Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Drug delivery, 2018-04, Vol.25 (1), p.1055-1065

Ort / Verlag

England: Taylor & Francis

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.