Elucidation of the molecular mechanism of induction/activation of regulatory B cells and its application to regulation of intestinal inflammation

• Project/Area Number: 26460970
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Shimane University
• Principal Investigator: Ishihara Shunji 島根大学, 医学部, 准教授 (80263531)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 炎症性腸疾患 / 腸管免疫 / 制御性B細胞 / IL-10 / アポトーシス / ＩＬ-10

Outline of Final Research Achievements

Although we recently reported anti-inflammatory roles of regulatory B cell (Breg), methodologies regarding the effective induction of Bregs remain unknown. Apoptosis is a programmed death of unwanted cells, and handling of apoptotic cells (ACs) is thought to have profound effects on immune-mediated disorders. In the present study, we injected ACs into a chronic colitis model in the presence and absence of co-transferred Bregs. We also injected syngeneic ACs into control mice as a control and into milk fat globule-epidermal growth factor 8 knockout (MFG-E8 KO) mice deficient of phagocytic function. Colitis severity of mice was reduced in the AC as opposed to control group. The AC-mediated effect was lost in the absence of Bregs. ACs induced splenic B cells to secrete significantly increased levels of IL-10 in wild mice but not MFG-E8 KO mice. Our results show that ACs are protective only in the presence of B cells and phagocytosis of ACs induced IL-10 producing Bregs.

