Investigation of intestinal macrophage in contribution to gut immune homeostasis and its disruption in Crohn's disease

• Project/Area Number: 21249048
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: HIBI Toshifumi 慶應義塾大学, 医学部, 教授 (50129623)
• Co-Investigator(Kenkyū-buntansha): KANAI Takanori 慶應義塾大学, 医学部, 准教授 (40245478) ; HISAMATSU Tadakazu 慶應義塾大学, 医学部, 講師 (60255437)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥46,150,000 (Direct Cost: ¥35,500,000、Indirect Cost: ¥10,650,000); Fiscal Year 2011: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2010: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2009: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
• Keywords: 炎症性腸疾患 / マクロファージ / 腸内細菌 / NK細胞 / サイトカイン

Research Abstract

We identified that resident intestinal macrophages include a subpopulation of MCP-1 dependent CCR2+IL-10 producing M. which contributes to gut homeostasis. In IL-10 KO mice, we showed intracellular signaling after phagocytosis is important for production of proinflammatory cytokines by intestinal macrophages. In human Crohn's disease, we demonstrated that intestinal macrophages interact with mucosal NK cells and contribute to enhance of Th1 immune response. Furthermore, our studies demonstrated that bile acids can induce differentiation into IL-12 hypo-producing DCs. Thus, conditioning and regulation of innate immune cells such as macrophages and dendritic cells(DCs) have a potential to be a therapeutic target of Crohn's disease.

Research Products

• [Journal Article] Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway (2012)
  • Author(s): Ichikawa R, Hisamatsu T, Hibi T, et al.
  • Journal Title: Immunology Volume: 136(2) Pages: 153-162
  • Peer Reviewed
• [Journal Article] 炎症性腸疾患におけるアミノ酸補給の意義 (2011)
  • Author(s): 久松理一、日比紀文
  • Journal Title: 日本消化吸収学会雑誌 Volume: 33(3) Pages: 352-361
  • NAID: 10029066191
  • Peer Reviewed
• [Journal Article] ヒト腸管自然免疫担当細胞による恒常性維持と炎症性腸疾患におけるその破綻 (2011)
  • Author(s): 久松理一、鎌田信彦、日比紀文
  • Journal Title: 細胞工学監修清野宏秀潤社 Volume: Vol.30 No.4 Pages: 366-370
• [Journal Article] 総説『クローン病の長期予後について考える』 (2011)
  • Author(s): 久松理一、日比紀文
  • Journal Title: 日本消化器病学会雑誌 Volume: 108巻3号 Pages: 373-380
  • Peer Reviewed
• [Journal Article] 特集:小腸疾患:診断と治療の進歩II.診療の進歩6 (2011)
  • Author(s): 久松理一、日比紀文
  • Journal Title: Crohn病日本内科学会雑誌 Volume: 第100巻第1号 Pages: 85-95
  • Peer Reviewed
• [Journal Article] Intracellular bacteria recognition contributes to maximal interleukin (IL)-12 production by IL-10-deficient macrophages Clin Exp Immunol (2011)
  • Author(s): Naruse H, Hisamatsu T, Kanai T, Hibi T, et al.
  • Volume: 164(1)
  • Pages: 137-144
  • Peer Reviewed
• [Journal Article] NFIL3 Is a Regulator of IL-12 p40 in Macrophages and Mucosal Immunity (2011)
  • Author(s): Kobayashi T, Hisamatsu T, Hibi T, Rothman PB, Kashiwada M
  • Journal Title: J Immunol Volume: 186(8) Pages: 4649-4655
  • Peer Reviewed
• [Journal Article] Regulatory T Cells Suppress Development of Colitis, Blocking Differentiation of T-Helper 17 Into Alternative T-Helper 1 Cells (2011)
  • Author(s): Sujino T, Kanai T, Hisamatsu T, Hibi T, et al.
  • Journal Title: Gastroenterology Volume: 141(3) Pages: 1014-1023
  • Peer Reviewed
• [Journal Article] Ectopic expression of blood type antigens in inflamed mucosa with higher incidence of FUT2 secretor status in colonic Crohn's disease (2011)
  • Author(s): Miyoshi J, Hisamatsu T, Kanai T, Hibi T, et al.
