The development of regulatory T cell therapy using leukocyte apheresis for inflammatory bowel disease

• Project/Area Number: 19590716
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NAGAHORI Masakazu Tokyo Medical and Dental University, 医学部附属病院, 助教 (60420254)
• Co-Investigator(Kenkyū-buntansha): WATANABE Mamoru 東京医科歯科大学, 大学院・医歯学総合研究科・消化器病態学, 教授 (10175127) ; KANAI Takanori 慶應義塾大学, 内科, 准教授 (40245478) ; FUKAO Taro 慶應義塾大学, 医学部, 助教 (20401127)
• Co-Investigator(Renkei-kenkyūsha): WATANABE Mamoru 東京医科歯科大学, 大学院・医歯学総合研究科・消化器病態学, 教授 (10175127) ; KANAI Takanori 慶應義塾大学, 内科, 准教授 (40245478)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 炎症性腸疾患 / 白血球除去療法 / 新規治療法 / 潰瘍性大腸炎 / クローン病

Research Abstract

研究期間内に、ヒト単球にはCD14++CD16-、CD14-CD16+の異なるフェノタイプの存在を明らかとした。さらに、CD14-CD16+単球はHLA-DRおよび共刺激分子CD86の発現がより高く、さらに、TNFα、IL-12, IL-18といったproinflammatoryサイトカインの産生もより高値であった。これら単球のうち、CD14-CD16+単球に対して、抗ヒトTNFα抗体インフリキシマブは強いアポプトーシス活性を有し、ヒト炎症性腸疾患における責任細胞がTNFαを含む様々なproinflammatoryサイトカインを産生するCD14-CD16+単球である可能性を示唆した。さらに、興味深いことに白血球除去療法のうちLCAP(せルソーバー)はCD14++CD16-単球に比べCD14-CD16+単球を選択的に除去することを明らかとした。このことは, 従来、臨床先行型に開発応用されてきた白血球除去療法の作用機序として、体外式抗TNFα抗体療法が想定され臨床的にも意義深い知見と言えるかもしれない。今後の研究期間内に、さらに特異的体外式抗TNFα療法として、白血球除去療法カラム内での抗TNFα抗体吸着ビーズの開発を展開する予定である。さらに今年度は白血球除去療法による上皮細胞への影響を解析し、除去療法後の上皮細胞のなかで増殖細胞が増加傾向で有ることを確認し、腸上皮再生作用の可能性も示唆された。今後の研究にて再生機構の詳細な解析を行う予定である。

