Development of a novel therapy for pancreatitis through activation of innate immunity

• Project/Area Number: 25293172
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: WATANABE TOMOHIRO 京都大学, 医学(系)研究科(研究院), 准教授 (40444468)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 膵炎 / 自然免疫反応 / 自然免疫 / NOD1 / IL-33 / IL-13

Outline of Final Research Achievements

Although bacterial translocation is sometimes seen in patients with severe pancreatitis, it remains largely unknown how innate immune responses against intestinal microflora regulate the development of pancreatitis. In our previous study, we identified nucleotide-binding oligomerization domain 1 (NOD1) as a pathogenic innate immune receptor for experimental pancreatitis. In this study, we developed a new model of chronic pancreatitis induced by repeated administration of NOD1 ligand and cerulein, a cholecystokinin receptor (CCKR) agonist. The development of chronic pancreatitis induced by synergistic activation of CCKR and NOD1 requires IL-33 and IFN-beta production by acinar cells. IL-33 produced by acinar cells induces pro-fibrogenic factors such as IL-13 by Th2 cells whereas IFN-beta induces Th1 responses. Therefore, synergistic activation of NOD1 and CCKR results in IL-33-dependent pancreatitis characterized by Th1 and Th2 responses.

Research Products

• [Journal Article] Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatiti (2016)
  • Author(s): Watanabe T, Sadakane Y, Yagama N, Sakurai T, Ezoe H, Kudo M, Chiba T, Strober W
  • Journal Title: Mucosal Immunol. Volume: in press Issue: 5 Pages: 1234-49
  • DOI: 10.1038/mi.2015.144
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 自己免疫性膵炎の診断について 診断基準の変遷と診断の現状 (2015)
  • Author(s): 内田 一茂, 岡崎 和一
  • Journal Title: 日本臨床免疫学会雑誌 Volume: 38 Issue: 7 Pages: 127-134
  • DOI: 10.4049/jimmunol.1500971
  • NAID: 130005089220
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6. (2014)
  • Author(s): Watanabe T, Asano N, Meng G, Yamashita K, Arai Y, Sakurai T, Kudo M, Fuss IJ, Kitani A, Shimosegawa T, Chiba T, Strober W.
  • Journal Title: Mucosal Immunol Volume: 1 Issue: 6 Pages: 1-1
  • DOI: 10.1038/mi.2014.19
  • Peer Reviewed / Open Access
• [Presentation] Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis (2014)
  • Author(s): Watanabe T
  • Organizer: JSGE-APAGE Joint Conference Asian-Pacific Topic Conference
  • Place of Presentation: Kobe
  • Year and Date: 2014-10-22
  • Invited
• [Presentation] Activation of Toll-like receptors and NOD-like receptors in monocytes and basophils is involved in the immunopathogenesis of IgG4-related disease (2014)
  • Author(s): Watanabe T
  • Organizer: International Symposium on IgG4-RD & Associated Conditions
  • Place of Presentation: Honolulu, USA
• [Book] Mucosal Immunology 4th Edition (2015)
  • Author(s): Watanabe T, Chiba T, Strober W
  • Total Pages: 2564
  • Publisher: Elsevier