The developing the novel therapy by analyzing HBV-genotype specific immune-response

• Project/Area Number: 16K09335
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nagoya City University
• Principal Investigator: Kondo Yasuteru 名古屋市立大学, 大学院医学研究科, 研究員 (70455822)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: miRNAs / PD-L1 / HBV / miR34c-5p / アポトーシス / 免疫修飾因子 / ジェノタイプ / エキソソーム / miRNA / 免疫

Outline of Final Research Achievements

The aim of this study is to identify the specific miRNAs that could induce the differential immune response between HBV genotype B and C. One miRNA (miR34c) expression in the hepatocytes and exosomes was different between genotypes B and C (p<0.01). The network analysis indicated that miR34c could affect the apoptosis and PD-L1 expression. The transfection of the miR34c mimic could significantly suppress the expression of PD-L1 in monocytes. The amount of miR-34c in exosomes of Genotype C was significantly lower than that of Genotype B. Therefore, the expression of PD-L1 on the immune cells might not be suppressed in genotype C.

Academic Significance and Societal Importance of the Research Achievements

HBVジェノタイプBとCでは免疫反応が異なることが想定されていたが、メカニズムについては未だ不明な点が多かった。本研究によりmiR34c発現がジェノタイプBとCで異なることを見出した。このmiR34cの発現をコントロールすることによりHBV特異的な免疫反応を効率良く誘導出来る可能性があり、その結果としてウイルスの排除に役立つ可能性がある。HBVは未だ生体内から排除することが難しく、今回の結果は、これらの問題の解決に寄与する可能性がある。

