The difference of immune modification in rheumatoid arthritis patients between IL-6 blockade with tocilizumab and T cell inactivation with abatacept

• Project/Area Number: 25461481
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Tokyo Medical University
• Principal Investigator: MURAKAMI Miho 東京医科大学, 医学部, 助教(特任) (30595591)
• Co-Investigator(Kenkyū-buntansha): NISHIMOTO Norihiro 東京医科大学, 医学部, 兼任教授 (80273663) ; 松谷 隆治 和歌山県立医科大学, 医学部, 講師 (70372290)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 関節リウマチ / interleukin-6 / トシリズマブ / T細胞 / B細胞 / サイトカイン / CD4 / CD25 / Interleukin-6 / Ｔ細胞 / アバタセプト

Outline of Final Research Achievements

Tocilizmab (TCZ) is a humanized anti-human IL-6 receptor antibody. We investigated whether IL-6 blockade with TCZ decreases the proportion of CD25+CD4+ T cells in ACPA positive rheumatoid arthritis (RA) patients. DAS28-ESR and SDAI were significantly reduced at 24 and 48 weeks of TCZ treatment compared with those at baseline. The proportion of CD4+ cells was significantly increased at 24 and 48 weeks compared with that at baseline. However, the proportion of CD25+CD4+ cells and that of regulatory T (Treg) cells in CD4+ cells were not significantly changed during TCZ treatment. Meanwhile, abatacept, a biologic blocking T cell co-stimulation, decreased the proportion of CD25+CD4+ T cells but not that of Treg cells in CD4+ cells in ACPA positive RA patients. In conclusions, IL-6 blockade has therapeutic effects on RA patients. Some other mechanisms, besides a decrease in CD4+ activation or an increase in Treg cell proportion, contribute the therapeutic effect of IL-6 blockade.

