): Imamoto T, Nakazawa D, Shida H, Suzuki A, Otsuka N, Tomaru U, Ishizu A
  • Journal Title: Clin Exp Rheumatol Volume: 32 Pages: 149-150
  • NAID: 120005397871
  • Peer Reviewed
• [Journal Article] Treatment for cutaneous arteritis patients with mononeuritis multiplex and elevated C-reactive protein. (2013)
  • Author(s): Kawakami T, Okudaira A, Okano T, Takeuchi S, Kimura S, Soma Y, Ishizu A, Arimura Y, Kobayashi S, Ozaki S
  • Journal Title: J Dermatol Volume: 40 Issue: 12 Pages: 955-961
  • DOI: 10.1111/1346-8138.12303
  • Peer Reviewed
• [Journal Article] Possible implication of disordered neutrophil extracellular traps in the pathogenesis of MPO-ANCA-associated vasculitis. (2013)
  • Author(s): Nakazawa D, Tomaru U, Ishizu A
  • Journal Title: Clin Exp Nephrol Volume: 17 Issue: 5 Pages: 631-633
  • DOI: 10.1007/s10157-012-0738-8
  • NAID: 120005372301
  • Peer Reviewed
• [Journal Article] Possible implication of Fcγ receptor-mediated trogocytosis in susceptibility to systemic autoimmune disease. (2013)
  • Author(s): Masuda S, Iwasaki S, Tomaru U, Baba T, Katsumata K, Ishizu A
  • Journal Title: Clin Dev Immunol Volume: 2013 Pages: 345745-345745
  • DOI: 10.1155/2013/345745
  • Peer Reviewed
• [Journal Article] Lysosomal-associated membrane protein-2 plays an important role in the pathogenesis of primary cutaneous vasculitis. (2013)
  • Author(s): Takeuchi S, Kimura S, Soma Y, Waki M, Yamaguchi M, Nakazawa D, Tomaru U, Ishizu A, Kawakami T
  • Journal Title: Rheumatology Volume: 52 Issue: 9 Pages: 1592-1598
  • DOI: 10.1093/rheumatology/ket159
  • Peer Reviewed
• [Journal Article] Prediction of response to treatment by gene expression profiling of peripheral blood in patients with microscopic polyangiitis. (2013)
  • Author(s): Ishizu A, Tomaru U, Murai T, Yamamoto T, Atsumi T, Yoshiki T, Yumura W, Yamagata K, Yamada H, Kumagai S, Kurokawa MS, Suka M, Makino H, Ozaki S.
  • Journal Title: PLOS ONE Volume: 8 Issue: 5 Pages: e63182-e63182
  • DOI: 10.1371/journal.pone.0063182
  • Peer Reviewed
• [Journal Article] Serum Anti-lysosomal-associated membrane protein-2 antibody levels in cutaneous polyarteritis nodosa (2013)
  • Author(s): Kawakami T, Ishizu A, Arimura Y, Soma Y.
  • Journal Title: Acta Derm Venereol Volume: 93(1) Issue: 1 Pages: 70-73
  • DOI: 10.2340/00015555-1418
  • Peer Reviewed
• [Journal Article] 血管炎症候群 : 抗好中球細胞質抗体 (2013)
  • Author(s): 石津明洋
  • Journal Title: 分子リウマチ治療 Volume: 6(4) Pages: 209-213
• [Journal Article] 血管炎の予後は予測できるか-予後因子探索の道- (2013)
  • Author(s): 石津明洋,外丸詩野,村井太一,山本智宏,吉木敬
  • Journal Title: 分子リウマチ治療 Volume: 6(2) Pages: 82-86
• [Journal Article] プロピルチオウラシルとNETsの異常形成・分解異常 (2013)
  • Author(s): 中沢大悟,外丸詩野,西尾妙織,渥美達也,石津明洋
  • Journal Title: 日本臨床71増刊号「血管炎」 Pages: 244-249
• [Journal Article] 自己反応性NKT細胞と血管炎 (2013)
  • Author(s): 飯沼千景,脇雅,山口まどか,外丸詩野,石津明洋
  • Journal Title: 日本臨床71増刊号「血管炎」 Pages: 502-505
• [Journal Article] Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation. (2013)
  • Author(s): Fukaya S
  • Journal Title: Lab Invest. Volume: 93 Issue: 1 Pages: 72-80
  • DOI: 10.1038/labinvest.2012.153
  • Peer Reviewed
• [Journal Article] Abnormal conformation and impaired degradation of NETs induced by propylthiouracil: Implication of disordered NETs in MPO-ANCA-associated vasculitis (2012)
  • Author(s): Nakazawa, D., Tomaru, U., Suzuki, A., Hasegawa, R., Kobayashi, T., Nishio, S., Kasahara, M. and Ishizu, A
  • Journal Title: Arthritis Rheum Volume: 64(11) Issue: 11 Pages: 3779-3787
  • DOI: 10.1002/art.34619
  • Peer Reviewed
• [Journal Article] Abundant neutrophil extracellular traps in thrombus of patient with microscopic polyangiitis (2012)
  • Author(s): Nakazawa, D., Tomaru, U., Yamamoto, C., Jodo, S., Ishizu, A
  • Journal Title: Front Immunol Volume: 3 Pages: 333-333
  • DOI: 10.3389/fimmu.2012.00333
  • NAID: 120005372303
  • Peer Reviewed
• [Journal Article] Pathogenesis of Vasculitis in env-pX Rats (2012)
  • Author(s): Ishizu A, Yoshiki T.