Research Products

• [Journal Article] Requirement of Notch activation duringregeneration of the intestinal epithelia (2009)
  • Author(s): Okamoto R, Tsuchiya K, Nemoto Y, AkiyamaJ, Nakamura T, Kanai T, Watanabe M
  • Journal Title: Am Jphysiol GI & Liver 296 Pages: 23-35
  • Peer Reviewed
• [Journal Article] Signaling pathway via TNFα/NF κ B in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis. (2009)
  • Author(s): Onizawa M, Watanabe M, etal.
  • Journal Title: Am J Physiol GI & Liver. (in press)
  • Peer Reviewed
• [Journal Article] Requirement of Notch activation during regeneration of the intestinal epithelia. (2009)
  • Author(s): Okamoto R, Watanabe M, etal.
  • Journal Title: Am J Physiol GI & Liver. 296
  • Peer Reviewed
• [Journal Article] Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis. (2009)
  • Author(s): Nemoto Y, Watanabe M, et al.
  • Journal Title: Inflamm Bowel Dis. 14 Pages: 1491-1503
  • Peer Reviewed
• [Journal Article] Proteasomal degradation ofAtoh1 by aberrant Wnt signaling maintainsthe undifferentiated state of colon cancer (2008)
  • Author(s): Aragaki M, Tsuchiya K, Okamoto R, Yoshioka S, Nakamura T, Sakamoto N, KanaiT, Watanabe M
  • Journal Title: Biochem Biophys Res Commun 368 Pages: 923-929
  • Peer Reviewed
• [Journal Article] Negative feedback regulationof colitogenic CD4+ T cells by increasedgranulopoiesis (2008)
  • Author(s): Nemoto Y, Kanai T, Tohda S, Totsuka T, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Fukuda T, Miura O, Yagita H, Watanabe M
  • Journal Title: Inflamm Bowel Dis 14 Pages: 1491-1503
  • Peer Reviewed
• [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis (2008)
  • Author(s): Tomita T, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Sakamoto N, Watanabe M
  • Journal Title: J Immunol 180 Pages: 383-390
  • Peer Reviewed
• [Journal Article] MyD88-dependent pathway in T cells directly modulates the expansion and survival of colitogenic CD4+ T cells in chronic colitis (2008)
  • Author(s): Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S, Watanabe M
  • Journal Title: J Immunol 180 Pages: 5291-5299
  • Peer Reviewed
• [Journal Article] Colitogenic CD4^+ effector-memory T cellsactively recirculate in chronic coliticmice (2008)
  • Author(s): Tomita T, Kanai T, Nemoto Y, Fujii T, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Totsuka T, Watanabe M
  • Journal Title: Inflamm Bowel Dis 14 Pages: 1630-1640
  • Peer Reviewed
• [Journal Article] FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow. (2008)
  • Author(s): Fujii F, Watanabe M, et al.
  • Journal Title: Eur J Immunol. 38 Pages: 3290-3303
  • Peer Reviewed
• [Journal Article] Colitogenic CD4^+ effector-memory T cells actively recirculate in chronic colltic mice. (2008)
  • Author(s): Tomita T, Watanabe M, et al.
  • Journal Title: Inflamm Bowel Dis. 14 Pages: 1630-1640
  • Peer Reviewed
• [Journal Article] Flagellin stimulation suppresses IL-7 secretion of intestinal epithelial cells. (2008)
  • Author(s): Yoshioka A, Watanabe M, etal.
  • Journal Title: Cytokine. 44 Pages: 57-64
  • Peer Reviewed
• [Journal Article] Continuous generation of colitogenic CD4+ T cells in persistent colitis. (2008)
  • Author(s): Tomita T, Watanabe M, et al.
  • Journal Title: Eur J Immunol. 38 Pages: 1264-1274
  • Peer Reviewed
• [Journal Article] Inducible expression of microRNA-194 is regulated by HNF-1 during intestinal epithelial cell differentiation. (2008)
  • Author(s): Hino K, Watanabe M, et al.
  • Journal Title: RNA. 14 Pages: 1433-1442
  • Peer Reviewed
• [Journal Article] MyD88-dependent pathway in T cells directly modulates the expansion and survival of colitogenic CD4+ T cells in chronic colitis. (2008)
  • Author(s): Tomita T, Watanabe M, et al.
  • Journal Title: J Immunol. 180 Pages: 5291-5299
  • Peer Reviewed
• [Journal Article] Immunosenescent colitogenic CD4+ T cells convert to regulatory cells to suppress colitis. (2008)
  • Author(s): Totsuka T, Watanabe M, et al.
  • Journal Title: Eur J Immunol. 38 Pages: 1275-1286
  • Peer Reviewed
• [Journal Article] Proteasomal degradation of Atohl by aberrant Wnt signaling maintains the undifferentiated state of colon cancer. (2008)
  • Author(s): Aragaki M, Watanabe M, et al.
  • Journal Title: Biochem Biophys Res Commun. 368 Pages: 923-929
  • Peer Reviewed
• [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis. (2008)
