CD137-Mediated Pathogenesis from Chronic Hepatitis to Hepatocellular Carcinoma in Hepatitis B Virus-Transgenic Mice

Abstract

Chronic hepatitis B virus (HBV) infection is characterized by sustained liver inflammation with an influx of lymphocytes, which contributes to the development of cirrhosis and hepatocellular carcinoma. The mechanisms underlying this immune-mediated hepatic pathogenesis remain ill defined. We report in this article that repetitive infusion of anti-CD137 agonist mAb in HBV-transgenic mice closely mimics this process by sequentially inducing hepatitis, fibrosis, cirrhosis, and, ultimately, liver cancer. CD137 mAb initially triggers hepatic inflammatory infiltration due to activation of nonspecific CD8+ T cells with memory phenotype. CD8+ T cell-derived IFN-γ plays a central role in the progression of chronic liver diseases by actively recruiting hepatic macrophages to produce fibrosis-promoting cytokines and chemokines, including TNF-α, IL-6, and MCP-1. Importantly, the natural ligand of CD137 was upregulated significantly in circulating CD14+ monocytes in patients with chronic hepatitis B infection and closely correlated with development of liver cirrhosis. Thus, sustained CD137 stimulation may be a contributing factor for liver immunopathology in chronic HBV infection. Our studies reveal a common molecular pathway that is used to defend against viral infection but also causes chronic hepatic diseases.

Memory CD8+T Cells Are Sufficient To Alleviate Impaired Host Resistance to Influenza A Virus Infection Caused by Neonatal Oxygen Supplementation

“…Very few investigations have evaluated how memory CD8 ϩ T cells affect fibrosis development in infectious models. Previous studies have suggested that fibrosis associated with chronic hepatitis is promoted by nonspecific activation of memory CD8 ϩ T cells (28,40). For a bleomycin-induced fibrosis model, it was hypothesized that recently activated memory T cells may contribute to lung pathology via interaction with inflammatory dendritic cells (DCs) (1).…”

HBV Induced HCC: Major Risk Factors from Genetic to Molecular Level

“…As studies revealed that immune mediated necro-inflammation is another cause of HCC development [151]. It was found that CD8 + T cell causes hepatic inflammation derive by INF gamma [152]. It was demonstrated that metabolic syndrome (MS) was associated with both cryptogenic cirrhosis and nonalcoholic steatohepatitis, Currently MS can be consider as an independent and major risk factor for CHB infection related Cirrhosis [153–155] and HCC development [156].…”

The Comparison between HBV Transgenic Mice and Normal Mice after Being Injected Concanavalin A (Con A)

“…T cells in the livers can be used as the standard of damage for livers [23]; in this experiment, we detected the level of CD4+ cells and CD8+ cells by means of the flow cytometry detection. Comparing the two groups of mice, we could find that in 16 h after the injection of Concanavalin A, the concentration of the CD4+ and CD8+ in HBV transgenic mice livers is higher than that in the normal mice's livers, which told us that the HBV transgenic mice were more facile to be damaged by the stimulation than the normal mice in immunology.…”