  • Journal Title: Annals of Vascular Diseases Volume: 5 Issue: 3 Pages: 296-299
  • DOI: 10.3400/avd.ra.12.00063
  • NAID: 130004487963
  • ISSN: 1881-641X, 1881-6428
  • Peer Reviewed
• [Journal Article] Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities (2012)
  • Author(s): Tomaru U, Takahashi S, Ishizu A, Miyatake Y, Gohda A, Suzuki S, Ono A, Ohara J, Baba T, Murata S, Tanaka K, Kasahara M
  • Journal Title: Am.J.Pathol. Volume: 180 Issue: 3 Pages: 963-972
  • DOI: 10.1016/j.ajpath.2011.11.012
  • Peer Reviewed
• [Journal Article] Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirp α+dendritic cells :a murine model (2012)
  • Author(s): Baba, T., Badr Mel, S., Tomaru, U., Ishizu, A., Mukaida, N
  • Journal Title: PLoS ONE Volume: 7(7) Issue: 7 Pages: e41154-e41154
  • DOI: 10.1371/journal.pone.0041154
  • NAID: 120004419373
  • Peer Reviewed
• [Journal Article] Decrease of peripheral and intestinal NKG2A-positive T cells in patients with ulcerative colitis (2012)
  • Author(s): Katsurada, T., Kobayashi, W., Tomaru, U.,Baba, T., Furukawa, S., Ishizu, A., Takeda, K., Sakamoto, N., Asaka, M., Takeda, H. and Kasahara, M
  • Journal Title: PLoS ONE7 Volume: (9) Issue: 9 Pages: e44113-e44113
  • DOI: 10.1371/journal.pone.0044113
  • Peer Reviewed
• [Journal Article] Mechanism of Fc γreceptor-mediated trogocytosis-based false-positive results in flow cytometry (2012)
  • Author(s): Masuda, S., Iwasaki, S., Tomaru, U., Sato, J., Kawakami, A., Ichijo, K., Sogo, S., Baba, T.,Katsumata, K., Kasahara, M. and Ishizu, A
  • Journal Title: PLoS ONE Volume: 7(12) Issue: 12 Pages: e52918-e52918
  • DOI: 10.1371/journal.pone.0052918
  • NAID: 120005183187
  • Peer Reviewed
• [Journal Article] Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis : the JMAAV study (2011)
  • Author(s): Ozaki S, Atsumi T, Hayashi T, Ishizu A, Kobayashi S, Kumagai S, Kurihara Y, Kurokawa M, Makino H, Nagafuchi H, Nakabayashi K, Nishimoto N, Suka M, Tomino Y, Yamada H, Yamagata K, Yoshida M, Yumura W
  • Journal Title: Mod Rheumatol Volume: (Epub ahead of print) Issue: 3 Pages: 394-404
  • DOI: 10.1007/s10165-011-0525-5
  • NAID: 10030782228
  • Peer Reviewed
• [Presentation] High induction and low degradation abilities on neutrophil extracellular traps of sera in patients with MPO-ANCA-associated vasculitis (2013)
  • Author(s): Nakazawa D, Tomaru U, Yoshida M, Nishio S, Shida H, Atsumi T, Ishizu A.
  • Organizer: ASN 2013
  • Place of Presentation: Atlanta, GA, USA
• [Presentation] 好中球細胞外トラップ(NETs)の異常とMPO-ANCA関連血管炎の発症 (2013)
  • Author(s): 中沢大悟,外丸詩野,西尾妙織,渥美達也,笠原正典,石津明洋
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 自己血管内皮細胞反応性NKT細胞による血管炎発症モデル (2013)
  • Author(s): 川上愛,飯沼千景,脇雅,山口まどか,外丸詩野,笠原正典,吉木敬,石津明洋
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 顕微鏡的多発血管炎と血栓症はMPO-ANCAと好中球細胞外トラップを介して関連する (2013)
  • Author(s): 今本鉄平,中沢大悟,大塚紀幸,外丸詩野,笠原正典,石津明洋
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] リツキシマブ投与後に日和見感染を併発した顕微鏡的多発血管炎の一剖検例 (2013)
  • Author(s): 味藤静,外丸詩野,大塚紀幸,石津明洋,笠原正典
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 顕微鏡的多発血管炎(MPA)患者に合併した深部静脈血栓における過剰なNETs形成 (2013)
  • Author(s): 中沢大悟,外丸詩野,浄土智,渥美達也,石津明洋
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] Implication of vascular endothelial cell-reactive NKT cells in pathogenesis of small vessel vasculitis in rats (2013)
  • Author(s): Ishizu A, Tomaru U, Iinuma C, Waki M, Kawakami A, Sasaki N, Yoshiki T.
