Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions

• Minayoshi, Yuki

• Maeda, Hitoshi

• Yanagisawa, Hiroki

• Hamasaki, Keisuke

• Mizuta, Yuki

• Nishida, Kento

• Kinoshita, Ryo

• Enoki, Yuki

• Imafuku, Tadasi

• Chuang, Victor Tuan Giam

• Koga, Tomoaki

• Fujiwara, Yukio

• Takeya, Motohiro

• Sonoda, Kayoko

• Wakayama, Tomohiko

• Taguchi, Kazuaki

• Ishima, Yu

• Ishida, Tatsuhiro

• Iwakiri, Yasuko

• Tanaka, Motohiko

• Sasaki, Yutaka

• Watanabe, Hiroshi

• Otagiri, Masaki

• Maruyama, Toru

Abstract

Because of its multifaceted anti-inflammatory and immunomodulatory effects, delivering type-I interferon to Kupffer cells has the potential to function as a novel type of therapy for the treatment of various types of hepatitis. We report herein on the preparation of a Kupffer cell targeting type-I interferon, an albumin-IFNα2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFNα2b, attached by combining albumin fusion technology and site-directed mutagenesis. The presence of this unique oligosaccharide permits the protein to be efficiently, rapidly and preferentially distributed to Kupffer cells. Likewise IFNα2b, Man-HSA(D494N)-IFNα2b caused a significant induction in the mRNA levels of IL-10, IL-1Ra, PD-L1 in RAW264.7 cells and mouse isolated Kupffer cells, and these inductions were largely inhibited by blocking the interferon receptor. These data indicate that Man-HSA(D494N)-IFNα2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFNα2b significantly inhibited liver injury in Concanavalin A (Con-A)-induced hepatitis model mice, and consequently improved their survival rate. Moreover, the post-administration of Man-HSA(D494N)-IFNα2b at 2 h after the Con-A challenge also exerted hepato-protective effects. In conclusion, this proof-of-concept study demonstrates the therapeutic effectiveness and utility of Kupffer cell targeting type-I interferon against hepatitis via its anti-inflammatory and immunomodulatory actions.

Journal

• Drug Delivery

  Drug Delivery 25 (1), 1055-1065, 2018-04-24

  Taylor & Francis

Keywords

• Type-I interferon
• Kupffer cell
• albumin fusion technology
• mannose
• anti-inflammation
• immunomodulation

Details

• CRID: 1050569094120036480
• NII Article ID: 120006941111
• NII Book ID: AA10999339
• ISSN: 10717544
• ISSN: 15210464
• DOI: 10.1080/10717544.2018.1464083
• Web Site: http://repo.lib.tokushima-u.ac.jp/115087
• Web Site: https://www.tandfonline.com/doi/pdf/10.1080/10717544.2018.1464083
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN