Therapy targeting folate receptor beta expressing macrophages in chronic inflammation

• Project/Area Number: 23591441
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kagoshima University
• Principal Investigator: MATSUYAMA Takami 鹿児島大学, 医歯(薬)学総合研究科, 教授 (30145479)
• Co-Investigator(Kenkyū-buntansha): NAGAI Taku 鹿児島大学, 医歯学総合研究科, 講師 (90363647)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 葉酸リセプター / イムノトキシン / 国際情報交換 / 抗体 / アメリカ合衆国 / マクロファージ

Research Abstract

We assessed the antiarthrogenic and the antifibrotic effects ofdepletion of FRbeta-expressing macrophages in methylated BSA induced arthritis and bleomycin induced skin fibrosis models using a recombinant immunotoxin to FRbeta, respectively. Skin fibrosis was evaluated by the change of skin thickness and hydroxyproline content on Day 29. The TGFbeta1 mRNA levels in the treated skin were assessed by quantitative real-time RT-PCR on Day 9. Anti-FRbeta-PE38 treatment led to a dramatic reduction in the number of FRbeta-expressing macrophages. Additionally, skin thickness and hydroxyproline content, were markedly reduced. TGFbeta1 mRNA levels were also down-regulated after the treatment. TGFbeta1 expression was enriched in FRbeta-expressing macrophages compared with FRbeta-negative macrophages. Anti-FRbeta-PE38 treatment efficiently depleted FRbeta-expressing macrophages and consequently alleviated BLM-induced skin fibrosis.