  • Journal Title: J Gastroenterol Volume: 46(9) Pages: 1056-1063
  • NAID: 10029706720
  • Peer Reviewed
• [Journal Article] Rothman PB, Kashiwada M, Plevy SE.NFIL3 Is a Regulator of IL-12 p40 in Macrophages and Mucosal Immunity (2011)
  • Author(s): Kobayashi T, Hisamatsu T, Hibi T, et al, 他8名、11番目
  • Journal Title: J Immunol Volume: 186(8) Pages: 4649-4655
  • Peer Reviewed
• [Journal Article] Intracellular bacteria recognition contributes to maximal interleukin (IL)-12 production by IL-10-deficient macrophages (2011)
  • Author(s): Naruse H, Hisamatsu T, Kanai T, Hibi T, et al, 他7名、11番目
  • Journal Title: Clin Exp Immunol Volume: 164(1) Pages: 137-144
  • Peer Reviewed
• [Journal Article] Intracellular bacteria recognition contributes to maximal interleukin (IL)-12 production by IL-10-deficient macrophages. (2011)
  • Author(s): Naruse H, Hisamatsu T, Yamauchi Y, Chang JE, Matsuoka K, Kitazume MT, Arai K, Ando S, Kanai T, Kamada N, Hibi T.
  • Journal Title: Clin Exp Immunol. Volume: Feb24
  • Peer Reviewed
• [Journal Article] 特集:小腸疾患:診断と治療の進歩II.診療の進歩6.Crohn病 (2011)
  • Author(s): 久松理一、日比紀文
  • Journal Title: 日本内科学会雑誌 Volume: 第100巻第1号 Pages: 85-95
  • Peer Reviewed
• [Journal Article] ヒト腸管自然免疫担当細胞による恒常性維持と炎症性腸疾患におけるその破綻 (2011)
  • Author(s): 久松理一、鎌田信彦、日比紀文
  • Journal Title: 細胞工学(監修清野宏)(秀潤社) Volume: Vol.30 No.4 Pages: 366-370
• [Journal Article] 炎症性腸疾患におけるアミノ酸補給の意義 (2011)
  • Author(s): 久松理一、日比紀文
  • Journal Title: 日本消化吸収学会雑誌総説 Volume: (in press)
  • NAID: 10029066191
  • Peer Reviewed
• [Journal Article] アミノ酸と免疫 (2010)
  • Author(s): 久松理一、日比紀文
  • Journal Title: Functinal Food Volume: 第11号Vol.4 No.1 Pages: 16-22
• [Journal Article] 血漿アミノ酸プロファイルを用いたIBDの診断IBD Research先端医学社 (2010)
  • Author(s): 久松理一、日比紀文
  • Volume: 12月号vol.4 no.4
  • Pages: 38-42
• [Journal Article] 特集:生体防御と自然免疫-最近の知見Workshop実臨床のトピックスIBD発症進展における自然免疫の役割 (2010)
  • Author(s): 久松理一、日比紀文
  • Journal Title: 侵襲と免疫 Volume: Vol.19 No.2 Pages: 39-42
• [Journal Article] Competitio between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis (2010)
  • Author(s): Mikami Y, Kanai T, Hisamatsu T, Hibi T., et al.
  • Journal Title: Eur J Immunol Volume: 40(9) Pages: 2409-2422
  • Peer Reviewed
• [Journal Article] Imbalance of NKp44(+) NKp46(-) and NKp44(-) NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease (2010)
  • Author(s): Takayama T, Hisamatsu T, Kanai T, Hibi T., et al.
  • Journal Title: Gastroenterology Volume: 139(3) Pages: 882-892
  • Peer Reviewed
• [Journal Article] TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn's disease (2010)
  • Author(s): Kamada N, Hisamatsu T, Kanai T, Hibi T., et al.
  • Journal Title: Inflamm Bowel Dis Volume: 16(4) Pages: 568-575
  • Peer Reviewed
• [Journal Article] Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset (2010)
  • Author(s): Takada Y, Hisamatsu T, Kanai T, Hibi T., et al.
