The analysis of IFN-lambda related innate immunity and the mechanism of immne escape of HBV using human induced pluripotent stem cell-derived hepatic cell lines.

• Project/Area Number: 17K15931
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MURAKAWA Miyako 東京医科歯科大学, 医学部附属病院, 助教 (20733851)
• Research Collaborator: ASANIHA Yasuhiro ; KAKINUMA Sei
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: インターフェロンラムダ / ウイルス性肝炎 / 発癌 / B型肝炎 / IFNλ / ウイルス / 免疫 / iPS細胞

Outline of Final Research Achievements

We investigated the role of IFN-λ on chronic viral hepatitis using both human induced pluripotent stem cell-derived hepatic cell lines and liver biopsy samples, blood samples, and clinical data obtained from the patients with viral hepatitis. The difference of anti-viral effect and expression of ISGs according to the expression levels of IFNL were shown in our study. Moreover, we found that the risk for HCC development were high in the patients under the antiviral treatment with higher expression levels of serum IFN-λ3. Additionally, by the sub-analysis of HBV clinical data, we confirmed the relationship between diabetes mellitus and HCC development in the patients in whom HBV replication were suppressed well.

Academic Significance and Societal Importance of the Research Achievements

今回、新規抗HBV治療薬の開発に直結する成果は得られなかったが、IFNλの機能には未だ不明点が多い中で、ウイルスが駆除された状況でもIFNλ3が誘導され、かつその後の発癌とも関連するという新たな知見は、今後問題となり続ける抗ウイルス治療後発癌に対する治療戦略における新たなターゲットを見出せた点で有意義である。また、IFNλ3の抗HBV作用について臨床データを用いた再検証を行う中で、現在急増している糖尿病がHBV肝癌に関わることを示したことは、癌健診の啓蒙などの社会的意義も大きい。