Research Products

• [Journal Article] IL-6 阻害薬と関節リウマチの骨・軟骨病変の制御 (2015)
  • Author(s): 村上美帆 西本憲弘
  • Journal Title: CLINICAL CALＣIUM Volume: 25 Pages: 1851-1857
  • Open Access
• [Journal Article] Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab. (2014)
  • Author(s): Tsuru T, Terao K, Murakami M, Matsutani T, Suzaki M, Amamoto T, Nakashima H, Akiyama A, Nishimoto N.
  • Journal Title: Mod Rheumatol. Volume: 24 Issue: 3 Pages: 511-516
  • DOI: 10.3109/14397595.2013.843743
  • Peer Reviewed / Open Access
• [Journal Article] 生物学的製剤：使い方と安全性 トシリズマブ -IV vs SC- (2014)
  • Author(s): 西本憲弘，村上美帆
  • Journal Title: Mebio Volume: 31 Pages: 54-61
• [Journal Article] KSHV関連Castleman病におけるヒトおよびウイルスIL-6の役割 (2014)
  • Author(s): 村上美帆, 西本憲弘
  • Journal Title: 血液内科 Volume: 69 Pages: 449-454
  • NAID: 40020208006
• [Journal Article] Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study. (2014)
  • Author(s): Nishimoto N, Amano K, Hirabayashi Y, Horiuchi T, Ishii T, Iwahashi M, Iwamoto M, Kohsaka H, Kondo M, Matsubara T, Mimura T, Miyahara H, Ohta S, Saeki Y, Saito K, Sano H, Takasugi K, Takeuchi T, Tohma S, Tsuru T, Ueki Y, Yamana J, Hashimoto J, Matsutani T, Murakami M, Takagi N.
  • Journal Title: Mod Rheumatol Volume: 24(1) Issue: 1 Pages: 26-32
  • DOI: 10.3109/14397595.2013.854080
  • Peer Reviewed
• [Journal Article] Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement. (2013)
  • Author(s): Schoels MM, van der Heijde D, Breedveld FC, Burmester GR, Dougados M, Emery P, Ferraccioli G, Gabay C, Gibofsky A, Gomez-Reino JJ, Jones G, Kvien TK, Murakami M, Nishimoto N, Smolen JS.
  • Journal Title: Ann Rheum Dis Volume: 72(4) Issue: 4 Pages: 583-589
  • DOI: 10.1136/annrheumdis-2012-202470
  • Peer Reviewed
• [Journal Article] Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions (2013)
  • Author(s): Smolen JS, Schoels MM, Nishimoto N, Breedveld FC, Burmester GR, Dougados M, Emery P, Ferraccioli G, Gabay C, Gibofsky A, Gomez-Reino JJ, Jones G, Kvien TK, Murakami M, 他21名
  • Journal Title: Ann Rheum Dis Volume: 72(4) Issue: 4 Pages: 482-492
  • DOI: 10.1136/annrheumdis-2012-202469
  • Peer Reviewed
• [Journal Article] Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study. (2013)
  • Author(s): Nishimoto N, Amano K, Hirabayashi Y, Horiuchi T, Ishii T, Iwahashi M, Iwamoto M, Kohsaka H, Kondo M, Matsubara T, Mimura T, Miyahara H, Ohta S, Saeki Y, Saito K, Sano H, Takasugi K, Takeuchi T, Tohma S, Tsuru T, Ueki Y, Yamana J, Hashimoto J, Matsutani T, Murakami M, Takagi N.
  • Journal Title: Mod Rheumatol Volume: 24(1) Issue: 1 Pages: 17-25
  • DOI: 10.3109/14397595.2013.854079
  • Peer Reviewed
• [Journal Article] 炎症性自己免疫疾患における治療標的としてのIL-6 (2013)
  • Author(s): 西本憲弘，村上美帆
  • Journal Title: 日本臨床増刊号「血管炎」 Volume: 71（増刊号1） Pages: 623-629
• [Journal Article] 水銀による自己抗体産生誘導．臨床免疫・アレルギー科 (2013)
  • Author(s): 松谷隆治，村上美帆，西本憲弘
  • Journal Title: 臨床免疫・アレルギー科 Volume: 59（5） Pages: 611-613
• [Journal Article] 成人病発症Still病 (2013)
  • Author(s): 西本憲弘，村上美帆
  • Journal Title: 内科 Volume: 112（1） Pages: 73-76
• [Presentation] IL-6 BLOCKADE WITH TOCILIZUMAB DOES NOT SUPPRESS CD4+T CELL ACTIVATION AT 48 WEEKS OF THE TREATMENT. (2016)
  • Author(s): Miho Murakami, Taro Kuritani, Norihiro Nishimoto
  • Organizer: Annual European Congress of Rheumatology EULAR 2016
  • Place of Presentation: London, UK
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] IL-6阻害治療による関節リウマチ患者のCD25+CD4+活性化T細胞の割合の変化 (2016)
  • Author(s): 村上美帆、栗谷太郎、西本憲弘
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-04-21
• [Presentation] T CELL CD80/CD86 CO-STIMULATORY BLOCKADE EFFECTIVELY SUPPRESSES CD25 (+) IN CD4 (+) T CELL SUBPOPULATION BUT NOT THE ACPA TITERS IN THE COURSE OF 48-WEEK TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS (2014)
  • Author(s): Miho Murakami, Mari Ito, Masahiro Sekiguchi, Kiyoshi Matsui, Masayasu Kitano, Yoshitaka Imura, Koichiro Ohmura, 4Takao Fujii, Takanori Kuroiwa, Keiji Maeda, Satoshi Morita, Yutaka Kawahito, Tsuneyo Mimori, Hajime Sano, Norihiro Nishimoto