Research Products

• [Journal Article] Depletion of folate receptorβ-expressing macrophages alleviates bleomycin-induced experimental skin fibrosis (2014)
  • Author(s): Hua Li, Taku Nagai, Kazuhisa Hasui, Takami Matsuyama
  • Journal Title: Modern Rheumatology Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Macrophage uptake and accumulation of folates is polarization-dependent in vitro and in vivo, and is regulated by activin A (2014)
  • Author(s): Rafael Samaniego, Blanca Soler Palacios, Angeles Dominguez-Soto, Carlos Vidal, Azucena Salas, Takami Matsuyama, Carmen Sanchez-Torres, Inmaculada de la Torre, Maria Eugenia Miranda-Carus,Paloma Sanchez-Mateos, and Amaya Puig-Kruger
  • Journal Title: Journal of Leukocyte Biology Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Depletion of folate receptor β-expressing macrophages alleviates bleomycin-induced experimental skin fibrosis. (2014)
  • Author(s): Li H, Nagai T, Hasui K, Matsuyama T.
  • Journal Title: Modern Rheumatology Volume: in press
  • Peer Reviewed
• [Journal Article] Macrophage uptake and accumulation of folates are polarization-dependent in vitro and in vivo and are regulated by activin A. (2014)
  • Author(s): Samaniego R, Palacios BS, Domiguez-Soto A, Vidal C, Salas A, Matsuyama T, Sanchez-Torres C, de la Torre I, Miranda-Caros ME, Sanchez-Mateos P, Puig-Kruger A.
  • Journal Title: J Leukoc Biol. Volume: in press
  • Peer Reviewed
• [Journal Article] Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles (2012)
  • Author(s): Tsuneyoshi Y, Tanaka M, Nagai T, Sunahara N, Matsuda T, Sonoda T, Ijiri K, Komiya S, Matsuyama T
  • Journal Title: Scand J Rheumatol Volume: 41(2) Pages: 132-40
  • Peer Reviewed
• [Journal Article] Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis (2012)
  • Author(s): Nagai T, Kyo A, Hasui K, Takao S, Matsuyama T
  • Journal Title: Arthritis research & therapy Volume: 14(3)
  • Peer Reviewed
• [Journal Article] Novel Therapy for Atherosclerosis Using Recombinant Immunotoxin Against Folate Receptorβ―expressing Macrophages (2012)
  • Author(s): Furusho Y, Miyata M, Matsuyama T, Nagai T, Akasaki Y, Hamada N, Miyauchi T, Ikeda Y, Shirasawa T, Ide K, Tei C
  • Journal Title: Journal of the American Heart Association Volume: 1(4)
  • Peer Reviewed
• [Journal Article] The Prolyl Hydroxylase PHD3 Identifies Q :1; 2; 3 Proinflammatory Macrophages and its Expression Is Regulated by Activin A (2012)
  • Author(s): Mar´ıa M. Escribese, Elena Sierra-Filardi, Concha Nieto, Rafa Samaniego,†Carmen Sa´nchez-Torres,‡Takami Matsuyama, Elisabeth Calderon-Go´mez, Miguel A. Vega, Azucena Salas,Paloma Sa´nchez-Mateos, and Angel L. Corbı
  • Journal Title: J Immunol Volume: 189(4) Pages: 1946-54
  • Peer Reviewed
• [Journal Article] Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis. (2012)
  • Author(s): Nagai T, Kyo A, Hasui K, Takao S, Matsuyama T.
  • Journal Title: Arthritis Res Ther. 2012 Volume: １４
  • Peer Reviewed
• [Journal Article] The prolyl hydroxylase PHD3 identifies proinflammatory macrophages and its expression is regulated by activin A. (2012)
  • Author(s): Escribese MM, Sierra-Filardi E, Nieto C, Samaniego R, Sánchez-Torres C, Matsuyama T, Calderon-Gómez E, Vega MA, Salas A, Sánchez-Mateos P, Corbí AL.
  • Journal Title: J Immunol. Volume: １８９ Pages: 1946-54
  • Peer Reviewed
• [Journal Article] Novel Therapy for Atherosclerosis Using Recombinant Immunotoxin Against Folate Receptor β-Expressing Macrophages. (2012)
  • Author(s): Furusho Y, Miyata M, Matsuyama T, Nagai T, Li H, Akasaki Y, Hamada N, Miyauchi T, Ikeda Y, Shirasawa T, Ide K, Tei C.
  • Journal Title: J Am Heart Assoc. Volume: １（４）
  • Peer Reviewed
• [Journal Article] Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles. (2012)
  • Author(s): Tsuneyoshi Y, Tanaka M, Nagai T, Sunahara N, Matsuda T, Sonoda T, Ijiri K, Komiya S, Matsuyama T.
  • Journal Title: Scand J Rheumatol. Volume: ４１（２） Pages: 132-40
• [Presentation] 葉酸リセプターβ発現マクロファージを標的とした強皮症モデルの治療に関する研究 (2013)
  • Author(s): 李花、永井拓、松山隆美
  • Organizer: 第57回日本リウマチ学会
  • Place of Presentation: 横浜
  • Year and Date: 2013-04-19
• [Presentation] The detection of a soluble folate receptor beta in rheumatoid arthritis under anti-TNF therapy (2013)
  • Author(s): 永井拓、大坪秀雄、李花、松田剛正、松山隆美
  • Organizer: 第57回日本リウマチ学会
  • Place of Presentation: 横浜
  • Year and Date: 2013-04-19
• [Presentation] Targeting FR-b-expressing macrophages in inflammatory diseases (2012)
  • Author(s): 松山隆美
  • Organizer: 第4回葉酸リセプターとトランスポーターシンポジウム
  • Place of Presentation: メキシコ
  • Year and Date: 2012-10-09
• [Presentation] Immunotherapy of antigen-induced rat arthritis with an anti-folate receptor beta Recombinant immunotoxin (2012)
  • Author(s): Taku Nagai, Nobuhiko Sunahara, Takemasa Matsuda, Takami Matsuyama
  • Organizer: 第56回日本リウマチ学会
  • Place of Presentation: 京都
  • Year and Date: 2012-04-27
• [Patent(Industrial Property Rights)] 強皮症治療剤 (2013)
  • Inventor(s): 松山隆美、李花、永井拓
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-054090
  • Filing Date: 2013-03-15
  • Overseas
• [Patent(Industrial Property Rights)] 軟骨又は骨の破壊の診断薬 (2012)
  • Inventor(s): 松山隆美、永井拓
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-241968
  • Filing Date: 2012-11-01
  • Overseas
• [Patent(Industrial Property Rights)] 葉酸リセプターα及びβを認識する抗体 (2012)
  • Inventor(s): 松山隆美、永井拓、蓮井和久、高尾尊身
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-281525
  • Filing Date: 2012-12-25
  • Overseas
• [Patent(Industrial Property Rights)] リコンビナント抗葉酸受容体-βイムノトキシンによる強皮症の治療 (2012)
  • Inventor(s): 李花、松山隆美、永井拓、蓮井和久
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-281525
  • Filing Date: 2012-12-25