Research Products

• [Journal Article] .Association of serum IFN-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents. (2019)
  • Author(s): Emi Inoue-Shinomiya, Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Jun Tsuchiya, Ayako Sato, Tomoyuki Tsunoda, Masato Miyoshi, Sayuri Nitta, Fukiko Kawai-Kitahata, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Kazumoto Murata, Masashi Mizokami, Mamoru Watanabe.
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 5 Pages: 500-511
  • DOI: 10.1111/hepr.13307
  • Peer Reviewed / Open Access
• [Journal Article] Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients (2019)
  • Author(s): Nitta S, Asahina Y, Kato T, Tsuchiya J, Inoue-Shinomiya E, Sato A, Tsunoda T, Miyoshi M, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Hikita H, Takehara T, Watanabe M.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5722-5722
  • DOI: 10.1038/s41598-019-42114-z
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Fibrocystin Promotes Interleukin-8-Dependent Proliferation and CTGF Production of Biliary Epithelium. (2019)
  • Author(s): Tsunoda T, Kakinuma S, Miyoshi M, Kamiya A, Kaneko S, Sato A, Tsuchiya J, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Sogo T, Komatsu H, Mukouchi R, Inui A, Fujisawa T, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Journal of Heptatology Volume: 印刷中 Issue: 1 Pages: 143-152
  • DOI: 10.1016/j.jhep.2019.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells. (2019)
  • Author(s): Miyoshi M, Kakinuma S, Kamiya A, Tsunoda T, Tsuchiya J, Sato A, Kaneko S, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2072-2072
  • DOI: 10.1038/s41598-018-37430-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diabetic Retinopathy as a Risk Factor Associated with the Development of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. (2019)
  • Author(s): Azuma S, Asahina Y, Kakinuma S, Azuma K, Miyoshi M, Inoue E, Tsunoda T, Sato A, Kaneko S, Nagata H, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Tomita M, Nakagawa M, Watanabe M.
  • Journal Title: Digestive Diseases Volume: 37 Issue: 3 Pages: 247-254
  • DOI: 10.1159/000493580
  • Peer Reviewed
• [Journal Article] Association Between Alanine Aminotransferase Elevation And UGT1A1*6 Polymorphisms In Daclatasvir And Asunaprevir Combination Therapy For Chronic Hepatitis C. (2017)
  • Author(s): Maekawa S, Sato M, Kuratomi N, Inoue T, Suzuki Y, Tatsumi A, Miura M, Matsuda S, Muraoka M, Nakakuki N, Amemiya F, Takano S, Fukasawa M, Nakayama Y, Yamaguchi T, Sato T, Sakamoto M, Murakawa M, Nakagawa M, Asahina Y, Enomoto N.
  • Journal Title: J Gastroenterol Volume: 印刷中 Issue: 6 Pages: 780-786
  • DOI: 10.1007/s00535-017-1405-3
  • Peer Reviewed / Open Access
• [Journal Article] Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. (2017)
  • Author(s): Nagata H, Nakagawa M, Asahina Y, Sato A, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Nouchi T, Sakai H, Tomita M, Watanabe M
  • Journal Title: J Hepatol Volume: 67 Issue: 5 Pages: 933-939
  • DOI: 10.1016/j.jhep.2017.05.028
  • Peer Reviewed / Open Access
• [Journal Article] ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin. (2017)
  • Author(s): Murakawa M, Asahina Y, Nagata H, Nakagawa M, Kakinuma S, Nitta S, Kawai-Kitahata F, Otani S, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Sato A, Itsui Y, Azuma S, Nouchi T, Furumoto Y, Asano T, Chuganji Y, Tohda S, Watanabe M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 11 Pages: 1212-1218
  • DOI: 10.1111/hepr.12867
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic IFNL4 expression is associated with non-response to interferonbased therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients. (2017)
  • Author(s): Murakawa M, Asahina Y, Kawai-Kitahata F, Nakagawa M, Nitta S, Otani S, Nagata H, Kaneko S, Asano Y, Tsunoda T, Miyoshi M, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Iijima S, Tsuchiya K, Izumi N, Tohda S, Watanabe M.
  • Journal Title: J Med Virol Volume: in press Issue: 7 Pages: 1241-1247
  • DOI: 10.1002/jmv.24763
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bone Morphogenetic Protein-4 Modulates Proliferation and Terminal Differentiation of Fetal Hepatic Stem/Progenitor Cells. (2016)
  • Author(s): Goto F, Kakinuma S, Miyoshi M, Tsunoda T, Kaneko S, Sato A, Asano Y, Otani S, Azuma S, Nagata H, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Asahina Y, Watanabe M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 9 Pages: 941-952
  • DOI: 10.1111/hepr.12823
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] The association of serum IFN-λ3 levels with liver fibrosis and hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents. (2019)
  • Author(s): Miyako Murakawa, Emi Inoue-Shinomiya, Yasuhiro Asahina, Mina Nakagawa, Jun Tsuchiya, Ayako Sato, Masato Miyoshi, Tomoyuki Tsunoda, Fukiko Kawai-Kitahata, Sayuri Nitta, Yasuhiro Itsui, Sei Kakinuma, Seishin Azuma, Mamoru Watanabe
