感染症に対するインターフェロンラムダ３の応答性とその特異的な機能の解明

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23390117
• Research Institution: 独立行政法人国立国際医療研究センター
• Principal Investigator: 溝上 雅史 独立行政法人国立国際医療研究センター, その他部局等, その他 (40166038)
• Co-Investigator(Kenkyū-buntansha): 杉山 真也 独立行政法人国立国際医療研究センター, その他部局等, その他 (20612427) ; 村田 一素 独立行政法人国立国際医療研究センター, その他部局等, その他 (40345971) ; 鈴木 善幸 名古屋市立大学, その他の研究科, 教授 (70353430)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: インターフェロンラムダ / 転写 / シグナル伝達 / 進化 / 受容体

Research Abstract

C型慢性肝炎に対するペグインターフェロン/リバビリン併用療法 (Peg-IFN/RBV)の治療効果予測としてIL28B遺伝子多型は非常に重要な宿主因子である。IL28B遺伝子がコードする蛋白IFN-lambda3の定量系を独自開発し、患者末梢血単核球刺激後の上清中IFN-lambda3を測定したところ、IFN-lambda3誘導能によって治療効果予測が可能であり、それはIL28B遺伝子多型による予測よりも高い予測率を示した。さらに患者治療前血清中のIFN-lambda3にても治療効果予測は可能であった。C型肝炎の治療はウイルスそのものを標的としたdirect acting antiviralsに移行しつつあるが、経済的な問題からアジアを中心とした地域では依然、Peg-IFN/RBVが使用される。遺伝子診断は高度技術が必要で、かつ高価であるため、実行困難であるが、我々の開発した手法は容易かつ安価であり臨床応用に有用と考えられた。
IFN-lambda3の主な産生細胞は、樹状細胞のうちBDCA3およびBDCA4分画であることを証明し、BDCA3陽性樹状細胞は宿主に感染したC型肝炎ウイルスを認識し、toll-like receptor 3を介してIFN-lambda3を産生することを証明した。
IL28B近傍の遺伝子、IFN-lambda4、は日本人においてはIL28Bと強い連鎖不平衡を認めるため、Peg-IFN/RBV治療効果予測におけるIFN-lambda4の追加効果はない。そこで我々はウズベキスタンにおける治療効果とIFN-lambda4の関係を調べたところ、IL28B遺伝子多型にIFN-lambda4遺伝子多型を追加することによって治療効果予測は著明に高率となり、遺伝子解析における人種差の重要性を指摘した.

