These results might account for the low rate of fetal transmissio

These results might account for the low rate of fetal transmission and the associated risk of placental damage and preterm labor. Disclosures: The following people have nothing to disclose: Silvia Giugliano, Lucy Golden-Mason, Anita Kramer, Michael Gale, Virginia D. Winn, Hugo R. Rosen BACKGROUD&AIMS: The polymorphisms in IL-28B (IFN-λ3) gene are strongly associated with HCV clearance. However, the precise role of IFN-λ in HCV

elimination is largely unknown. It is generally accepted that the augmentation of intrahepatic ISGs, induced by endogenous IFNs, is prerequisite for anti-HCV response. Hepatocytes are reported to produce IFN-λs but not IFN-α/β, and drive intrahepatic ISGs; BAY 80-6946 molecular weight however, an involvement of other IFN-producers, such as dendritic cells (DCs) is yet to be determined. We reported that human BDCA3+DCs are main producer of IFN-λs in response to HCV (Hepatology 201 3). Thus, we aimed to clarify the roles of intrahepatic MLN0128 manufacturer BDCA3+DCs and IFN-λs in the induction of ISGs in adjacent HCV-infected hepatocytes by using an in vitro culture system. METHODS: We compared the frequency of DCs in the periphery and in the liver from paired donors. Immuno-histo-chemical analysis was done for identification of intrahepatic BDCA3+DCs. For the functional analysis, we freshly sorted DCs from 400ml of peripheral

blood or from intra-hepatic lymphocytes collected from surgically-resected non-cancerous MCE liver tissue. We co-cultured DCs with JFH-1-infected Huh 7.5.1 cells and quantified IFN-γs and IFN-λ by ELISA. Known 13 ISGs and HCVRNA levels in Huh7.5.1 were examined by qRT-PCR. RESULTS: The frequency of BDCA3+DCs in PBMC was extremely low (0.05%) but significantly higher in liver-infiltrated lymphocytes (0.3%). BDCA3+DCs, as defined as BDCA3+CLEC9A+ cells, were mainly localized in sinusoid lesions of the liver. BDCA3+DCs, from PBMC and liver, released large

amount of IFN-λ and pDCs released IFN-α in the presence of JFH-1-Huh7.5.1. The supernatants collected from HCV-stimulated BDCA3+DCs or pDCs suppressed HCV replication in a concentration-dependent manner, indicating that DCs are able to release bioactive IFNs. Most of 1 3 ISGs were significantly induced, and the up-regulated ISG profiles did not differ between BDCA3+DCs and pDCs. The induction of antiviral ISGs with BDCA3+DCs, such as ISG 15 and IFIT1, was positively correlated with the quantity of IFN-λ3 (ISG 15, r2=0.8, P<0.0001, IFIT1, r2=0.7, P<0.0001, respectively). In contrast, no correlation was found between the induction of RNF125orCXCL10and IFN-λ3 levels. ISG15 and IFIT1 were significantly more induced with BDCA3+DCs from IL-28B major than the mionor. CONCLUSIONS:Human BDCA3+DCs, being accumulated in the liver, produce IFN-λ in the presence of HCV-infected hepatocytes.

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