抗IL-6阻害治療をツールとした炎症性自己免疫疾患の発症機構の解明

2009 Fiscal Year Annual Research Report

• Project/Area Number: 21390299
• Research Institution: Wakayama Medical University
• Principal Investigator: 西本 憲弘 Wakayama Medical University, 医学部, 教授 (80273663)
• Co-Investigator(Kenkyū-buntansha): 安達 康雄 和歌山県立医科大学, 医学部, 博士研究員 (10253882)
• Keywords: IL-6 / DNAマイクロアレイ / バイオインフォーマティクス / 関節リウマチ / 年性特発性関節炎 / 全身性エリテマトーデス / S100タンパク / defensin

Research Abstract

IL-6阻害治療とDNAマイクロアレイによる網羅的遺伝子発現解析、ならびにバイオインフォーマティクスを用いて、関節リウマチ(RA)と若年性特発性関節炎(JIA)の病態解析を行った。その解析から特定された分子についてin vitroにおける機能解析を行った。また全身性エリテマトーデス(SLE)のサイトカインネットワーク異常と細胞機能異常について検討した。
1)サイトカインネットワーク異常の検討:gene ontologyに基づく細胞機能異常を検討した。さらに、各機能カテゴリーに属する異常発現分子のネットワーク解析を行った。
(1)JIAではIL-6阻害治療によりミトコンドリアDNAでコードされた遺伝子発現低下が回復し、ミトコンドリアの修復、複製にかかわるSLC25A4、NRF1、OPA1発現も正常化した。また、アポトーシスに関わるp53、p53AIP、DAPK1、SEMA6は発現が抑制され、アポトーシスの抑制が示唆された。マクロファージ活性化を示すIL-18,IFN-γ,TNFを中心とするネットワークの異常も回復した。
(2)SLEでインターフェロンとTNFのネットワーク異常を明らかにした。SLEにおいてもミトコンドリアの機能異常の存在を見出した。
2)カルシウム結合タンパクS100ファミリーの機能解析:S100A4はRAと多関節型JIAで高発現し、IL-6阻害治療で低下する。S100A4のsiRNAを破骨細胞に導入したところ、分化が抑制された。現在S100A4の遺伝子欠損マウスを作成中であり、関節炎モデルマウスを作製して関節破壊の抑制効果を検討する予定である。
3)抗菌ペプチドであるdefensinα1,α3もIL-6阻害により過剰発現が正常化した。defensinα1,α3に免疫グロブリンFc部位をTagとして付加し、発現を安定化させ、非増殖型アデノウイルスに組み込み、defensin発現ベクターを作製した。現在これらの機能を検討中である。

Research Products

• [Journal Article] Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis-meta-analysis of 6 initial trials and 5 long-term extensions- (2010)
  • Author(s): Nishimoto N, Ito K, Takagi N
  • Journal Title: Mod Rheumatol (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Early administration of IL-6RA does not prevent radiation-induced lung injury in mice. (2010)
  • Author(s): Ogata T, Yamazaki H, Teshima T, Kihara A, Suzumoto Y, Inoue T, Nishimoto N, Matsuura N
  • Journal Title: Radiat Oncol 12 Pages: 401
  • Peer Reviewed
• [Journal Article] DNA microarray analysis of rheumatoid arthritis susceptibility genes identified by genome-wide association studies(GWAS) (2010)
  • Author(s): Sugino H, Lee H, Nishimoto N
  • Journal Title: Arthritis Res Ther 12 Pages: 401
  • Peer Reviewed
• [Journal Article] Interleukin-6 as a therapeutic target in candidate inflammatory diseases (2010)
  • Author(s): Nishimoto N
  • Journal Title: Clin Pharmacol Ther 87 Pages: 483-487
  • Peer Reviewed
• [Journal Article] VEGF targeting in mesotheliomas using an interleukin-6 signal inhibitor based on adenovirus gene delivery (2010)
  • Author(s): Adachi Y, Yoshio-Hoshino N, Aoki C, Nishimoto N
  • Journal Title: Articancer Res (in press)
  • Peer Reviewed
• [Journal Article] Cytokine networks in systemic lupus erythematosus (2010)
  • Author(s): Lee H, Sugino H, Nishimoto N
  • Journal Title: J Biomed Biotechnal (in press)
  • Peer Reviewed
• [Journal Article] Laboratory and febrile features after joint surgery in rheumatoid arthritis patients treated with tocilizumab (2009)
  • Author(s): Hirao M, Hashimoto J, Tsuboi H, Nampei A, Nakahara H, Yoshio N, Mima T, Yoshikawa H, Nishimoto N
  • Journal Title: Ann Rheum Dis 68 Pages: 654-657
  • Peer Reviewed