  • Author(s): Tomita T, Watanabe M, et al.
  • Journal Title: J Immunol. 180 Pages: 383-390
  • Peer Reviewed
• [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis. (2008)
  • Author(s): Ito Y, Watanabe M, et al.
  • Journal Title: Am J Physiol GI & Liver. 394
  • Peer Reviewed
• [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis. (2008)
  • Author(s): Tomita T, Kanai T, et. al.
  • Journal Title: Journal of Immunology 180 Pages: 383-390
  • Peer Reviewed
• [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4^+ T cell-mediated colitis. (2008)
  • Author(s): Ito Y, Kanai T, et. al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 294(In press)
  • Peer Reviewed
• [Journal Article] Intestinal lamina propriaretaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation (2007)
  • Author(s): Makita S, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Yamamoto M, Kiyono H, Watanabe M
  • Journal Title: J Immunol 178 Pages: 4937-4946
  • Peer Reviewed
• [Journal Article] Bonemarrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis (2007)
  • Author(s): Nemoto Y, Kanai T, Makita S, Okamoto R, Totsuka T, Takeda K, Watanabe M
  • Journal Title: Gastroenterology 132 Pages: 176-189
  • NAID: 40015644486
  • Peer Reviewed
• [Journal Article] IL-7 is essential for the development and the persistence of chronic colitis (2007)
  • Author(s): Totsuka T, Kanai T, Nemoto Y, Makita S,Okamoto R, Tsuchiya K, Watanabe M
  • Journal Title: J Immunol 178 Pages: 4737-4748
  • Peer Reviewed
• [Journal Article] Reciprocal targetingof Hath1 and β-catenin by Wnt-glycogensynthase kinase 3βin human colon cancer (2007)
  • Author(s): Tsuchiya K, Nakamura T, Okamoto R, Kanai T, Watanabe M
  • Journal Title: Gastroenterology 132 Pages: 208-220
  • Peer Reviewed
• [Journal Article] Extracorporeal Elimination of TNFα-Producing CD14 dullCD16 Monocytes in Leukocytapheresis Therapy for Ulcerative Colitis (2007)
  • Author(s): Kanai T, Makita S, Kawamura T, Nemoto Y, Kubota D, Nagayama K, Totsuka T,Watanabe M
  • Journal Title: Inflamm Bowel Dis 13 Pages: 284-290
  • Peer Reviewed
• [Presentation] Dysregulated differentiation of intestinal epithelia in UC (2008)
  • Author(s): Okamoto R, Tsuchiya K, Nakamura T, Kanai T, Watanabe M
  • Organizer: 3rd Japan-Korea IBD Symposium
  • Place of Presentation: Korea(Seoul)
  • Year and Date: 2008-09-20
• [Presentation] 炎症性腸疾患 : いつ疑うか? いつ専門医へ紹介するか? (2008)
  • Author(s): 長堀正和
  • Organizer: 第1回消化器疾患勉強会
  • Place of Presentation: 東京
  • Year and Date: 2008-06-25
• [Presentation] Notch signaling suppresses the transcriptional activity of Hath1 Gene, resulting in the undifferentiated form of human intestinal epithelial cells (2008)
  • Author(s): Tsuchiya K, Inoue K, Aragaki M, Okamoto R, Nakamura T, Kanai T, Watanabe M
  • Organizer: DDW 2008
  • Place of Presentation: San Diego
  • Year and Date: 2008-05-20
• [Presentation] Stabilization of Atoh1 protein induces Mucin2 gene expression in human colon cancer cells (2007)
  • Author(s): Tsuchiya K, Okamoto R, Kanai T, Watanabe M
  • Organizer: DDW 2007
  • Place of Presentation: Washington, D.C.
  • Year and Date: 2007-05-23
• [Presentation] IL-7 is essential for the development and persistence of chronic colitis (2007)
  • Author(s): Totsuka T, Kanai T, Nemoto Y, Tomita T, Makita S, Totsuka T, Watanabe M
  • Organizer: DDW 2007
  • Place of Presentation: Washington, D.C.
  • Year and Date: 2007-05-22
• [Presentation] Activated notch signaling suppresses generation of goblet cells in the human intestinal mucosa (2007)
  • Author(s): Okamoto R, Tsuchiya K, Kanai T, Watanabe M
  • Organizer: DDW 2007
  • Place of Presentation: Washington, D.C.
  • Year and Date: 2007-05-20
• [Presentation] Blockade of TNF-α inhibits tumor progression in colitis-associated cancer (2007)
  • Author(s): Onizawa M, Kanai T, Nemoto Y, OshimaS, Makita S, Okamoto R, Totsuka T, YagitaH, Watanabe M
  • Organizer: DDW 2007
  • Place of Presentation: Washington, D.C.
  • Year and Date: 2007-05-20
• [Book] Medicina 炎症性腸疾患の病態 潰瘍性大腸炎とCrohn病の危険因子を中心に (2008)
  • Author(s): 長堀正和, 渡辺 守
  • Publisher: 医学書院
• [Book] セカンドオピニオン実践ガイドMedical Practice(臨時増刊号)「炎症性腸疾患診療の基本的流れ-治療指針に基づいた実地医療-」 (2007)
  • Author(s): 長堀正和、渡辺 守
  • Publisher: 文光堂
• [Book] 臨床消化器内科「特集炎症性腸疾患におけるAZA/6-MPの役割 AZA/6-MPの効果発現」 (2007)
  • Author(s): 長堀正和、久保田大輔、渡辺 守
  • Publisher: 日本メディカルセンター