Research Products

• [Journal Article] Decreased Frequency of Intestinal Regulatory CD5+ B Cells in Colonic Inflammation (2016)
  • Author(s): Mishima Y, Ishihara S, Oka A, Fukuba N, Oshima N, Sonoyama H, Yamashita N, Tada Y, Kusunoki R, Moriyama I, Yuki T, Kawashima K, Kinoshita Y
  • Journal Title: PLoS One Volume: 11 Issue: 1 Pages: e0146191-e0146191
  • DOI: 10.1371/journal.pone.0146191
  • Peer Reviewed / Open Access
• [Journal Article] Down-regulation of serotonin reuptake transporter gene expression in healing colonic mucosa in presence of remaining low grade inflammation in ulcerative colitis (2016)
  • Author(s): Tada Y, Ishihara S, Kawashima K, Fukuba N, Sonoyama H, Kusunoki R, Oka A, Mishima Y, Oshima N, Moriyama I, Yuki T, Ishikawa N, Araki A, Harada Y, Maruyama R, Kinoshita Y
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 印刷中 Issue: 8 Pages: 1443-1452
  • DOI: 10.1111/jgh.13268
  • Peer Reviewed
• [Journal Article] Fecal calprotectin level correlated with both endoscopic severity and disease extent in ulcerative colitis (2016)
  • Author(s): Kawashima K, Ishihara S, Yuki T, Fukuba N, Oshima N, Kazumori H, Sonoyama H, Yamashita N, Tada Y, Kusunoki R, Oka A, Mishima Y, Moriyama I, Kinoshita Y
  • Journal Title: BMC Gastroenterology Volume: 16 Issue: 1 Pages: 47-47
  • DOI: 10.1186/s12876-016-0462-z
  • Peer Reviewed / Open Access
• [Journal Article] Eosinophilic Esophagitis, Eosinophilic Gastroenteritis, and Eosinophilic Colitis: Common Mechanisms and Differences between East and West (2016)
  • Author(s): Ishihara S, Kinoshita Y, Schoepfer A.
  • Journal Title: Inflammatory Intestinal Diseases Volume: 1 Issue: 2 Pages: 63-69
  • DOI: 10.1159/000445131
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bile acids induce Delta-like 1 expression via Cdx2-dependent pathway in the development of Barrett's esophagus. (2016)
  • Author(s): Tamagawa Y, Ishimura N, Uno G, Aimi M, Oshima N, Yuki T, Sato S, Ishihara S, Kinoshita Y
  • Journal Title: Laboratory Investigation Volume: 96 Issue: 3 Pages: 325-337
  • DOI: 10.1038/labinvest.2015.137
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Recent Progress in the Research of Eosinophilic Esophagitis and Gastroenteritis. (2016)
  • Author(s): Kinoshita Y, Ishimura N, Oshima N, Mikami H, Okimoto E, Jiao DJ, Ishihara S.
  • Journal Title: Digestion Volume: 93 Issue: 1 Pages: 7-12
  • DOI: 10.1159/000441668
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic Efficacy of pH-Dependent Release Formulation of Mesalazine on Active Ulcerative Colitis Resistant to Time-Dependent Release Formulation: Analysis of Fecal Calprotectin Concentration (2016)
  • Author(s): Kawashima K, Ishihara S, Yuki T, Onishi K, Kushiyama Y, Fujishiro H, Miyaoka Y, Yuki M, Komazawa Y, Tanimura T, Sonoyama H, Tada Y, Kusunoki R, Oka A, Fukuba N, Oshima N, Moriyama I, Kinoshita Y
  • Journal Title: Biomed Res Int Volume: 2014 Pages: 342751-342751
  • DOI: 10.1155/2014/342751
  • Peer Reviewed
• [Journal Article] Role of milk fat globule-epidermal growth factor 8 in colonic inflammation and carcinogenesis (2015)
  • Author(s): Kusunoki R, Ishihara S, Tada Y, Oka A, Sonoyama H, Fukuba N, Oshima N, Moriyama I, Yuki T,Kawashima K, Ansary MM, Tajima Y, Maruyama R, Nabika T, Kinoshita Y
  • Journal Title: J Gastroenterol. Volume: 50 Issue: 8 Pages: 862-875
  • DOI: 10.1007/s00535-014-1036-x
  • Peer Reviewed
• [Journal Article] An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease (2015)
  • Author(s): Yoshimura N, Yokoyama Y, Matsuoka K, Takahashi H, Iwakiri R, Yamamoto T, Nakagawa T, Fukuchi T, Motoya S, Kunisaki R, Kato S, Hirai F, Ishiguro Y, Tanida S, Hiraoka S, Mitsuyama K, Ishihara S, Tanaka S, Otaka M, Osada T, Kagaya T, Suzuki Y, Nakase H, Hanai H, Watanabe K, Kashiwagi N, Hibi T
  • Journal Title: BMC Gastroenterology Volume: 15 Issue: 1 Pages: 163-163
  • DOI: 10.1186/s12876-015-0390-3
  • Peer Reviewed
• [Journal Article] Role of milk fat globule-epidermal growth factor 8 in colonic inflammation and carcinogenesis (2015)
  • Author(s): Kusunoki R, Ishihara S, Tada Y, Oka A, Sonoyama H, Fukuba N, Oshima N, Moriyama I, Yuki T, Kawashima K, Ansary MM, Tajima Y, Maruyama R, Nabika T, Kinoshita Y
  • Journal Title: J Gastroenterol. Volume: Epub ahead of print
• [Journal Article] Role of regulatory B cells in chronic intestinal inflammation: association with pathogenesis of Crohn's disease (2014)
  • Author(s): Oka A, Ishihara S, Mishima Y, Tada Y, Kusunoki R, Fukuba N, Yuki T, Kawashima K, Matsumoto S, Kinoshita Y
  • Journal Title: Inflamm Bowel Dis Volume: 20 Issue: 2 Pages: 315-28
  • DOI: 10.1097/01.mib.0000437983.14544.d5
  • Peer Reviewed
• [Journal Article] Apoptotic cells ameliorate chronic intestinal inflammation by enhancing regulatory B cell function (2014)
