Challenge to the cell therapy by reprogramming colitogenic memory T cells

• Project/Area Number: 24659375
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: KANAI Takanori 慶應義塾大学, 医学部, 教授 (40245478)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 炎症性腸疾患 / Th17細胞 / Th1細胞 / 腸管免疫 / 遺伝子導入 / 制御性T細胞 / 細胞療法 / メモリーT細胞

Research Abstract

We reported that the persistence of colitogenic memory cells are responsible for recurrence of inflammatory bowel disease (IBD). This study aimed to investigate the regulation of the colitigenic memory cells, leading to the development of new therapy for suppression of IBD recurrence. The results of the study is as below: 1. Th17 cells were induced under the influence of Lymphoid tissue inducer-like cell, 2. Classical Th1 cells obtained colitogenesity in the presence of alternative Th1 cells, 3. Clostridium butyricum, which is used as probiotics, induced anti-inflammatory macrophages. These results suggest the involvement of various cell types in the development of chronic inflammation of IBD.

Research Products

• [Journal Article] Macrophages and dendritic cells emerge in the liver during intestinal inflammation and predjspose the liver to inflammation. (2014)
  • Author(s): Mikami Y, Mizuno S, Nakamoto N, Hayashi A, Sujino T, Sato T, Kamada N, Matsuoka K, Hisamatsu T, Ebinuma H, Hibi T, Yoshimura A, Kanai T.
  • Journal Title: PLoS One Volume: 9 Issue: 1 Pages: 1-1
  • DOI: 10.1371/journal.pone.0084619
  • Peer Reviewed
• [Journal Article] A Single Strain of Clostridium butyricum Induces Intestinal I L-10-Producing Macrophages to Suppress Acute Exlperimental Colitis in Mice. (2013)
  • Author(s): Hayashi A, Sato T, Kamada N, Mikami Y, Matsuoka K, Hisamatsu T, Hlbi T, Roers A, Yagita H, Ohteki T, Yoshimura A, Kanai T.
  • Journal Title: Cell Host Microbe Volume: 13 Issue: 6 Pages: 711-22
  • DOI: 10.1016/j.chom.2013.05.013
  • Peer Reviewed
• [Journal Article] Th1/Th17-Mediated Interstitial Pneumonia in Chronic Colitis Mice Independent of Intestinal Microbiota. (2013)
  • Author(s): Nemoto Y, Watanabe M et al
  • Journal Title: J Immunol. Volume: 190 Issue: 12 Pages: 6616-6625
  • DOI: 10.4049/jimmunol.1202930
  • Peer Reviewed
• [Journal Article] Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4+ memory T cells. (2013)
  • Author(s): Nemoto Y, Nakamura T, Watanabe M et al
  • Journal Title: Gut. Volume: 62 Issue: 8 Pages: 1142-1152
  • DOI: 10.1136/gutjnl-2012-302029
  • 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] 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: Immunology Letters Volume: 150 Issue: 1-2 Pages: 123-9
  • DOI: 10.1016/j.imlet.2013.01.010
  • Peer Reviewed
• [Journal Article] T-helper 17 and Interleukin-17-Producing Lymphoid Tissue Inducer-Like T 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 Issue: 5 Pages: 1288-1297
  • DOI: 10.1053/j.gastro.2012.07.108
  • Peer Reviewed
• [Journal Article] ROR_Yt-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation. (2012)
  • Author(s): Kanai T, Mikami Y, Sujino T, Hisamatsu T, Hibi T.
  • Journal Title: Mucosal Immunology Volume: 5 Issue: 3 Pages: 240-247
  • DOI: 10.1038/mi.2012.6
  • Peer Reviewed
• [Journal Article] The development of colitogenic CD4(+) T cells is regulated by IL-7 in collaboration with NK cell function in a murine model of colitis (2012)
  • Author(s): Yamaji O, Nagaishi T, Totsuka T, Onizawa M, Suzuki M, Tsuge N, Hasegawa A, Okamoto R, Tsuchiya K, Nakamura T, Arase H, Kanai T, Watanabe M.
  • Journal Title: J Immunol Volume: 188 Issue: 4 Pages: 2524-36
  • DOI: 10.1152/ajpgi.00071.2008
  • Peer Reviewed
• [Presentation] Colitogenic Th17 Cells may Help the Generation of Colitogenic RORγt-Independent ClassicalTh1 Cells (2013)
  • Author(s): Saigusa K, Kanai T, Sujino T, Handa T, Hayashi A, Mikami Y,Mizuno S, Matsumoto A, Matuoka Y, Sato T, Hisamatsu T, Hibi T.
  • Organizer: 16th International Congress of Mucosal Immunology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2013-07-17
• [Presentation] Clostridium Butyricum Regulates IL-10 Production in Normal and Inflammatory Conditions Through Different Target Cells (2013)
  • Author(s): Hayashi A, Kanai T, Sato T, Mikami Y, Matsuoka K, Hisamatsu T, Yoshimura A, Kamada N, Yagita H, Hibi T.
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: Orlando, USA
  • Year and Date: 2013-05-19
• [Presentation] 炎症性腸疾患と健常にそれぞれ存在する腸管Th17細胞の決定的な相違の追求 (2012)
  • Author(s): 金井隆典、筋野智久、三上洋平、日比紀文
  • Organizer: 第40回日本臨床免疫学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-09-27
• [Presentation] 腸管におけるRorgt依存的lnnate Lymphoid cells(lLCs)の機能解析及び炎症制御能の解明 (2012)
  • Author(s): 木村佳代子、金井隆典、林篤史、筋野智久、三上洋平、半田一己、松岡克善、佐藤俊朗、久松理一、日比紀文
  • Organizer: 第49回日本消化器病学会総会
  • Place of Presentation: 鹿児島
  • Year and Date: 2012-07-05