Research Products

• [Journal Article] Hepatitis C Virus infection could affect the pathogenesis of ischemic heart diseases in northern part of Japan (2019)
  • Author(s): Fukuda R and Kondo Y
  • Journal Title: Hepatol Res. Volume: 49(3) Issue: 3 Pages: 355-359
  • DOI: 10.1111/hepr.13283
  • Peer Reviewed
• [Journal Article] Complete Atrioventricular Block Associated with Pembrolizumab-induced Acute Myocarditis: The Need for Close Cardiac Monitoring (2018)
  • Author(s): Katsume Y, Isawa T, Toi Y, Fukuda R, Kondo Y, Sugawara S and Ootomo T
  • Journal Title: Internal Medicine Volume: 57 Issue: 21 Pages: 3157-3162
  • DOI: 10.2169/internalmedicine.0255-17
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-11-01
  • Peer Reviewed
• [Journal Article] Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers (2018)
  • Author(s): Honma M, Sawada S, Ueno Y, Murakami K, Yamada T, Gao J, Kodama S, Izumi T, Takahashi K, Tsukita S, Uno K, Imai J, Kakazu E, Kondo Y, Mizuno K, Kawagishi N, Shimosegawa T, Katagiri H.
  • Journal Title: Int J Obes (Lond). Volume: 42 Issue: 9 Pages: 1544
  • DOI: 10.1038/s41366-018-0062-9
  • URL: https://localhost/en/publications/03d6071c-a6ce-48bd-ab6c-265d2bcab08d
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. (2017)
  • Author(s): Matsuura K, Honda M, et al.
  • Journal Title: Gastroenterology. Volume: - Issue: 6 Pages: 1383-1394
  • DOI: 10.1053/j.gastro.2017.01.041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatitis C virus has a genetically determined lymphotropism through co-receptor B7.2 (2017)
  • Author(s): Chen CL, Huang JY, Wang CH, Tahara SM, Zhou L, Kondo Y, Schechter J, Su L, Lai MM, Wakita T, Cosset FL, Jung JU, Machida K
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 13882-13882
  • DOI: 10.1038/ncomms13882
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of Hypoxia Inducible Factor 1α Subunit Pathway in Steatotic Liver Contributes to Formation of Cholestrol Gallstones. (2017)
  • Author(s): Asai Y, Yamada T, Tsukita S, Takahashi K, Maekawa M, Honma M, Ikeda M, Murakami K, Munakata Y, Shirai Y, Kodama S, Sugisawa T, Chiba Y, Kondo Y, Kaneko K, Uno K, Sawada S, Imai J, Nakamura Y, Yamaguchi H, Tanaka K, Sasano H, Mano N, Ueno Y, Shimosegawa T, Katagiri H
  • Journal Title: Gastroenterology Volume: 印刷中 Issue: 6 Pages: 30012-4
  • DOI: 10.1053/j.gastro.2017.01.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The expression of miR-125b-5p is increased in the serum of patients with chronic hepatitis B infection and inhibits the detection of hepatitis B virus surface antigen. (2016)
  • Author(s): Ninomiya M, Kondo Y, Kimura O, Funayama R, Nagashima T, Kogure T, Morosawa T, Tanaka Y, Nakayama K, Shimosegawa T.
  • Journal Title: J Viral Hepat. Volume: in press Issue: 5 Pages: 330-9
  • DOI: 10.1111/jvh.12522
  • Peer Reviewed
• [Journal Article] Reactivation of resolved hepatitis B virus infection with immune escape mutations after long-term corticosteroid therapy (2016)
  • Author(s): Inoue J, Kondo Y, Wakui Y, Kogure T, Morosawa T, Fujisaka Y, Umetsu T, Takai S, Nakamura T, Shimosegawa T
  • Journal Title: Clin J Gastroenterol Volume: 9 Issue: 2 Pages: 93-98
  • DOI: 10.1007/s12328-016-0631-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Global, cancer-specific microRNA cluster hypomethylation was functionally associated with the development of non-B non-C hepatocellular carcinoma. (2016)
  • Author(s): Nojima M, Matsui T, Tamori A, Kubo S, Shirabe K, Kimura K, Shimada M, Utsunomiya T, Kondo Y, Iio E, Naito Y, Ochiya T, Tanaka Y.
  • Journal Title: Molecular Cancer Volume: 15 Issue: 1 Pages: 31-31
  • DOI: 10.1186/s12943-016-0514-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The authors are equally contributed to this manuscript. PD-L1+MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment (2016)
  • Author(s): Iwata T, Kondo Y, Kimura O, Morosawa T, Fujisaka Y, Umetsu T, Kogure T, Inoue J, Nakagome Y, Shimosegawa T
  • Journal Title: Sci Rep. Volume: 14;6 Issue: 1
  • DOI: 10.1038/srep39296
  • Peer Reviewed / Open Access
• [Presentation] 免疫細胞におけるmiRNA発現変化はNF-κBシグナルを介して抗ウイルス免疫病態に不利に影響する (2018)
  • Author(s): 近藤泰輝、福田遼、田中靖人
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] HCV発がんに関与する末梢血単核球と血清中miRNAsの網羅的検討 (2018)
  • Author(s): 近藤泰輝、小暮高之、福田遼
  • Organizer: 第26回日本消化器病関連学会週間
• [Presentation] Differential expression of miR34c could affect the immune response of HBV infection (2018)
  • Author(s): Yasuteru Kondo, Takayuki Kogure, Kazuho Ikeo, Ryo Fukuda, Yasuhito Tanaka
  • Organizer: AASLD2018
• [Presentation] 次世代シーケンサーを用いたHBVジェノタイプ間で異なる発現をするmiRNAsの網羅的探索と機能解析 (2018)
  • Author(s): 近藤泰輝、福田遼、田中靖人
  • Organizer: 第42回日本肝臓学会東部会
• [Presentation] Differential expression of miRNAs could affect the immunopathogenesis of HBV infection (2017)
  • Author(s): Yasuteru Kondo, Takayuki Kogure, Norikazu Monma, Ryo Funayama, Keiko Nakayama, Kazuho Ikeo, Yasuhito Tanaka
  • Organizer: APASL2017 Annual Meeting
  • Place of Presentation: 上海（中国）
  • Year and Date: 2017-02-15
  • Int'l Joint Research
• [Presentation] 慢性C型肝炎、透析症例における免疫細胞プロファイルとインターフェロンフリー治療効果の関係 (2017)
  • Author(s): 近藤泰輝
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] B-TACEとC-TACEの早期治療効果の比較 (2017)
  • Author(s): 近藤泰輝
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 糖質制限食のNAFLD患者に与える治療効果と免疫細胞解析 (2017)
  • Author(s): 近藤泰輝
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 肝細胞癌治療におけるルストロンボパグ複数回使用による影響 (2017)
  • Author(s): 近藤泰輝
  • Organizer: JDDW2017
• [Presentation] 骨髄由来免疫抑制細胞の新規肝癌バイオマーカーとしての応用 (2016)
  • Author(s): 近藤泰輝、岩田朋晃、諸沢樹
  • Organizer: 第52回 日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉県・千葉市）
  • Year and Date: 2016-05-19
• [Presentation] パネルディスカッション4「B型肝炎ウイルス排除にむけて～創薬への新知見～」核酸アナログ-IFN Sequential療法反応性予測因子の同定 (2016)
  • Author(s): 近藤泰輝、諸沢樹、藤坂泰之
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都・新宿区）
  • Year and Date: 2016-04-21