Roles of cytomegalovirus in refractory inflammatory bowel disease

• Project/Area Number: 18K15747
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kyoto University
• Principal Investigator: Yamamoto Shuji 京都大学, 医学研究科, 特定病院助教 (00789638)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 炎症性腸疾患 / 潰瘍性大腸炎 / サイトメガロウイルス / ulcerative colitis / cytomegalovirus

Outline of Final Research Achievements

Our objective was to elucidate the roles of cytomegalovirus (CMV) in refractory inflammatory bowel disease (IBD), using T cell receptor α knock out mice infected with murine CMV.
We found 1) the mouse model we used replicated phenotypes of human refractory IBD with CMV reactivation and 2) the infection of murine CMV altered Th2 dominant T cell differentiation in the inflamed colonic mucosa toward Th1/17 dominant one in T cell receptor α knock out mice.
Our mouse model could be useful for further elucidation of the mechanism by which CMV infection influences the response to medical therapies in patients with IBD.

Academic Significance and Societal Importance of the Research Achievements

炎症性腸疾患(inflammatory bowel disease, IBD) には治療に難渋する重症例、治療抵抗例が存在する。サイトメガロウイルス(cytomegalovirus, CMV) は、IBD、特に潰瘍性大腸炎における重症化、難治化の要因の1 つと考えられているが、その機序については明らかでない。
本研究では、ヒトIBD 患者におけるCMV 再活性化例と類似した治療抵抗性を示すCMV感染合併IBDマウスモデルを確立することに成功した。このマウスモデルを使用することでIBDにおける難治化のメカニズムを詳細に検討することが可能となった。

