OX40-mediated immune regulation in viral hepatitis and hepatocellular carcinoma

OX40介导的病毒性肝炎和肝细胞癌的免疫调节

• 批准号: 279710275
• 负责人: Professor Dr. Tobias Böttler
• 金额: --
• 依托单位: Klinik für Innere Medizin II - Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/279710275?language=en
• 关键词: OX40; mediated; immune; regulation; viral

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.

肝炎病毒的持续感染是进行性肝病的主要危险因素，在全球数百万慢性感染者中会导致严重的并发症，如慢性肝功能衰竭和肝细胞癌(HCC)。尽管近年来针对丙型肝炎病毒感染的新疗法的开发取得了很大进展，但目前治疗慢性病毒性肝炎和肝细胞癌的方法有很大的局限性。然而，对预防性疫苗的迫切需求仍然存在，迫切需要新的治疗策略来应对慢性乙肝感染和肝癌，因为目前的治疗方法无法为受影响的个体提供治愈。基于T细胞的免疫疗法被认为是一种很有前途的方法来治疗慢性感染患者的乙肝病毒和治疗恶性肿瘤，如肝癌。事实上，癌症免疫疗法已被《科学》杂志选为2013年年度突破。为了建立基于T细胞的免疫治疗方案，对病毒特异性(和肿瘤特异性)T细胞反应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然不完全清楚，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肝细胞癌背景下T细胞功能障碍的见解。虽然在鉴定和表征负向调节T细胞反应的抑制通路方面已经做了很大的努力，但在这些情况下能够正向调节T细胞反应的途径还没有得到全面的分析。因此，为了解决这一缺陷，我们建议确定在持续性病毒性肝炎和肝细胞癌期间有可能挽救功能失调的免疫反应的途径。重要的是，申请者可以在慢性病毒的小鼠模型中证明，通过肿瘤坏死因子受体超家族成员OX40的信号在维持功能性免疫反应方面起着关键作用。然而，OX40在人类病毒性肝炎中是否主动维持T细胞反应，或者OX40刺激是否具有增强病毒特异性或肿瘤特异性T细胞反应的能力从未被分析过。因此，需要详细分析共刺激OX40分子及其相关的肿瘤坏死因子受体家族成员及其在调节T细胞反应中的作用，以便更深入地了解适应性免疫在慢性病毒性肝炎和肝细胞癌的背景下是如何调节的。这些知识对于建立针对乙肝病毒感染和肝细胞癌的免疫治疗方法至关重要。