OX40-mediated immune regulation in viral hepatitis and hepatocellular carcinoma

肝炎病毒的持续感染是进展性肝病的主要风险因素，在全世界数百万慢性感染个体中引起严重并发症，如慢性肝衰竭和肝细胞癌（HCC）。目前慢性病毒性肝炎和HCC的治疗方法有很大的局限性，尽管近年来在开发抗HCV感染的新疗法方面取得了很大进展。然而，对预防性疫苗的迫切需求仍然存在，并且迫切需要新的治疗策略来应对慢性HBV感染和肝癌，因为当前的疗法不能为受影响的个体提供治愈。基于T细胞的免疫疗法已经被认为是一种有前途的方法来应对慢性感染患者中的HBV和治疗恶性肿瘤如HCC。事实上，癌症免疫疗法已被《科学》杂志选为2013年的突破性进展。为了建立基于T细胞的免疫疗法的方案，对病毒特异性（和肿瘤特异性）T细胞应答的详细了解是至关重要的。事实上，控制病毒性肝炎临床结果的免疫学决定因素仍不完全清楚，需要进一步研究。过去十年的研究提供了关于慢性病毒性肝炎和HCC背景下T细胞功能障碍的见解。虽然在鉴定和表征负调节T细胞应答的抑制性途径方面已经做出了很大努力，但在这些背景下可以正调节T细胞应答的途径尚未得到全面分析。因此，为了解决这一缺点，我们建议确定在持续性病毒性肝炎以及HCC期间有可能挽救功能失调的免疫反应的途径。重要的是，申请人可以在慢性病毒的小鼠模型中证明，通过TNF受体超家族成员OX 40的信号是维持功能性免疫应答的关键参与者。然而，OX 40是否积极维持人类病毒性肝炎中的T细胞应答或OX 40刺激是否具有增强HBV、HCV或HCC中的病毒特异性或肿瘤特异性T细胞应答的能力从未被分析过。共刺激OX 40分子及其相关的TNF-α的详细分析，受体家族成员及其在调节T细胞应答中的作用是必需的，以便更深入地了解慢性病毒性肝炎和肝细胞癌背景下如何调节适应性免疫。这些知识对于建立HBV感染和HCC的免疫方法至关重要。

Persistent infections with hepatitis viruses are major risk factors for progressive liver disease causing severe complications such as chronic liver failure and hepatocellular carcinoma (HCC) in millions of chronically infected individuals worldwide. Current therapies for chronic viral hepatitis and HCC have major limitations although great advances have been made in the development of novel therapeutics against HCV infection in recent years. However, the pressing need for a preventive vaccine persists and new therapeutic strategies to tackle chronic HBV infection and liver cancer are desperately needed as current therapies fail to offer a cure for affected individuals.T cell based immunotherapy has been suggested to be a promising approach to tackle HBV in chronically infected patients and to treat malignancies such as HCC. Indeed, cancer-immunotherapy has been selected as breakthrough-of-the-year 2013 by SCIENCE magazine. In order to establish protocols for T cell based immunotherapies, a detailed knowledge of the virus-specific (and tumor-specific) T cell responses is of critical importance. Indeed, the immunologic determinants that govern the clinical outcome of viral hepatitis remain incompletely understood and require further investigation. The last decade of research has provided insights on T cell dysfunctions in the setting of chronic viral hepatitis and HCC. And while great efforts have been made in the identification and characterization of the inhibitory pathways that negatively regulate T cell responses, pathways that can positively regulate T cell responses in these contexts have not been comprehensively analyzed. Thus, in order to address this shortcoming, we propose to identify the pathways that bear the potential to rescue the dysfunctional immune responses during persistent viral hepatitis as well as HCC. Importantly, the applicant could demonstrate in a mouse model of chronic viral that signals through the TNF-receptor superfamily member OX40 are crucial players in maintaining functional immune responses. However, whether OX40 actively sustains T cell responses in viral hepatitis in humans or whether OX40 stimulation has the ability to enhance virus-specific or tumor-specific T cell responses in HBV, HCV or HCC has never been analyzed.Thus, a detailed analysis of the co-stimulatory OX40 molecule and its related TNF-receptor family members and their role in regulating T cell responses is required in order to gain a deeper understanding of how adaptive immunity is regulated in the setting of chronic viral hepatitis and hepatocellular carcinoma. Such knowledge will be vital for the establishment of immunotherapeutic approaches in HBV-infection and HCC.