  • Author(s): Ansary Md. Mu, Ishihara S, Oka A, Kusunoki R, Oshima N, Yuki T, Kawashima K, Maegawa H, Kashiwagi N, Kinoshita Y
  • Journal Title: Inflamm Bowel Dis Volume: 20 Issue: 12 Pages: 2308-2320
  • DOI: 10.1097/mib.0000000000000240
  • Peer Reviewed
• [Journal Article] Prevalence of irritable bowel syndrome-like symptoms in ulcerative colitis patients with clinical and endoscopic evidence of remission: prospective multicenter study (2014)
  • Author(s): Fukuba N, Ishihara S, Tada Y, Oshima N, Moriyama I, Yuki T, Kawashima K, Kushiyama Y, Fujishiro H, Kinoshita Y
  • Journal Title: Scand J Gastroenterol Volume: 49 Issue: 6 Pages: 674-680
  • DOI: 10.3109/00365521.2014.898084
  • Peer Reviewed
• [Presentation] Epidermaldifferentiation complex protein involucrin is down-regukated in eosinophikic esophagitis (2016)
  • Author(s): Oshima N, Ishihara S, Fukuba N, Kawashima K, Ishimura N, Kinoshita Y
  • Organizer: Asian pacific Digestive Week 2016
  • Place of Presentation: Kobe Convention Center, Hyogo, Japan
  • Year and Date: 2016-11-02
• [Presentation] Presistent decrease in colonic regulatory CD5+ B cell pissibly associated with pathogenesis of inflammatory bowel disease (2016)
  • Author(s): Mishima Y, Ishihara S, Oka A, Fukuba N, Oshima N, Sonoyama H, Yamashita N, Tada Y, kusunoki R, Moriyama I, yuki T, Kawashima K, Kinoshita Y
  • Organizer: The 4th Annual Meeting of Asian Organization for Crohn's & Colitis
  • Place of Presentation: Kyoto International Conference Center, Kyoto, Japan
  • Year and Date: 2016-07-07
• [Presentation] Psychological state of subjects with irritable bowel syndrome and headache: annual health check-up survey results (2015)
  • Author(s): Kawashima K, Ishihara S, Uemura Y, Kazumori H, Katsube T, Sonoyama H, Tada Y, Kusunoki R, Oka A, Fukuba N, Oshima N, Yuki T, Kinoshita Y
  • Organizer: Digestive Disease Week 2015
  • Place of Presentation: Washington, USA
  • Year and Date: 2015-05-17
  • Int'l Joint Research
• [Presentation] Fecal calprotectin concentration correlated with both endoscopic severity and disease extent in ulcerative colitis: Analysis of sum of Mayo endoscopic subscore for five colon segments (2015)
  • Author(s): Kawashima K, Ishihara S, Yuki T, Sonoyama H, Tada Y, Oka A, Kusunoki R, Fukuba N, Oshima N, Moriyama I, Kinoshita Y
  • Organizer: Digestive Disease Week 2015
  • Place of Presentation: Washington, USA
  • Year and Date: 2015-05-17
  • Int'l Joint Research
• [Presentation] Apoptotic neutrophils ameliorate intestinal inflammation (2015)
  • Author(s): Ishihara S, Kawashima K, Sonoyama H, Tada Y, Oka A, Kusunoki R, Fukuna N, Oshima N, Moriyama I, Yuki T, Maegawa H, Kashiwagi N, Kinoshita Y
  • Organizer: 10th Congress of European European Crohn's Colitis Organisation（ECCO）
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2015-02-20
• [Presentation] Matrix Metalloproteinase-3 Concentration Correlates with Clinical and Endoscopic Evidence of Ulcerative Colitis (2015)
  • Author(s): Kawashima K, Ishihara S, Sonoyama H, Tada Y, Oka A, Kusunoki R, Fukuba N, Oshima N, Moriyama I, Yuki T, Kinoshita Y
  • Organizer: 10th Congress of European European Crohn's Colitis Organisation（ECCO）
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2015-02-20
• [Presentation] Serum amyloid A level correlated with endoscopic findings in patients with Crohn's disease-possible biomarker for evaluating mucosal healing (2015)
  • Author(s): Tada Y, Ishihara S, Sonoyama H, Oka A, Fukuba N, Oshima N, Moriyama I, Yuki T, Kawashima K, Kinoshita Y
  • Organizer: 10th Congress of European European Crohn's Colitis Organisation（ECCO）
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2015-02-20
• [Presentation] 腸管炎症におけるIL-33の役割 (2015)
  • Author(s): 園山 浩紀、大嶋 直樹、石原 俊治、山下 詔嗣、多田 育賢、岡 明彦、福庭 暢彦、森山 一郎、結城 崇史、川島 耕作、木下 芳一
  • Organizer: 第11回日本消化管学会総会学術集会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-02-13
• [Presentation] ワークショップ：腸疾患病態研究の進歩－免疫と腸内環境－；制御性B細胞による腸管免疫の機能維持とその破綻による腸炎発症機序の検討 (2014)
  • Author(s): 岡 明彦、石原 俊治、木下 芳一
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム（東京）
  • Year and Date: 2014-04-26
• [Presentation] Research Forum：炎症性腸疾患の病態と診断 (2014)
  • Author(s): 川島 耕作、石原 俊治 結城 崇史、園山 浩紀、多田 育賢、岡 明彦、楠 龍策、福庭 暢彦、大嶋 直樹、木下 芳一
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム（東京）
  • Year and Date: 2014-04-23
• [Book] Methods Mol Biol. :TGF-β detection and measurement in murine B cells: pros and cons of the different techniques (2014)
  • Author(s): Mishima Y, Ishihara S, Hansen JJ, Kinoshita Y
  • Publisher: Human Press
• [Book] MFG-E8 and Inflammation:Anti-Inflammatory Role of MFG-E8 in the Intestinal Tract (2014)
  • Author(s): Ishihara S, Kusunoki R, Kinoshita Y
  • Publisher: Springer Science+Business Media