  • Journal Title: J Immunol Volume: 184(5) Pages: 2671-2676
  • Peer Reviewed
• [Journal Article] Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset. (2010)
  • Author(s): Takada Y, Hisamatsu T, Kamada N, Kitazume MT, Honda H, Oshima Y, Saito R, Takayama T, Kobayashi T, Chinen H, Mikami Y, Kanai T, Okamoto S, Hibi T
  • Journal Title: J Immunol Volume: 184(5) Pages: 2671-2676
  • Peer Reviewed
• [Journal Article] TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn's disease. (2010)
  • Author(s): Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Takayama T, Kitazume MT, Okamoto S, Koganei K, Sugita A, Kanai T, Hibi T.
  • Journal Title: Inflamm Bowel Dis. Volume: 16(4) Pages: 568-575
  • Peer Reviewed
• [Journal Article] Imbalance of NKp44 (+)NKp46(-) and NKp44(-)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease. (2010)
  • Author(s): Takayama T, Kamada N, Chinen H, Okamoto S, Kitazume MT, Chang J, Matuzaki Y, Suzuki S, Sugita A, Koganei K, Hisamatsu T, Kanai T, Hibi T.
  • Journal Title: Gastroenterology Volume: Sep;139(3) Pages: 882-892
  • Peer Reviewed
• [Journal Article] Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis. (2010)
  • Author(s): Mikami Y, Kanai T, Sujino T, Ono Y, Hayashi A, Okazawa A, Kamada N, Matsuoka K, Hisamatsu T, Okamoto S, Takaishi H, Inone N, Ogata H, Hibi T.
  • Journal Title: Eur J Immunol. Volume: Sep;40(9) Pages: 2409-2422
  • Peer Reviewed
• [Journal Article] 特集:生体防御と自然免疫-最近の知見Workshop実臨床のトピックスIBD発症進展における自然免疫の役割 (2010)
  • Author(s): 久松理一, 日比紀文
  • Journal Title: 侵襲と免疫 メジカルビュー社 Volume: Vol.19 No.2 Pages: 39-42
• [Journal Article] 血漿アミノ酸プロファイルを用いたIBDの診断 (2010)
  • Author(s): 久松理一、日比紀文
  • Journal Title: IBD Research先端医学社 Volume: 12月号vol.4 no.4 Pages: 38-42
• [Journal Article] Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset (2010)
  • Author(s): Takada Y, Hisamatsu T, Kamada N, Kitazume MT, Honda H, Oshima Y, Saito R, Takayama T, Kobayashi T, Chinen H, Mikami Y, Kanai T, Okamoto S, Hibi T
  • Journal Title: J Immunol 184(5) Pages: 2671-2676
  • Peer Reviewed
• [Journal Article] TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn's disease (2010)
  • Author(s): Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Takayama T, Kitazume MT, Okamoto S, Koganei K, Sugita A, Kanai T, Hibi T.
  • Journal Title: Inflamm Bowel Dis. 16(4) Pages: 568-575
  • Peer Reviewed
• [Journal Article] (2010)
  • Author(s): 久松理一, 日比紀文
  • Journal Title: 炎症性腸疾患と腸管局所免疫 Annual Review 消化器 8-15(中外医学社) Pages: 8-15
• [Journal Article] Human CD14+ macrophages in intestinal lamina propria exhibit potent antigen-presenting ability (2009)
  • Author(s): Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Kitazume MT, Takayama T, Okamoto S, Koganei K, Sugita A, Kanai T, Hibi T
  • Journal Title: J Immunol. 183(3) Pages: 1724-1731
  • Peer Reviewed
• [Journal Article] Retinoic acid contributes to the induction of IL-12-hypoproducing dendritic cells (2009)
  • Author(s): Wada Y, Hisamatsu T, Kamada N, Okamoto S, Hibi T.
  • Journal Title: Inflamm Bowel Dis. 15(10) Pages: 1548-1556
  • Peer Reviewed
• [Journal Article] Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages (2009)
  • Author(s): Andou A, Hisamatsu T, Okamoto S, Chinen H, Kamada N, Kobayashi T, Hashimoto M, Okutsu T, Shimbo K, Takeda T, Matsumoto H, Sato A, Ohtsu H, Suzuki M, Hibi T.