  • Organizer: 16^<th> International Vasculitis and ANCA Workshop
  • Place of Presentation: Paris, France
• [Presentation] Prediction of outcome of treatment by gene expression profiling of peripheral blood in patients with microscopic polyangiitis (2013)
  • Author(s): Ishizu A, Tomaru U, Murai T, Yamamoto T, Atsumi T, Yoshiki T.
  • Organizer: 16^<th> International Vasculitis and ANCA Workshop
  • Place of Presentation: Paris, France
• [Presentation] Abundant neutrophil extracellular traps in thrombus of patient with microscopic polyangiitis (2013)
  • Author(s): Nakazawa D, Tomaru U, Jodo S, Nishio S, Atsumi T, Ishizu A.
  • Organizer: 16^<th> International Vasculitis and ANCA Workshop
  • Place of Presentation: Paris, France
• [Presentation] 顕微鏡的多発血管炎（MPA）患者に合併した深部静脈血栓における過剰なNETs形成 (2013)
  • Author(s): 中沢大悟，外丸詩野，浄土 智，渥美達也，石津明洋
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都国際会館（京都市）
• [Presentation] 好中球細胞外トラップ（NETs）の異常とMPO-ANCA関連血管炎の発症 (2013)
  • Author(s): 中沢大悟，外丸詩野，西尾妙織，渥美達也，笠原正典，石津明洋
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館（札幌市）
• [Presentation] 自己血管内皮細胞反応性NKT細胞による血管炎発症モデル (2013)
  • Author(s): 川上 愛，飯沼千景，脇 雅，山口まどか，外丸詩野，笠原正典，吉木 敬，石津明洋
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館（札幌市）
• [Presentation] 顕微鏡的多発血管炎と血栓症はMPO-ANCAと好中球細胞外トラップを介して関連する (2013)
  • Author(s): 今本鉄平，中沢大悟，大塚紀幸，外丸詩野，笠原正典，石津明洋
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館（札幌市）
• [Presentation] リツキシマブ投与後に日和見感染を併発した顕微鏡的多発血管炎の一剖検例 (2013)
  • Author(s): 味藤 静，外丸詩野，大塚紀幸，石津明洋，笠原正典
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館（札幌市）
• [Presentation] Establishment of NKT cell clone from vasculitis-prone rats, which recognizes autoantigen but not alpha-galactosylceramide presented by CD1d. (2013)
  • Author(s): Kawakami A, Iinuma C, Waki M, Yamaguchi M, Tomaru U, Kasahara M, Ishizu A
  • Organizer: 第42回日本免疫学会総会・学術集会
  • Place of Presentation: 幕張メッセ（千葉市）
• [Presentation] Implication of vascular endothelial cell-reactive invariant NKT cells in pathogenesis of small vessel vasculitis in rats (2013)
  • Author(s): Ishizu A et al.
  • Organizer: 16th International Vasculitis and ANCA Workshop
  • Place of Presentation: Institut des Cordeliers in Paris（フランス）
• [Presentation] Prediction of outcome of treatment by gene expression profiling of peripheral blood in patients with microscopic polyangiitis (2013)
  • Author(s): Ishizu A et al.
  • Organizer: 16th International Vasculitis and ANCA Workshop
  • Place of Presentation: Institut des Cordeliers in Paris（フランス）
• [Presentation] Abundant neutrophil extracellular traps (NETs) in thrombus of patient with MPO-ANCA associated vasculitis (MPO-AAV) (2013)
  • Author(s): Nakazawa D et al.
  • Organizer: 16th International Vasculitis and ANCA Workshop
  • Place of Presentation: Institut des Cordeliers in Paris（フランス）
• [Presentation] 血管炎の新分類と新たな発症メカニズムの提唱 (2012)
  • Author(s): 石津明洋
  • Organizer: 第9回日本病理学会カンファレンス
  • Place of Presentation: 山口
  • Year and Date: 2012-08-07
• [Presentation] Establishment of NKT cell clone from vasculitis-prone rats, which recognizes autoantigen but notα-galactosylceramide presented by CD1d (2012)
  • Author(s): Kawakami A, Iinuma C, Waki M, Yamaguchi M, Tomaru U, Kasahara M, Ishizu A.