• [Journal Article] Interaleukin-11 and paired immunoglobulin-like type 2 receptor alpha expression correlates with tha number of joints with active arthritis in systemic juvenile idiopathic arthritis. (2009)
  • Author(s): Mima T, Ishikawa S, Aoki C, Yoshio-Hoshino N, Adachi Y, Imagawa T, Mori M, Tomiita M, Iwata N, Murata T, Miyoshi M, Takei S, Aihara Y, Yokota S, Matsubara K, Nishimoto N
  • Journal Title: Ann Rheum Dis 68 Pages: 286-287
  • Peer Reviewed
• [Journal Article] Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizmab treatment : s report of two cases (2009)
  • Author(s): Fujiwara H, Nishimoto N, Hamano Y, Asanuma N, Miki S, Kasayama S, Suemura M
  • Journal Title: Mod Rheumatol 19 Pages: 64-68
  • Peer Reviewed
• [Journal Article] A case report of a patient with refractory adult-onset Still's disease who successfully treated with Tocilizumab over 6years (2009)
  • Author(s): Nakahara H, Mima T, Hoshino Yoshio-Naoko, Matsushita M, Hashimoto J, Nishimoto N
  • Journal Title: Mod Rheumatol 19 Pages: 69-72
  • Peer Reviewed
• [Journal Article] Study of active controlled tocilizumab monotherapy for rheumatoid artriris patients with an inadequate response to methotrexate(SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy (2009)
  • Author(s): Nishimoto N, Miyasaka N, Yamamloto K, Kawai S, Takeuchi T, Azumi J., Kishimoto T
  • Journal Title: Mod Rheumatol 19 Pages: 12-19
  • Peer Reviewed
• [Journal Article] A combination of biochemical markers of cartilage and bone turnover, radiographic damage and body mass index to predict the progression of joint destruction in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs (2009)
  • Author(s): Hashimoto J, Garnero P, van der Heijde D, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Yoshikawa H, Nishimoto N
  • Journal Title: Mod Rheumatol 19 Pages: 273-282
  • Peer Reviewed
• [Journal Article] Interactions among type I and type II interferon, tumor necrosis factor, and ^[○!R]-estradiol in the regulation of immune response-related gene expressions in systemic lupus erythematosus (2009)
  • Author(s): Lee H, Mima T, Sugino H, Aoki C, Hoshino-N.Y, Matsubara K, Nishimoto N
  • Journal Title: Arthritis Research & Therapy 11R1 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Myonucleus-related properties in soles muscle fibers of mdx Mice.2009 (2009)
  • Author(s): Terada M, Yong Bo Lan, Kawano F, Ohira T, Higo Y, Nakai N, Imaizumi K, Ogura A, Nishimoto N, Adachi Y, Ohira Y
  • Journal Title: Cell Tissues Organs 191 Pages: 248-259
  • Peer Reviewed
• [Journal Article] A case of peripheral neuropathy and skin ulcer in a patient with rheumatoid arthritis after a single infusion of tocilizumab (2009)
  • Author(s): Sugiura F, Kojima T, Oguchi T, Urata S, Yuzawa Y, Sakakibara A, Hayashi H, Nishimoto N, Ishiguro N
  • Journal Title: Mod Rheumatol 19 Pages: 199-203
  • Peer Reviewed
• [Journal Article] Effect of Interleukin-6 Receptor Blockage on Renal Injury in Apolipoprotein E-Deficient Mice (2009)
  • Author(s): Tomiyama-Hanayama M, Rakugi H, Kohara M, Mima T, Adachi Y, Ohishi M, Katsuya T, Hoshida Y, Aozasa K, Ogihara T, Nishimoto N
  • Journal Title: Am J Physiol Renal Physiol 297 Pages: 679-684
