Mucosal IgG plasma cell as a novel therapeutic target in the pathogenesis of ulcerative colitis .

• Project/Area Number: 24590951
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: HISAMATSU Tadakazu 慶應義塾大学, 医学部, 講師 (60255437)
• Co-Investigator(Kenkyū-buntansha): TOKUTAKE Mina 慶應義塾大学, 医学部, 研究員 (30468524)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 潰瘍性大腸炎 / IgG産生形質細胞 / ケモカイン受容体 / 免疫複合体 / IgG形質細胞

Outline of Final Research Achievements

Chronic inflammation characterized by IgG-producing plasma cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC).IgG plasma cells that were markedly increased in number in the inflamed mucosa of UC patients showed a distinct expression profile (CCR10 low /CXCR4 high) compared with IgA plasma cells (CCR10 high/CXCR4 low).IgG-immunocomplex(IC) stimulation activated intestinal CD14+ macrophages that were increased in number in the inflamed mucosa of UC patients via FcgR, and induced the extensive production of pro-inflammatory cytokines. IgG-IC may promote inflammatory response in CD14+ macrophages independent from signaling pathway in bacteria stimulation. IgG-IC signaling via FcgR and IgG plasma cell could be novel therapeutic targets for UC.

Research Products

• [Journal Article] Fecal Microbiota Transplantation for Gastrointestinal Diseases (2014)
  • Author(s): Matsuoka K, Kanai T.
  • Journal Title: The Keio Journal of Medicine Volume: 63 Issue: 4 Pages: 69-74
  • DOI: 10.2302/kjm.2014-0006-RE
  • NAID: 130004713429
  • ISSN: 0022-9717, 1880-1293
  • Peer Reviewed
• [Journal Article] Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation (2013)
  • Author(s): Uo M
  • Journal Title: Gut Volume: in press Issue: 12 Pages: 1734-44
  • DOI: 10.1136/gutjnl-2012-303063
  • Peer Reviewed
• [Journal Article] 炎症性腸疾患の病態解明と治療の進歩 (2013)
  • Author(s): 久松理一，日比紀文
  • Journal Title: 日本内科学会雑誌 Volume: 102巻, 臨時増刊号
  • Peer Reviewed
• [Journal Article] TGR5 signaling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease. (2013)
  • Author(s): Yoneno K, Hisamatsu T, Shimamura K, Kamada N, Ichikawa R, Kitazume MT, Mori M, Uo M, Namikawa Y, Matsuoka K, Sato T, KoganeiK, Sugita A, Kanai T and Hibi T
  • Journal Title: Immunology Volume: 139(1) Pages: 19-29
  • Peer Reviewed
• [Journal Article] Dendritic cells administered intrarectally penetrate the intestinal barrier to break intestinal tolerance via Th2-medeiated colitis in mice. (2013)
  • Author(s): Handa T, Kanai T, Sato T, Mikami Y, Sujino T, Hayashi A, Mizuno S, Matsumoto A, Hisamatsu T, Hibi T.
  • Journal Title: Immunol Lett. Volume: 150(1-2) Pages: 123-9
  • Peer Reviewed
• [Journal Article] Immune aspects of the pathogenesis of inflammatory bowel disease. (2013)
  • Author(s): Hisamatsu T, Kanai T, Yohei Mikami, Yoneno K, Matsuoka K, Hibi T
  • Journal Title: Pharmacol Ther. Volume: 137(3) Pages: 283-97
  • Peer Reviewed
• [Journal Article] Activated Hepatic Stellate Cells Mediate the Differentiation of Macrophages. (2013)
  • Author(s): Chang J, Hisamatsu T, Shimamura K, Yoneno K, Adachi M, Naruse H, Igarashi T, Higuchi H, Matsuoka K, Kitazume MT, Ando S, Kamada N, Kanai T, and Hibi T.
  • Journal Title: Hepatology Research Volume: [Epub ahead of print]
  • NAID: 10031194568
  • Peer Reviewed
• [Journal Article] Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells (2012)
  • Author(s): Nishida A, Nagahama K, Imaeda H, Ogawa A, Lau CW, Kobayashi T, Hisamatsu T, Preffer FI, Mizoguchi E, Ikeuchi H, Hibi T, Fukuda M, Andoh A, Blumberg RS, Mizoguchi A
  • Journal Title: J Exp Med. Volume: 209(13) Pages: 2383-94
  • Peer Reviewed
• [Journal Article] -Is the dendritic cell a missing piece in the pathogenesis model of post-infectious irritable bowel syndrome?- Editorial for “Characteristics of intestinal lamina propria dendritic cells in a mouse model of postinfectious irritable bowel syndrome.” (2012)
  • Author(s): Hisamatsu T, Hibi T
  • Journal Title: J Gastroenterol Hepatol. Volume: 27(5) Pages: 847-8
  • Peer Reviewed
• [Journal Article] T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice. (2012)
  • Author(s): Ono Y, Kanai T, Sujino T, Nemoto Y, Kanai Y, Mikami Y, Hayashi A, Matsumoto A, Takaishi H, Ogata H, Matsuoka K, Hisamatsu T, Watanabe M, Hibi T.
  • Journal Title: Gastroenterology. Volume: 143(5) Pages: 1288-97
  • Peer Reviewed
• [Journal Article] Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. (2012)
  • Author(s): Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, Higuchi H, Matsuoka K, Watanabe M, Itoh H, Kanai T, Hisamatsu T, Hibi T.
  • Journal Title: Immunology. Volume: 136(2) Pages: 153-62
  • Peer Reviewed
• [Journal Article] Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease. (2012)
  • Author(s): Hisamatsu T, Okamoto S, Hashimoto M, Muramatsu T, Andou A, Uo M, Kitazume MT, Matsuoka K, Yajima T, Inoue N, Kanai T, Ogata H, Iwao Y, Yamakado M, Sakai R, Ono N, Ando T, Suzuki M, Hibi T.
  • Journal Title: PLoS One. Volume: 7(1):
  • Peer Reviewed
• [Presentation] Intestinal CXCR4+IgG+ immature plasma cells contribute to the pathogenesis of ulcerative colitis through IgG-immune complex-FcR signaling (2012)
  • Author(s): Hisamatsu T, Uo M, Miyoshi J, Yoneno K, Matsuoka K, Kanai T, Hibi T.
  • Organizer: The 14th Meeting of International Conference on Ulcer Research
  • Place of Presentation: Tokyo
• [Presentation] Mucosal IgG+CXCR4+ plasma cells contribute to the pathogenesis of ulcerative colitis through FcR-mediated activation of CD14+ macrophages. (2012)
  • Author(s): Hisamatsu T, Uo M, Hibi T.
  • Organizer: The 3rd International Forum the 98th General Meeting of JSGE
  • Place of Presentation: Tokyo
  • Invited