Abstract
ObjectiveThe aim of this study was to longitudinally evaluate and analyze the role of interleukin-22-producing CD4 positive cells (IL-22) in the pathogenesis of Hepatitis C Virus recurrence after Orthotopic Liver Transplantation (HCV-OLT).Methods15 HCV-OLT, 15 age- and gender- matched non-HCV post-OLT (OLT) and 15 hepatitis C virus infected (HCV) patients were enrolled into our study from the liver transplantation and research center at Beijing 302 Hospital. We determined the frequencies of IL-22 using flow cytometry and expression of IL-22 mRNA using PCR in peripheral blood and liver tissue. We also divided HCV-OLT patients into rapid fibrosis progression (RFP) and slow fibrosis progression (SFP), examined IL-22 cells and analyzed the correlations between IL-22 frequencies and liver injury, fibrosis and clinical parameters. Moreover, we investigated the role of IL-22 in Human Hepatic Stellate Cells (HSCs).ResultsThe levels of serum IL-22, frequencies of IL-22 producing cells in peripheral blood mononuclear cells, and expression of IL-22 mRNA and protein in the liver in the HCV-OLT group were significantly higher than that in the HCV and OLT groups. Furthermore, eight (53.3%) patients developed RFP after two years; another three patients were diagnosed liver cirrhosis. The frequencies of IL-22 were much higher in RFP compared with SFP, while no significant difference existed between OLT and SFP. Intrahepatic IL-22 positive cells were located in fibrotic areas and significantly correlated with α-smooth muscle actin (α-SMA) and fibrosis staging scores, not with grading scores and HCRVNA. In vitro, IL-22 administration prevented HSCs apoptosis, promoted HSCs proliferation and activation, up-regulated the expression of HSC-sourced growth factors including α-SMA, TGF-β and TIMP-1, and increased the production of liver fibrosis markers including laminin, hyaluronic acid and collagen type IV.ConclusionPeripheral and intrahepatic IL-22 is up-regulated and plays a pathological role in exacerbating liver fibrosis by activating HSCs in HCV-OLT patients, which may predict RFP and serve as an attractive target for anti-fibrotic therapy.
Highlights
Chronic hepatitis C virus (HCV) infection is a major public health problem, with an estimated 130 to 170 million people currently infected worldwide and an additional 3 to 4 million are newly infected each year [1]
The frequencies of interleukin-22producing CD4 positive cells (IL-22) were much higher in rapid fibrosis progression (RFP) compared with slow fibrosis progression (SFP), while no significant difference existed between orthotopic liver transplantation (OLT) and SFP
Given IL-22 cells were co-localized with α-smooth muscle actin (α-SMA)+ Hepatic Stellate Cells (HSCs) in the portal area and positively correlated with liver fibrosis and progression of HCV recurrence after OLT (HCV-OLT), we further investigated the influence of IL-22 in regulating HSCs
Summary
Chronic hepatitis C virus (HCV) infection is a major public health problem, with an estimated 130 to 170 million people currently infected worldwide and an additional 3 to 4 million are newly infected each year [1]. HCV-related disease represents the most common indication for orthotopic liver transplantation (OLT) [4], accounting for around 40% of all cases on the United States waiting list [5]. Projections have showed a constant increase in the number of patients with HCV-related ESLD who will be listed for OLT over the 10 years [6]. Several certain pre-OLT factors such as donor age, severity of illness, as well as recipient and donor race have been associated with an increased risk of disease progression and worse post-OLT outcomes [10,11,12,13,14,15,16,17,18,19,20]. After OLT, persistent low-level inflammation and loss of viral control mechanisms from systemic immunosuppression are likely causes for the severe, accelerated progression of HCV-related cirrhosis [8, 21]. The pathogenesis is one of the most important issues in HCV-associated liver fibrosis research after OLT
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