NK/DC 细胞间对话在HCV感染中的作用及机制

Hepatitis C virus (HCV) infection is routinely managed clinically using pegylated interferon α and ribavirin. However, only half of the treated patients respond to this standard care. The mechanisms of non-responsiveness to the therapy are currently unclear. We have recently discovered that a cross-talk between NK cell and liver resident macrophage, Kupffer cell, exerts immune regulatory function in liver, both kupffer cell and monocyte-derived DC are inhibited by HCV Core protein. A similar cross-talk exists between NK cells and monocyte-derived DC. This leads us to hypothesized that HCV infection down modulates the cross-talk between NK and Kupffer cells in the liver, such a down regulation is reflected in the blood as an interference of the cross-talk between NK and DC, and interferon α treatment restores these cross-talk completely in some individuals but not in others. In present proposal, we further test these hypotheses. We will investigate in vivo the phenotype and function of NK and DC in a cohort of patients with HCV infection to analyze the role of NK/DC crosstalk and pegylated interferon α/ribavirin therapy; by developing NK/DC co-culture with HCV and pegylated interferon α/ribavirin therapy, we will expolit the mechamism of HCV modulate NK/DC crosstalk and pegylated interferon α/ribavirin therapy by restoring NK/DC crosstalk in HCV infection. A better understanding of how HCV and pegylated interferon α/ribavirin affects DC/NK crosstalk will facilitate the development of new antiviral drug and therapeutic strategies for patients with chronic HCV infection.

干扰素联合利巴韦林是国际上公认的慢性丙型肝炎抗病毒治疗的标准方案，但仍有大约一半患者对这个标准治疗无效，治疗无应答的机理尚不清楚。我们前期的研究结果表明:NK和枯否细胞间的对话在肝内发挥重要的免疫调节功能；HCV编码蛋白抑制枯否细胞抗病毒活性和外周血DC的分化发育。本课题拟进一步研究HCV调节DC/NK细胞间对话以及干扰素联合利巴韦林治疗如何解除HCV对DC/NK细胞间对话的抑制。我们将通过大样本调查HCV感染人群DC和NK细胞表型、功能变化研究DC/NK细胞对话在HCV感染及干扰素联合利巴韦林标准治疗HCV感染中的作用；建立体外DC/NK 细胞与HCV病毒/干扰素联合利巴韦林共培养系统，揭示HCV对DC/NK细胞间对话的调节机制以及干扰素联合利巴韦林治疗如何介导DC/NK细胞间对话恢复。这将有可能从DC/NK细胞间对话这个新的靶点开发新的丙肝治疗药物，并对临床慢性丙型肝炎的治疗提供指导。

干扰素联合利巴韦林是国际上公认的慢性丙型肝炎抗病毒治疗的标准方案，但仍有大约一半患者对这个标准治疗无效，治疗无应答的机理尚不清楚。我们前期的研究结果表明:NK和枯否细胞间的对话在肝内发挥重要的免疫调节功能；HCV编码蛋白抑制枯否细胞抗病毒活性和外周血DC的分化发育。本课题进一步研究HCV调节DC/NK细胞间对话以及干扰素联合利巴韦林治疗如何解除HCV对DC/NK细胞间对话的抑制。我们按计划进行了如下的实验研究：1）体内实验研究HCV感染对DC 和NK细胞作用。2）建立了DC/NK细胞共培养和HCV病毒培养系统，从而体外实验研究HCV调控DC/NK细胞对话机制。3）体内实验研究干扰素联合利巴韦林标准治疗对DC 和NK细胞的作用。4）体外实验研究干扰素联合利巴韦林标准治疗调节DC/NK细胞对话的机制。通过上述实验研究，我们总体上阐明了DC/NK细胞间对话在抗HCV感染免疫应答和干扰素联合利巴韦林标准治疗HCV感染中的作用, HCV对DC/NK细胞间对话的调节机制以及干扰素联合利巴韦林治疗介导DC/NK细胞间对话恢复。虽然有些实验研究没有达到我们的预期结果，我们还是基本上完成了我们的研究目标。在本项国家自然科学基金面上项目的资助下，本课题的研究得以顺利的进行。本实验室以第一作者和通讯作者并以本项目基金作为第一标注，我们已经在高水平国际期刊上发表科研论文6篇，总计影响因子近45分，最高单篇影响因子达16.66。另在国内期刊发表综述论文一篇。