Ex vivo induction of IFN-λ3 by a TLR7 agonist determines response to Peg-IFN/Ribavirin therapy in chronic hepatitis C patients

• Published in: Journal of gastroenterology Vol. 49; no. 1; pp. 126 - 137
• Main Authors: Murata, Kazumoto, Sugiyama, Masaya, Kimura, Tatsuji, Yoshio, Sachiyo, Kanto, Tatsuya, Kirikae, Ikue, Saito, Hiroaki, Aoki, Yoshihiko, Hiramine, Satoshi, Matsui, Teppei, Ito, Kiyoaki, Korenaga, Masaaki, Imamura, Masatoshi, Masaki, Naohiko, Mizokami, Masashi
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 2014
• Subjects: Abdominal Surgery; Aged; Aminoquinolines - pharmacology; Antiviral Agents - therapeutic use; Biliary Tract; Cells, Cultured; Colorectal Surgery; Dendritic Cells - metabolism; Drug Therapy, Combination; Female; Gastroenterology; Genotype; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Hepatology; Humans; Imiquimod; Interferon-alpha - therapeutic use; Interferons; Interleukins - biosynthesis; Interleukins - blood; Interleukins - genetics; Leukocytes, Mononuclear - metabolism; Male; Medicine; Medicine & Public Health; Middle Aged; Original Article—Liver; Original —Liver, Pancreas, and Biliary Tract; Pancreas; Polymorphism, Single Nucleotide; Prognosis; Ribavirin - therapeutic use; RNA, Messenger - genetics; Surgical Oncology; Toll-Like Receptor 7 - agonists; Treatment Outcome; IL28B; Chronic hepatitis C; IFN-λ3; Peg-IFN/RBV
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-013-0814-1

Background Genetic variation around interleukin-28B ( IL28B ), encoding IFN-λ3, predict non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy in chronic hepatitis C (CHC). However, it remains unclear the expression and the role of IL28B itself. The aim of this study is to develop easy and useful methods for the prediction of treatment outcomes. Methods The mRNA and protein levels of IFN-λ3 induced by ex vivo stimulation of peripheral blood mononuclear cells (PBMC) or magnetically selected dendritic cells (DCs) with toll-like receptor agonists (TLR3; poly I:C, TLR7; R-837) were measured by the quantitative real-time polymerase chain reaction and our newly developed chemiluminescence enzyme immunoassays, respectively, and compared with the clinical data. Results We found that BDCA-4 + plasmacytoid and BDCA-3 + myeloid DCs were the main producers of IFN-λs when stimulated with R-837 and poly I:C, respectively. Detectable levels of IFN-λs were inducible even in a small amount of PBMC, and IFN-λ3 was more robustly up-regulated by R-837 in PBMC of CHC patients with favorable genotype for the response to Peg-IFN/RBV (TT in rs8099917 ) than those with TG/GG. Importantly, the protein levels of IFN-λ3 induced by R-837 clearly differentiated the response to Peg-IFN/RBV treatment ( p  = 1.0 × 10 −10 ), including cases that IL28B genotyping failed to predict the treatment response. The measurement of IFN-λ3 protein more accurately predicted treatment efficacies (95.7 %) than that of IL28B genotyping (65.2 %). Conclusions Genetic variations around IL28B basically affect IFN-λ3 production, but different amounts of IFN-λ3 protein determines the outcomes of Peg-IFN/RBV treatment. This study, for the first time, presents compelling evidence that IL28B confer a functional phenotype.