  • Peer Reviewed
• [Journal Article] Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis(the STREAM study): evidence of safety and efficacy in a 5-year extension study. (2009)
  • Author(s): Nishimoto N, Miyasaka N, Yamamloto K, Kawai S, Takeuchi T, Azumi J
  • Journal Title: Ann Rheum Dis 68 Pages: 1580-1584
  • Peer Reviewed
• [Journal Article] Specifically modified osteopontin in rheumatoid arthritis fibroblast-like synoviocytes supports interaction with B cells and enhances production of IL-6 (2009)
  • Author(s): Take Y, Nakata K, Hashimoto J, Tsuboi H, Nishimoto N, Ochi T, Yoshikawa H
  • Journal Title: Arthritis Rheum 60 Pages: 3591-3601
  • Peer Reviewed
• [Journal Article] Clinical value of blocking IL-6 receptor. 2009 ;(5) (2009)
  • Author(s): Mima T, Nishimoto N
  • Journal Title: Current Opimion in Rheumatology 21 Pages: 224-230
  • Peer Reviewed
• [Presentation] ApoE欠損マウスの腎障害におけるインターロキシン6受容体阻害の効果 (2090)
  • Author(s): 華山真理, 楽木宏実, 美馬亨, 安達康雄, 勝谷友宏, 小原政治, 青笹克之, 萩原俊男, 西本憲弘
  • Organizer: 第32回日本高血圧学会総会
  • Place of Presentation: 大津プリンスホテル.滋賀
  • Year and Date: 2090-10-02
• [Presentation] Up-regulation of hemophilic cell adhesion-related molecules in peripheral blood may contribute to patho-genesis of rheumatoid arthritis(RA) (2009)
  • Author(s): 李慧敏, 杉野英彦, 安達康雄, 青木千恵子, 西本憲弘
  • Organizer: 第37回日本臨床免疫学会 2-20
  • Place of Presentation: 東京
  • Year and Date: 20091113-20091115
• [Presentation] DNA Microarray Analysis Revealed Abnormal Networks of Immune Response Molecules in Bone Marrow Cells from Patients with Rheumayoid Arthtitis(RA) (2009)
  • Author(s): Lee H, Sugino H, Adachi Y, Ochi T, Nishimoto N
  • Organizer: ACR/ARHP2009
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 20091016-20091023
• [Presentation] About half of S100 cluster genes on chromosome 1q21.1 are up-regulated in patients with rheumatoid arthritis(RA), systemic lupus erythematosus(SLE), polyarticular type juvenile idiopathic (2009)
  • Author(s): Sugino H, Aoki C, Lee H, Adachi Y, Matsubara K, Ochi T, Nishimoto N
  • Organizer: ACR/ARHP2009
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 20091016-20091023
• [Presentation] The peripheral blood genes that account for predictability of clinical response to tocilizumab(TCZ)treatment, corticosteroid dose reduction, and serum IL-6 normalization at week 48 on systemic onset juvenile arthriris(sJIA) (2009)
  • Author(s): Nishimoto N, Kawata Y, Lee H, Aoki C, Sugino H, Imagawa T, Mori M, Tomiita M, Murata T, Miyoshi M, Takei S, Aihara Y, Ochi T, Yokota S
  • Organizer: ACR/ARHP2009
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 20091016-20091023
• [Presentation] Normalisation In Serum IL-6 Levels Is A Good Biomarker For The Patients Who Can Cease The Corticosteroid Without Flare During IL-6 Receptor Inhibition Therapy Whth Tocilizumab (2009)
  • Author(s): Tsuru T, Terao K, Suzuki M, Nakashima H, Akiyama A, Nishimoto N
  • Organizer: EULAR2009
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 20090610-20090613
• [Presentation] Experience with Mycobacterium tuberculosis Infection Reported in the Tocilizumab Worldwide RA Safety Database. (2009)