  • Journal Title: Gastroenterology 136(2) Pages: 564-574
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): 高山哲朗, 久松理一
  • Journal Title: 【消化器疾患の分子医学 基礎医学から臨床へ】腸管免疫の分子機構臨床消化器内科24巻2号(日本メディカルセンター) Pages: 217-223
• [Journal Article] (2009)
  • Author(s): 久松理一, 日比紀文
  • Journal Title: ATG16L1とTNFSF15G.I Research vol.17 no.6(先端医学社) Pages: 548-550
• [Journal Article] (2009)
  • Author(s): 齊藤理子, 久松理一, 日比紀文
  • Journal Title: マクロファージからのIL-23産生と大腸炎、共生菌の関与臨床免疫・アレルギー科52巻4号(科学評論社) Pages: 384-388
• [Journal Article] (2009)
  • Author(s): 久松理一, 日比紀文
  • Journal Title: Th-17細胞の機能はどこまで明らかになれたか?IBD Research vol.2 no.4(先端医学社) Pages: 308-313
• [Journal Article] (2009)
  • Author(s): 久松理一, 日比紀文
  • Journal Title: 腸管マクロファージとIBD IBD Research vol.3 no.3(先端医学者) Pages: 183-187
• [Presentation] Collaboration between the East Asia IBD Society and ECCO (2012)
  • Author(s): Toshifumi Hibi
  • Organizer: ECCO Meeting
  • Place of Presentation: Spain
• [Presentation] Role of Endoscopy in daily clinical practice : example from Japan (2012)
  • Author(s): Toshifumi Hibi
  • Organizer: Leading Change in IBD Meeting
  • Place of Presentation: Prague
• [Presentation] Role of Endoscopy in daily clinical practice : example from Japan (2012)
  • Author(s): Toshifumi Hibi
  • Organizer: Leading Change in IBD Meeting
  • Place of Presentation: Prague Ceska Republika(招待講演)
• [Presentation] Collaboration between the East Asia IBD Society and ECCO (2012)
  • Author(s): Toshifumi Hibi
  • Organizer: ECCO Meeting
  • Place of Presentation: Barcelona Spain(招待講演)
• [Presentation] 難治性潰瘍性大腸炎に対するタクロリムス経口投与の治療効果と限界 (2011)
  • Author(s): 久松理一
  • Organizer: JDDW2011
  • Place of Presentation: 福岡
• [Presentation] How to avoid malpractice and deal with difficult IBD cases (2011)
  • Author(s): Toshifumi Hibi
  • Organizer: IBD Update
  • Place of Presentation: 台湾
• [Presentation] Intestinal CXCR4+IgG+Immature Plasma Cells Contribute to the Pathogenesis of Ulcerative Colitis through IgG-Immune Complex-FcgR Signaling (2011)
  • Author(s): Tadakazu Hisamatsu
  • Organizer: The 15th ICMI
  • Place of Presentation: Paris France
• [Presentation] How to avoid malpractice and deal with difficult IBD cases (2011)
  • Author(s): Toshifumi Hibi
  • Organizer: IBD Update II
  • Place of Presentation: 台北台湾(招待講演)
• [Presentation] 難治性潰瘍性大腸炎に対するタクロリムス経口投与の治療効果と限界 (2011)
  • Author(s): 久松理一
  • Organizer: JDDW2011
  • Place of Presentation: 福岡国際会議場(福岡県)
• [Presentation] Intestinal CXCR4+IgG+ Immature Plasma Cells Contribute to the Pathogenesis of Ulcerative Colitis through IgG-Immune Complex-FcgR Signaling (2011)
  • Author(s): Tadakazu Hisamatsu
  • Organizer: The 15th ICMI
  • Place of Presentation: Paris France
• [Presentation] 日比紀文Current Therapy of IBDCurrent Concepts (2010)
  • Author(s): 日比紀文
  • Organizer: IBD Symposium
  • Place of Presentation: Taipei台湾
  • Year and Date: 2010-08-21
• [Presentation] Current Therapy of IBD-Current Concepts (2010)
  • Author(s): 日比紀文