  • Organizer: 第42回日本免疫学会総会・学術集会
  • Place of Presentation: 千葉
• [Presentation] Abnormal conformation and impaired degradation of neutrophil extracellular traps (NETs) induced by propylthiouracil (PTU) : Implication of disordered NETs in MPO-ANCA-associated vasculitis (MPO-AAV) (2012)
  • Author(s): Nakazawa D, Tomaru U, Nishio S, Atsumi T, Kasahara M, Ishizu A.
  • Organizer: 第41回日本免疫学会総会・学術集会
  • Place of Presentation: 神戸
• [Presentation] 自己血管内皮細胞反応性NKT細胞による血管炎発症モデル (2012)
  • Author(s): 石津明洋,外丸詩野,吉木敬
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] プロピルチオウラシルによるNETs (neutrophil extracellular traps)の形成および分解障害とMPO-ANCAの産生 : MPO-ANCA関連血管炎の発症機序 (2012)
  • Author(s): 中沢大悟,外丸詩野,石津明洋
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] 皮膚型結節性多発動脈炎における血中抗LAMP-2抗体は上昇している (2012)
  • Author(s): 川上民裕,石津明洋,有村義宏
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] Autoreactive NKT cell-mediated small vessel vasculitis in rats (2012)
  • Author(s): Ishizu A.
  • Organizer: The Asia Pacific Meeting of Vasculitis and ANCA Workshop 2012
  • Place of Presentation: Shinagawa, Tokyo, Japan
• [Presentation] Prediction of prognosis by gene expression profiling of peripheral blood in Japanese patients with MPO-ANCA-associated vasculitis after standard treatment : JMAAV subanalysis (2012)
  • Author(s): Ishizu A, Tomaru U, Murai T, Yamamoto T, Yoshiki T, Yumura W, Yamagata K, Yamada H, Kumagai S, Kurokawa MS, Suka M, Makino H, Ozaki S.
  • Organizer: The Asia Pacific Meeting of Vasculitis and ANCA Workshop 2012
  • Place of Presentation: Shinagawa, Tokyo, Japan
• [Presentation] Abnormal formation and impaired degradation of neutrophil extracellular traps induced by propylthiouracil are implicated in the pathogenesis of MPO-ANCA-associated vasculitis (2012)
  • Author(s): Nakazawa D, Nishio S, Shibasaki S, Tomaru U, Kasahara M, Ishizu A.
  • Organizer: The Asia Pacific Meeting of Vasculitis and ANCA Workshop 2012
  • Place of Presentation: Shinagawa, Tokyo, Japan
• [Presentation] The presence of anti-LAMP-2 antibody induces cutaneous vasculitis of rats (2012)
  • Author(s): Takeuchi S, Soma Y, Waki M, Yamaguchi M, Nakazawa D, Tomaru U, Ishizu A.
  • Organizer: The Asia Pacific Meeting of Vasculitis and ANCA Workshop 2012
  • Place of Presentation: Shinagawa, Tokyo, Japan
• [Presentation] 自己血管内皮細胞反応性NKT細胞による血管炎発症モデル (2012)
  • Author(s): 石津明洋ほか
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都）
• [Presentation] プロピルチオウラシルによるNETs (neutrophil extracellular traps)の形成および分解障害とMPO-ANCAの産生：MPO-ANCA関連血管炎の発症機序 (2012)
  • Author(s): 中沢大悟ほか
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都）
• [Presentation] 皮膚型結節性多発動脈炎における血中抗LAMP-2抗体は上昇している (2012)
  • Author(s): 川上民裕ほか
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都）
• [Presentation] 血管炎の新分類と新たな発症メカニズムの提唱 (2012)
  • Author(s): 石津明洋
  • Organizer: 第9回日本病理学会カンファレンス
  • Place of Presentation: ホテルニュータナカ（山口市）
  • Invited
• [Remarks] 北海道大学学術成果コレクション(HUSCAP)
  • URL: http://hdl.handle.net/2115/54623
• [Remarks]
  • URL: http://hdl.handle.net/2115/54630
• [Remarks]
  • URL: http://hdl.handle.net/2115/54674
• [Remarks]
  • URL: http://hdl.handle.net/2115/54864
• [Remarks] 北海道大学学術成果コレクション（HUSCAP）
  • URL: http://hdl.handle.net/2115/54623
• [Remarks] 北海道大学学術成果コレクション（HUSCAP）
  • URL: http://hdl.handle.net/2115/54630
• [Remarks] 北海道大学学術成果コレクション（HUSCAP）
  • URL: http://hdl.handle.net/2115/54674
• [Remarks] 北海道大学学術成果コレクション（HUSCAP）
  • URL: http://hdl.handle.net/2115/54864