  • Organizer: EULAR2014
  • Place of Presentation: Paris, France
  • Year and Date: 2014-06-11 – 2014-06-14
• [Presentation] T CELL CD80/CD86 CO-STIMULATORY BLOCKADE DOES NOT SUPPRESS CD8 (+) SUBPOPULATION IN THE COURSE OF 48-WEEK TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS (2014)
  • Author(s): Miho Murakami, Mari Ito, Masahiro Sekiguchi, Kiyoshi Matsui, Masayasu Kitano, Yoshitaka Imura, Koichiro Ohmura, 4Takao Fujii, Takanori Kuroiwa, Keiji Maeda, Satoshi Morita, Yutaka Kawahito, Tsuneyo Mimori, Hajime Sano, Norihiro Nishimoto
  • Organizer: EULAR2014
  • Place of Presentation: Paris, France
  • Year and Date: 2014-06-11 – 2014-06-14
• [Presentation] RA患者に対するT 細胞共刺激シグナル抑制治療は抗環状シトルリン化ペプチド抗体価を下げない (2014)
  • Author(s): 村上美帆、伊藤眞里、福家有子、關口昌弘、松井聖、北野将康、井村嘉孝、大村浩一郎、藤井隆夫、黒岩孝則、前田恵治、川人豊、三森経世、佐野統、西本憲弘,
  • Organizer: 第５７回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンス新高輪、東京
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] RA 患者に対するT 細胞共刺激シグナル抑制治療はCD8 陽性サブセットには影響しない (2014)
  • Author(s): 伊藤眞里、村上美帆、福家有子、關口昌弘、松井聖、北野将康、井村嘉孝、大村浩一郎、藤井隆夫、黒岩孝則、前田恵治、川人豊、三森経世、佐野統、西本憲弘,
  • Organizer: 第５７回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンス新高輪、東京
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 抗環状シトルリン化ペプチド抗体陽性RA患者におけるT細胞の活性化 (2013)
  • Author(s): 村上美帆、松谷隆治、李穎、關口昌弘、松井聖、北野将康、大村浩一郎、井村嘉孝、 藤井隆夫、黒岩孝則、中原英子、前田恵治、村上孝作、森田智視、川人豊、三森経世、佐野統、西本憲弘
  • Organizer: 第57回日本リウマチ学会総会・学術集会．ポスター
  • Place of Presentation: 京都
• [Presentation] 関節リウマチの治療 生物学的製剤(TNF阻害薬以外) アバタセプト治療は抗環状シトルリン化ペプチド抗体陽性RA患者の活性化T細胞を抑制する (2013)
  • Author(s): 松谷隆治、李頴、村上美帆、關口昌弘、松井聖、北野将康、大村浩一郎、井村嘉孝、藤井隆夫、黒岩孝則、中原英子、前田恵治、村上孝作、川人豊、三森経世、佐野統、西本憲弘
  • Organizer: 第57回日本リウマチ学会総会・学術集会．口頭発表
  • Place of Presentation: 京都
• [Presentation] Comparison Of Pathological Features Of The Lung Lesions Of Systemic IgG4-Related Disease And Multicentric Castleman's Disease (2013)
  • Author(s): Y. Terasaki, S. Ikushima, Y. Ichimura, M. Ujita, Y. Matsuzawa, M. Arita, K. Tomii, Y. Komase, I. Ohwan, T. Kawamura, S. Izumi, M. Murakami, H. Ishimoto, H. Kimura, M. Bando, N. Hada, N. Nishimoto, S. Matsui, T. Ogura.
  • Organizer: American Thoracic Society 2013
  • Place of Presentation: Philadelphia
• [Presentation] Abatacept treatment suppresses T CELL activation in anti-cyclic citrullinated peptide antibody (ACPA) positive RA patients but not in acpa negative RA patients. (2013)
  • Author(s): T. Matsutani, M. Murakami, M. Sekiguchi, K. Matsui, M. Kitano, M. Namiki, K. Ohmura, Y. Imura, T. Fujii , T.Kuroiwa, H. Nakahara, S. Hika, K. Maeda, Y. Nozaki, M. Funauchi, K. Murakami, T. Ikawa, S. Irimajiri, A. Nampei, T. Azuma, T. Sasaki, A. Yokota, S. Morita, Y. Kawahito, T. Mimori, H. Sano, N. Nishimoto．
  • Organizer: EULAR 2013
  • Place of Presentation: Madrid. Spain
• [Presentation] Changes in cytokine profiles in rheumatoid arthritis patients during abatacept treatment. (2013)
  • Author(s): M. Murakami, T. Matsutani, M. Sekiguchi, K. Matsui, M. Kitano, M. Namiki, K. Ohmura, Y. Imura, T. Fujii, T. Kuroiwa, H. Nakahara, S. Higa, K. Maeda, Y. Nozaki, M. Funauchi, K. Murakami, T. Ikawa, S. Irimajiri, A. Nampei, T. Azuma, T. Sasaki, A. Yokota, S. Morita, Y. Kawahito, T. Mimori, H. Sano, N. Nishimoto.
  • Organizer: EULAR 2013
  • Place of Presentation: Madrid. Spain
• [Book] 膠原病・リウマチ・アレルギー研修ノート (2016)
  • Author(s): 村上美帆、西本憲弘、山本一彦 、住友秀次、亀田秀人、保田晋助、寺井千尋 、山崎聡、山岡邦宏、細矢 匡 、原田広顕，奥西勝秀 、 大村浩一郎 、 山本元久，高橋裕樹 、久保智史，田中良哉 、石井智徳 、松下 功、澤井高志、他
  • Total Pages: 574
  • Publisher: 診断と治療社
• [Book] 骨ペディア (2015)
  • Author(s): 西本憲弘、村上美帆、秋山治彦、安倍正博、網塚憲生、飯村忠浩、池川志郎、石井優、石丸大地、井関祥子、伊東昌子、稲田全規、井上大輔、今井祐記、今泉和則、今村健志、岩本潤、宇田川信之、江面陽一、遠藤直人、他
  • Total Pages: 327
  • Publisher: 羊土社
• [Book] 免疫・アレルギー疾患の分子標的と治療薬事典―生物学的製剤、低分子化合物のターゲット分子と作用機序、薬効のすべて (2013)
  • Author(s): 田中良哉編：西本憲弘、村上美帆
  • Total Pages: 375
  • Publisher: 羊土社
• [Book] リウマチ病セミナーXXIV (2013)
  • Author(s): 七川歡次監修：西本憲弘，村上美帆
  • Total Pages: 247
  • Publisher: 永井書店