| Co-Investigator(Kenkyū-buntansha) |
TAKEHARA Tetsuo Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (70335355)
HIRAMATSU Naoki Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (30362700)
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| Research Abstract |
The aim of the research project was to clarify the roles of dendritic cells (DC), including myeloid DC (MDC) or plasmacytoid DC (PDC), in the pathogenesis of hepatitis C virus-induced chronic hepatitis and hepatocellular carcinoma (HCC). In addition, we aimed to clarify the roles of DC system in the efficacy of IFN-a-based anti-HCV treatment.
The frequencies of blood MDC and PDC were decreased in HCV-infected patients compared to healthy donors. The abilities of both DC subsets, such as cytokine production and stimulation of T cells and NK cells, were significantly impaired as well. With regard to the capacity of Th polarization, MDC from the patients were less able to induce Thl response. However, PDC from the patients induced more IL-10-producing regulatory T cells, contributing to the alleviation of liver inflammation:
In chronic hepatitis C patients who underwent 48-week peg-IFNα and ribavirin therapy, we examined the frequencies of DC subsets and DC function throughout the therapy.
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In patients who attained sustained virological response (SVR), PDC frequency during the course was higher and DC ability at the end of therapy was better than those in patients who showed transient response (TR). These results demonstrate that maintenance of PDC frequency and DC function are involved in the IFN-mediated HCV eradication.
Dendritic cells utilize toll-like receptors (TLR), RIG-I and MDA-5 to sense virus and induce innate as well as adaptive immune responses. The expressions of TLR2,TLR4 and RIG-I in patients MDC were significantly higher than those in donor MDC. In contrast, TLR3 and MDA-5 expressions were comparable between them. When stimulated with specific agonists against TLR2,TLR3,TLR4 and RIG-I, MDC from the patients induced significantly less IFN-β and TNF-α, indicating signal transduction in the downstream of TLR and RIG-I was impaired in MDC from the patients. From the comprehensive RT-PCR analyses, the levels of TRIF and TRAF6 expression were significantly decreased in patient MDC, suggesting the possible role in HCV-induced signal interference.
In summary, DC system is a critical target of anti-HCV immune therapy: enhancing function of MDC leads to HCV eradication and that of PDC for retardation of disease progression, respectively. Less
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