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] IL28B polymorphisms and clinical implications for hepatitis C virus infection in Uzbekistan (2014)
  • Author(s): Khudayberganova D, Sugiyama M, Masaki N, Nishida N, Mukaide M, Sekler D, Latipov R, Nataliya K, Dildora S, Sharapov S, Usmanova G, Raxmanov M, Musabaev E, Mizokami M
  • Journal Title: PLoS One Volume: 24;9 Pages: e93011
  • DOI: 10.1371/journal.pone.0093011
• [Journal Article] Ex vivo induction of IFN-λ3 by a TLR7 agonist determines response to Peg-IFN/ribavirin therapy in chronic hepatitis C patients (2014)
  • Author(s): Murata K, Sugiyama M, Kimura T, Yoshio S, Kanto T, Kirikae I, Saito H, Aoki Y, Hiramine S, Matsui T, Ito K, Korenaga M, Imamura M, Masaki N, Mizokami M
  • Journal Title: J Gastroenterol Volume: 49 Pages: 126-137
  • DOI: 10.1007/s00535-013-0814-1
  • Peer Reviewed
• [Journal Article] Risk factors for long-term persistence of serum hepatitis B surface antigen following acute hepatitis B virus infection in Japanese adults (2014)
  • Author(s): Ito K, Yotsuyanagi H, Yatsuhashi H, Karino Y, Takikawa Y, Saito T, Arase Y, Imazeki F, Kurosaki M, Umemura T, Ichida T, Toyoda H, Yoneda M, Mita E, Yamamoto K, Michitaka K, Maeshiro T, Tanuma J, Tanaka Y, Sugiyama M, Murata K, Masaki N, Mizokami M; Japanese AHB Study Group
  • Journal Title: Hepatology Volume: 59 Pages: 89-97
  • DOI: 10.1002/hep.26635
  • Peer Reviewed
• [Journal Article] Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP) (2014)
  • Author(s): Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, Iwamoto M, Nakajima S, Tsukuda S, Borroto-Esoda K, Sugiyama M, Tanaka Y, Kanai Y, Kusuhara H, Mizokami M, Wakita T
  • Journal Title: Hepatology Volume: 59 Pages: 1726-1737
  • DOI: 10.1002/hep.26982
  • Peer Reviewed
• [Journal Article] New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia (2014)
  • Author(s): Nishida N, Sawai H, Kashiwase K, Mizokami M, et al
  • Journal Title: PLoS One Volume: 9 Pages: e86449
  • DOI: 10.1371/journal.pone.0086449
  • Peer Reviewed
• [Journal Article] Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-λ in response to hepatitis C virus (2013)
  • Author(s): Yoshio S, Kanto T, Kuroda S, Matsubara T, Higashitani K, Kakita N, Ishida H, Hiramatsu N, Nagano H, Sugiyama M, Murata K, Fukuhara T, Matsuura Y, Hayashi N, Mizokami M, Takehara T
  • Journal Title: Hepatology Volume: 57 Pages: 1705-15
  • DOI: 10.1002/hep.26182
• [Journal Article] Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection (2013)
  • Author(s): Nakagawa S, Hirata Y, Kameyama T, Tokunaga Y, Nishito Y, Hirabayashi K, Yano J, Ochiya T, Tateno C, Tanaka Y, Mizokami M, Tsukiyama-Kohara K, Inoue K, Yoshiba M, Takaoka A, Kohara M
  • Journal Title: PLoS One Volume: 8 Pages: e59611
  • DOI: 10.1371/journal.pone.0059611
• [Presentation] Pre-treatment levels of serum IFN-3 more accurately predict sustained virological response by pegylated interferon/ribavirin therapy than IL28B genotyping in chronic hepatitis C patients (2013)
  • Author(s): Aoki Y, Murata K,, Sugiyama M, Kimura T, Takeda T, Yoshio S, Yamagiwa Y, Korenaga M, Imamura M, Kanto T, Masaki N, Mizokami M
  • Organizer: The 64th annual meeting of the American association for the study of liver diseases
  • Place of Presentation: Washington DC
  • Year and Date: 20131101-20131105
• [Presentation] Polymorphisms consisting of (TA)n dinucleotide repeat near IL28B gene could improve the predictive value for HCV spontaneous clearance with IL28B SNPs (2013)
  • Author(s): Sugiyama M, Hiramine S, Furusho N, Ido A, Tsubouchi H, Watanabe H, Ueno Y, Korenaga M, Murata K,, Masaki N, Mizokami M
  • Organizer: The 64th annual meeting of the American association for the study of liver diseases
  • Place of Presentation: Washington DC
  • Year and Date: 20131101-20131105
• [Presentation] Significant roles of IFN-3 with reciprocal levels in serum and ex vivo stimulated PBMC in chronic hepatitis C (2013)
  • Author(s): Aoki Y, Murata K,, Sugiyama M, Kimura T, Takeda T, Yoshio S, Nishida N, Yamagiwa Y, Korenaga M, Imamura M, Kanto T, Masaki N, Jong-Hon Kang, Mizokami M
  • Organizer: The 64th annual meeting of the American association for the study of liver diseases
  • Place of Presentation: Washington DC
  • Year and Date: 20131101-20131105
• [Presentation] Number of peripheral BDCA4+dendritic cells determines the response to pegylated interferon/ribavirin therapy in chronic hepatitis C patients (2013)
  • Author(s): Murata K, Sugiyama M, Kimura T, Takeda T, Yoshio S, Aoki Y, Nishida N, Yamagiwa Y, Korenaga M, Imamura M, Kanto T, Masaki N, Mizokami M
  • Organizer: The 64th annual meeting of the American association for the study of liver diseases
  • Place of Presentation: Washington DC
  • Year and Date: 20131101-20131105
• [Presentation] Human BDCA3+dendritic cells as a potent interferon- producer and an enhancer of helper T cell and natural killer cell responsive to hepatitis C virus (2013)
  • Author(s): Yoshio S, Kanto T, Matsubara T, Sugiyama M, Murata K,, Mizokami M, Hayashi N, Takehara T
  • Organizer: The 64th annual meeting of the American association for the study of liver diseases
  • Place of Presentation: Washington DC
  • Year and Date: 20131101-20131105
• [Presentation] Human BDCA3+DC contribute to the induction of intrahepatic ISGs as a potent IFN- producer in HCV infection (2013)
  • Author(s): Yoshio S, Kanto T, Matsubara T, Sugiyama M, Murata K,, Fukuhara T, Matsuura Y, Mizokami M, Hayashi N, Takehara T
  • Organizer: The 64th annual meeting of the American association for the study of liver diseases
  • Place of Presentation: Washington DC
  • Year and Date: 20131101-20131105
• [Patent(Industrial Property Rights)] インターフェロン治療効果予測方法 (2013)
  • Inventor(s): 溝上雅史、杉山真也、 村田一素、木村達治、内藤成子
  • Industrial Property Rights Holder: 溝上雅史、杉山真也、 村田一素、木村達治、内藤成子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-228369
  • Filing Date: 2013-11-01
  • Acquisition Date: 2013-11-01