  • Organizer: IBD Symposium in Taipei
  • Place of Presentation: 台湾
  • Year and Date: 2010-08-21
• [Presentation] 血漿アミノ酸プロファイルを用いた炎症性腸疾患の診断・活動性モニタリング (2010)
  • Author(s): 久松理一、井上詠、松岡克善、斉藤理子、筋野智久、米野和明、三好潤、三上洋平、岩男泰、緒方晴彦、金井隆典、日比紀文、安藤朗、藤山佳秀、内山和彦、高木智久、内藤裕二、吉川敏一
  • Organizer: 難治性腸管障害調査研究班
  • Place of Presentation: 東京
  • Year and Date: 2010-07-30
• [Presentation] 潰瘍性大腸炎治療の新展開 (2010)
  • Author(s): 日比紀文
  • Organizer: 第89回日本消化器内視鏡学会九州支部例会支部例会ランチョンセミナー
  • Place of Presentation: 九州
  • Year and Date: 2010-06-19
• [Presentation] クローン病に対する成分栄養剤の作用機序-最新の知見を含めて- (2010)
  • Author(s): 久松理一
  • Organizer: 第7回肝・消化器代謝栄養研究会
  • Place of Presentation: 大阪
  • Year and Date: 2010-06-19
• [Presentation] クローン病に対する成分栄養剤の作用機序-最新の知見を含めて- (2010)
  • Author(s): 久松理一
  • Organizer: 第7回肝・消化器代謝栄養 研究会
  • Place of Presentation: 大阪
  • Year and Date: 2010-06-19
• [Presentation] Immunomodulation therapy for IBD (2010)
  • Author(s): 日比紀文
  • Organizer: 2010 Immune-Mediated Digestive Diseases Forum in China
  • Place of Presentation: 北京
  • Year and Date: 2010-06-13
• [Presentation] Japanese Patients With Moderately to Severely Active Crohn'sDisease Experience Improved Quality of Life With Adalimumab Treatment (2010)
  • Author(s): 日比紀文
  • Organizer: Digestive Disease Week 2010
  • Place of Presentation: New Orleans
  • Year and Date: 2010-05-03
• [Presentation] 炎症性腸疾患に対する抗体療法 (2010)
  • Author(s): 日比紀文
  • Organizer: 第107回日本内科学会講演会
  • Place of Presentation: 東京
  • Year and Date: 2010-04-11
• [Presentation] クローン病の病態解明と治療開発 (2010)
  • Author(s): 日比紀文
  • Organizer: 第6回日本消化管学会総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2010-02-20
• [Presentation] 炎症性腸疾患をアミノ酸代謝から考える (2010)
  • Author(s): 久松理一、日比紀文
  • Organizer: 第8回日本機能性食品医用学会総会シンポジウムI免疫と機能性食品
  • Place of Presentation: 大津ピアザ淡海
• [Presentation] 各種 Modality を用いたIBD診療の最前線 (2009)
  • Author(s): 日比紀文
  • Organizer: 第27回日本大腸検査学会
  • Place of Presentation: ベルサール九段
  • Year and Date: 2009-11-28
• [Presentation] 炎症性腸疾患診療の新時代 (2009)
  • Author(s): 日比紀文
  • Organizer: 第64回日本大腸肛門病学会学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2009-11-06
• [Book] 炎症性腸疾患 (2012)
  • Author(s): 久松理一、日比紀文
  • Publisher: 日本臨牀
• [Book] 潰瘍性大腸炎消化器疾患ガイドライン (2011)
  • Author(s): 久松理一、日比紀文
  • Publisher: 総合医学社
• [Book] G.I.Research IBDと炎症性サイトカイン-Th17- (2011)
  • Author(s): 久松理一、日比紀文
  • Publisher: 先端医学社
• [Book] 消化器BookシリーズNo.2特集:炎症性腸疾患の診断・治療 (2010)
  • Author(s): 日比紀文、久松理一
  • Total Pages: 340
  • Publisher: 医学書院出版
• [Book] 消化器BookシリーズNo.2特集:炎症性腸疾患の診断・治療 (2010)
  • Author(s): 日比紀文、久松理一
  • Total Pages: 213
  • Publisher: 羊土社出版
• [Book] 炎症性腸疾患の鑑別診断(日比紀文編)(炎症性腸疾患) (2010)
  • Author(s): 日比紀文
  • Total Pages: 340
  • Publisher: 医学書院
• [Book] 消化器BookシリーズNo.2特集:炎症性腸疾患の診断・治療(久松理一、日比紀文編) (2010)
  • Author(s): 日比紀文
  • Total Pages: 213
  • Publisher: 羊土社
• [Remarks]
  • URL: http://www.keio-med.jp/gastro/
• [Remarks]
  • URL: http://web.sc.itc.keio.ac.jp/medicine/ibd/index.html
• [Remarks]
  • URL: http://web.sc.itc.keio.ac.jp/medicine/ibd/index.html