Research Products

• [Journal Article] Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis (2019)
  • Author(s): Kakiuchi Nobuyuki et al.
  • Journal Title: Nature Volume: 577 Issue: 7789 Pages: 260-265
  • DOI: 10.1038/s41586-019-1856-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multiplexed monitoring of therapeutic antibodies for inflammatory diseases using Fab-selective proteolysis nSMOL coupled with LC-MS (2019)
  • Author(s): Iwamoto Noriko、Takanashi Megumi、Yokoyama Kotoko、Yonezawa Atsushi、Denda Masaya、Hashimoto Motomu、Tanaka Masao、Ito Hiromu、Matsuura Minoru、Yamamoto Shuji、Honzawa Yusuke、Matsubara Kazuo、Shimada Takashi
  • Journal Title: Journal of Immunological Methods Volume: 472 Pages: 44-54
  • DOI: 10.1016/j.jim.2019.06.014
  • Peer Reviewed / Open Access
• [Journal Article] Jejunal diaphragm disease associated with cytomegalovirus infection (2019)
  • Author(s): Kagebayashi Sumika、Yamamoto Shuji、Seno Hiroshi
  • Journal Title: Endoscopy International Open Volume: 07 Issue: 04 Pages: E533-E536
  • DOI: 10.1055/a-0848-8172
  • Peer Reviewed / Open Access
• [Journal Article] Segmental Xanthomatosis of the Ileum. (2019)
  • Author(s): Yamamoto S, Matsumura K, Seno H.
  • Journal Title: Clin Gastroenterol Hepatol Volume: 17 Issue: 3 Pages: e18-e18
  • DOI: 10.1016/j.cgh.2018.01.013
  • Peer Reviewed
• [Journal Article] Multiple Polypoid Lesions in the Ileum After Treatment for Primary Ileal Follicular Lymphoma. (2018)
  • Author(s): Kitamoto H, Kataoka T, Yamamoto S.
  • Journal Title: Gastroenterology. Volume: 156 Issue: 3 Pages: 552-553
  • DOI: 10.1053/j.gastro.2018.08.048
  • Peer Reviewed / Open Access
• [Journal Article] Unusual cause of a pancreatic mass. (2018)
  • Author(s): Sogabe Y, Yamamoto S, Kodama Y.
  • Journal Title: Gastrointest Endosc Volume: 88 Issue: 4 Pages: 770-771
  • DOI: 10.1016/j.gie.2018.06.006
  • Peer Reviewed
• [Journal Article] Mimicking small intestinal anisakiasis. (2018)
  • Author(s): Yamamoto S, Yamada M, Matsumura K.
  • Journal Title: Gastroenterology Volume: 154 Issue: 6 Pages: e9-e10
  • DOI: 10.1053/j.gastro.2017.08.020
  • Peer Reviewed
• [Presentation] 潰瘍性大腸炎におけるチオプリン製剤最適化の指標に関する検討 (2020)
  • Author(s): 北本博規、山本修司、本澤有介、妹尾浩
  • Organizer: 日本消化器病学会近畿支部 第112回例会
• [Presentation] Reactivation of Epstein-Barr virus and cytomegalovirus behaves differently in pathophysiology of ulcerative colitis (2020)
  • Author(s): Satoshi Yamada, Shuji Yamamoto, Yusuke Honzawa, Yuki Hayashi, Hiroki Kitamoto, Makoto Okabe, Hiroshi Seno
  • Organizer: 15th congress of ECCO
  • Int'l Joint Research
• [Presentation] 潰瘍性大腸炎治療の変化がCMV感染合併例の臨床転帰に及ぼす影響について (2019)
  • Author(s): 北本博規、山本修司、妹尾浩
  • Organizer: JDDW 2019
• [Presentation] HYA,A Metabolite of Linoleic Acid by the Commensal Bacteria, Ameliorates Colonic Inflammation in IL-10-deficient Mice Through the Alteration of Macrophage Function (2019)
  • Author(s): Makoto Okabe, Minoru Matsuura, Hiroki Kitamoto,Satoshi Yamada,Yusuke Honzawa, Shuji Yamamoto, Hiroshi Seno, Shigenobu Kishino,Jun Ogawa
  • Organizer: Digestive disease week 2019
  • Int'l Joint Research
• [Presentation] Risk factors of Epstein-Barr virus and cytomegalovirus reactivation in colonic mucosa of patients with artive ulcerative colitis (2019)
  • Author(s): Satoshi Yamada, Shuji Yamamoto, Yusuke Honzaawa, Hiroki Kitamoto, Makoto Okabe, Minoru Matsuura, Hiroshi Seno
  • Organizer: The 7th Annual Meeting of AOCC
  • Int'l Joint Research
• [Presentation] 潰瘍性大腸炎における上部消化管病変の検討 (2019)
  • Author(s): 山田聡 山本修司 本澤有介 妹尾浩
  • Organizer: 第102回 日本消化器内視鏡学会 近畿支部例会
• [Presentation] Reactivation of Epstein-Barr virus in the colonic mucosa of active ulcerative colitis (2019)
  • Author(s): Satoshi Yamada, Shuji Yamamoto, Hiroshi Seno
  • Organizer: JDDW 2019
• [Presentation] Efficacy and safety of tacrolimus therapy for elderly patients with ulcerative colitis (2019)
  • Author(s): Yusuke Honzawa, Shuji Yamamoto, Makoto Okabe, Hiroki Kitamoto, Satoshi Yamada, Hiroshi Seno
  • Organizer: The 7th Annual Meeting of AOCC
  • Int'l Joint Research
• [Presentation] クローン病狭窄例に対する経鼻内視鏡を用いた小腸内視鏡の試み－よりよい内視鏡評価を目指して－ (2019)
  • Author(s): 本澤有介、山本修司、妹尾浩
  • Organizer: JDDW 2019
• [Presentation] 当院における難治性潰瘍性大腸炎に対するGolimumabの使用経験 (2019)
  • Author(s): 北本博規、松浦稔、山本修司、妹尾浩
  • Organizer: 日本消化器病学会近畿支部 第110回例会
• [Presentation] Advance of medical therapies may improve the outcome of ulcerative colitis with cytomegalovirus infection (2019)
  • Author(s): Kitamoto H, Yamamoto S, Matsuura M, Honzawa Y, Yamada S, Okabe M, Seno H
  • Organizer: 14th Congress of ECCO
  • Int'l Joint Research
• [Presentation] サイトメガロウイルス再活性化を伴った潰瘍性大腸炎患者の内視鏡所見と臨床的背景に関する検討 (2018)
  • Author(s): 北本博規、松浦稔、岡部誠、山田聡、本澤有介、山本修司、妹尾浩
  • Organizer: 第9回日本炎症性腸疾患研究会学術集会
• [Presentation] Efficacy and safety of thiopurine and allopurinol cotherapy in thiopurine-naive Japanese UC patients (2018)
  • Author(s): Okabe M, Matsuura M, Kitamoto H, Yamada S, Honzawa Y, Yamamoto S, Seno H
  • Organizer: The 6th Annual Meeting of Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Impact of advance in medical therapies on clinical outcome in patients with ulcerative colitis concomitant cytomegalovirus infection (2018)
  • Author(s): Kitamoto H, Yamamoto S, Matsuura M, Honzawa Y, Yamada S, Okabe M, Seno H
  • Organizer: The 6th Annual Meeting of Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Endoscopic findings to predict therapeutic efficacy of anti-TNF agents on patients with ulcerative colitis (2018)
  • Author(s): Honzawa Y, Matsuura M, Kitamoto H, Okabe M, Yamada S, Yamamoto S, Seno H
  • Organizer: The 6th Annual Meeting of Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Remarks] 京都大学大学院医学研究科・消化器内科学ホームページ
  • URL: http://www.kuhp.kyoto-u.ac.jp/~gastro/gastro.html