  • Organizer: The International Liver Congress 2019 (EASL)
  • Int'l Joint Research
• [Presentation] B型慢性肝炎の長期経過におけるウイルス動態およびHBs抗原陰性化予測因子の検討 (2018)
  • Author(s): 村川美也子、朝比奈靖浩、渡辺守
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] B型慢性肝疾患に対する核酸アナログ治療例・未治療例における発癌背景因子の解析 (2018)
  • Author(s): 村川美也子、朝比奈靖浩、渡辺守
  • Organizer: 第22回日本肝臓学会大会 （JDDW2018)
• [Presentation] Genetic differences in hepatocellular carcinoma among chronic persistent hepatitis B virus infection with or without viral suppression and prior hepatitis B virus infection. (2017)
  • Author(s): Kawai-Kitahata F, Asahina Y, Kakinuma S, Murakawa M, Niita S, Nagata H, Kaneko S, Otani S, Miyoshi M, Tsunoda T, Sato A, Nakagawa M, Itsui Y, Azuma S, Tanaka S, Tanabe M, Maekawa S, Enomoto N, Watanabe M.
  • Organizer: EASL The International Liver Congress 2017
  • Int'l Joint Research
• [Presentation] 潰瘍性大腸炎に合併した急性膵炎の２例 (2017)
  • Author(s): 保志ゆりか、矢内真人、松岡克善、日比谷秀爾、勝倉暢洋、竹中健人、鬼澤道夫、北畑富貴子、村川美也子、新田沙由梨、藤井俊光、岡田英理子、井津井康浩、中川美奈、柿沼 晴、東 正新、長堀正和、大塚和朗
  • Organizer: 日本消化器病学会関東支部第344回例会
• [Presentation] 免疫抑制状態でのE 型肝炎慢性化症例の解析 (2017)
  • Author(s): 井津井康浩、大谷賢志、北畑富貴子、新田沙由梨、村川美也子、中川美奈、柿沼 晴、東 正新、高橋和明、朝比奈靖浩、渡辺 守
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] HCV-NS5A 阻害薬使用に関連する薬剤耐性変異ウイルスとその特徴 (2017)
  • Author(s): 新田沙由梨、村川美也子、永田紘子、佐藤綾子、三好正人、角田知之、浅野 侑、金子 俊、大谷賢志、北畑富貴子、東 正新、柿沼 晴、中川美奈、加藤孝宣、朝比奈靖浩、渡辺 守
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 食餌誘導性NASH モデルマウスにおけるMatrix Metalloporoteinase-2 の機能的解析 (2017)
  • Author(s): 柿沼 晴、浅野 侑、三好正人、佐藤綾子、角田知之、金子 俊、大谷賢志、永田紘子、北畑富貴子、村川美也子、新田沙由梨、井津井康浩、中川美奈、東 正新、朝比奈靖浩、渡辺 守
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] C 型慢性肝炎に対するIFN-based, IFN-free 治療後発癌および発癌予測因子についての検討. (2017)
  • Author(s): 永田紘子、中川美奈、朝比奈靖浩、柿沼 晴、東 正新、井津井康浩、新田沙由梨、村川美也子、北畑富貴子、金子 俊、浅野 侑、井上恵美、角田知之、三好正人、佐藤綾子、渡辺 守
  • Organizer: 第16回日本肝がん分子標的治療研究会
• [Presentation] ヒトiPS 細胞培養系を利用したHBV-HCV 共感染下でのHCV 排除により惹起されるHBV の再活性化メカニズムの解明 (2017)
  • Author(s): 金子 俊、柿沼 晴、朝比奈靖浩、紙谷聡英、三好正人、角田知之、四宮恵美、佐藤綾子、浅野 有、新田沙由梨、村川美也子、井津井靖浩、東 正新、渡辺 守
  • Organizer: 第24回肝細胞研究会
• [Presentation] 肝炎ウイルス制御下およびB 型肝炎ウイルス既往感染における肝細胞癌遺伝子変異の検討 (2017)
  • Author(s): 北畑富貴子、朝比奈靖浩、田中信二、村川美也子、新田沙由梨、柿沼 晴、永田紘子、金子 俊、浅野 侑、角田知之、三好正人、井上恵美、佐藤綾子、井津井康浩、中川美奈、東 正新、田邉 稔、前川伸哉、榎本信幸、渡辺 守
  • Organizer: 第53回日本肝癌研究会
• [Presentation] ヒトiPS 細胞由来肝臓系譜細胞による病態モデルの作成と先天性肝線維症の病態解析 (2017)
  • Author(s): 角田知之、柿沼 晴、三好正人、佐藤綾子、四宮恵美、金子 俊、浅野 侑、村川美也子、新田沙由梨、井津井康浩、東 正新、中川美奈、朝比奈靖浩、渡辺 守
  • Organizer: 第54回日本消化器免疫学会総会
• [Presentation] ２年間持続する貧血があり、イレウス症状を契機に診断に至った原発性小腸癌の１例 (2017)
  • Author(s): 近藤有紀、藤井 崇、日比谷秀爾、勝倉暢洋、竹中健人、鬼澤道夫、北畑富貴子、村川美也子、松岡克善、新田沙由梨、藤井俊光、岡田英理子、井津井康浩、齋藤詠子、中川美奈、柿沼 晴、長堀正和、大塚和朗、渡辺 守、高岡亜弓、山内慎一
  • Organizer: 日本消化器病学会関東支部第346回例会
• [Presentation] B 型慢性肝疾患における核酸アナログ治療成績と肝発癌予測因子の検討 (2017)
  • Author(s): 村川美也子、朝比奈靖浩、中川美奈、東 正新、柿沼 晴、井津井康浩、新田沙由梨、北畑富貴子、金子俊、永田紘子、浅野 侑、三好正人、角田知之、井上恵美、佐藤綾子、渡辺 守
  • Organizer: JDDW2017 第21回肝臓学会大会
• [Presentation] On-treatment higher levels of alpha-fetoprotein and M2BPGi are associated with development of hepatocellular carcinoma during nucleos(t)ide analog therapy in patients with HBV chronic infection. (2017)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Nitta S, Kawai-Kitahata F, Nagata H, Kaneko S, Asano Y, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Sato A, Itsui Y, Kakinuma S, Azuma S, Watanabe M.
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] The analysis of NS5A Resistance-Associated Substitutions (RAS): In vitro study of NS5A recombinant hepatitis C in infectious cell culture system for various RAS detected after treatment failure in chronic hepatitis C patients. (2017)
  • Author(s): Nitta S, Murakawa M, Kato T, Sato A, Tsunoda T, Miyoshi M, Asano Y, Kaneko S, Nagata H, Kawai-Kitahata F, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Asahina Y.
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] A novel culture model for coinfection of hepatitis B and hepatitis C viruses using human induced pluripotent stem cell-derived hepatic cells for analyses of changes in host-innate immune responses. (2017)
  • Author(s): Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Nitta S, Sato A, Asano Y, Nagata H, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Watanabe M.
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] Evaluation of an early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C patients treated with All-Oral DAAs - propensity score-matched analysis of a prospective database. (2017)
  • Author(s): Nakagawa M, Asahina Y, Nagata H, Kaneko S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Tanaka Y,Watanabe M.
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Book] B 型・C 型肝炎の抗ウイルス療法 最前線の治療エッセンス (2017)
  • Author(s): 村川美也子、中川美奈、朝比奈靖浩.
  • Total Pages: 195
  • Publisher: 医薬ジャーナル社
  • ISBN: 9784753228430