  • Author(s): Van Vollenhoven RF, Nishimoto N, Yamanaka H, Woodworth T, Schiff MH, Taylor A, Pope JE
  • Organizer: EULAR2009
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 20090610-20090613
• [Presentation] 関節リウマチに対するIL-6阻害治療の効果発現メカリズムと効果予測 (2009)
  • Author(s): 西本憲弘
  • Organizer: 第53回日本リウマチ学会総会・学術集会サテライトシンポジウムS-1
  • Place of Presentation: グランドプリンスホテル新高輪国際館パミール.東京
  • Year and Date: 20090424-20090426
• [Presentation] RAの関節破壊におけるIL-6の重要性 (2009)
  • Author(s): 西本憲弘
  • Organizer: 第53回日本リウマチ学会総会・学術集会シンポジウムサテライトシンポジウム サイトカインネットワークと関節破壊-何を目指すべきか- SLS5-1
  • Place of Presentation: グランドプリンスホテル新高輪.東京
  • Year and Date: 20090423-20090426
• [Presentation] トシリズマブのTNF阻害剤抵抗性関節リウマチに対する第III相試験-有効性と安全性ならびにIL-6阻害によるIL-17の変化 (2009)
  • Author(s): 美馬亨, 西本憲弘
  • Organizer: 第53回日本リウマチ学会ワークショップW23-1
  • Place of Presentation: グランドプリンスホテル新高輪.東京
  • Year and Date: 20090423-20090426
• [Presentation] Aberrant cytokine networks and metabolisms in patients with systemic onset and polyarticular type juvenile idiopathic arthritis(sJIA and pJIA) (2009)
  • Author(s): 西本憲弘
  • Organizer: 第37回日本免疫学会・学術集会 S3-6
  • Place of Presentation: 大阪国際会議場.大阪
  • Year and Date: 2009-12-03
• [Presentation] The IL-6 inhibition with tocilizumab in RA and Castleman's disease (2009)
  • Author(s): 西本憲弘
  • Organizer: Post EULAR Meeting 2009
  • Place of Presentation: Sao Paulo, Brazil
  • Year and Date: 2009-08-28
• [Presentation] Anti-IL6 receptor antibody therapy for autoimmune and malignant diseases (2009)
  • Author(s): 西本憲弘
  • Organizer: UAB Gene Therapy Seminar Series
  • Place of Presentation: Alabama, USA
  • Year and Date: 2009-06-16
• [Presentation] Gene expression profiling of S100 protein families in the peripheral blood from patients with RA, SLE, polyJIA and sJIA-correlation between S100A4 expression and joint destruction- (2009)
  • Author(s): Nishimoto N, Sugino H, Aoki C, Lee H, Matsubara K, Mima T.
  • Organizer: EULAR2009
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2009-06-12
• [Presentation] Gene expression profile in peripheral blood cells at baseline predicts tocilizumab responsiveness of patients with rheumatoid arthritis. (2009)
  • Author(s): Nishimoto N., Kawata Y., Aoki C., Mima T
  • Organizer: EULAR2009
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2009-06-12
• [Presentation] Tumor Necrosis Factor(TNF)Emerged as A Dominant Cytokine in Peripheral Blood Immunoregulatory Network of Lupus Nephritis Patient after Treatment. (2009)
  • Author(s): Lee H, Mima T, Sugino H, Aoki C, Nishimoto N.
  • Organizer: EULAR2009
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2009-06-11
• [Presentation] RA患者に対するトシリズマブの治療効果はDNAチップを用いて予測可能である (2009)
  • Author(s): 西本憲弘, 美馬亨, 川田祐一
  • Organizer: 第53回日本リウマチ学会ワークショップトシリズマブW23-3
  • Place of Presentation: グランドプリンスホテル新高輪.東京
  • Year and Date: 2009-04-25
• [Presentation] DNAチップによるSLEの遺伝子発現解析-ルーブス腎炎に対するエンドキサン大量療法により、インターフェロンによって誘導される遺伝子発現は低下した (2009)
  • Author(s): 李慧敏, 美馬亨, 杉野英彦, 安達康雄, 青木千恵子, 西本憲弘
  • Organizer: 第53回日本リウマチ学会ポスターセクションP2-257
  • Place of Presentation: グランドプリンスホテル新高輪.東京
  • Year and Date: 2009-04-24