第24届亚太地区肝脏研究协会年会（APASL 2014）于2014年3月12～15日在澳大利亚布里斯班召开。会上中国人民解放军第302医院肝病生物治疗研究中心王福生教授介绍了T细胞在HBV发病机制和免疫治疗中的作用。
 

王福生教授
 

乙型肝炎病毒（HBV）是人类急慢性肝炎、肝硬化和肝细胞癌的主要病因。HBV本身通常被认为是非致细胞病变型病毒。HBV感染的发病机制，至少有部分，归因于T细胞对HBV抗原的直接反应。特别是，HBV感染中适应性T细胞免疫衰竭的作用已被广泛认识。
 

第一，HBV感染导致肝脏炎症和纤维化，这与肝脏内T细胞反应紊乱有关，包括Th17,Treg和NK细胞。第二，HBV持续复制和维持高水平病毒蛋白，尤其是HBsAg，可能会持续抑制通过调控多种关键环节例如调节T细胞、免疫抑制因子（IL-10和TGF-β）和抑制分子（PD-1，Tim-3和CTLA-4）来针对HBV的免疫应答。但是，这个过程是如何发展的仍不清楚。第三，在慢性HBV感染中，越来越多的证据表明针对HBV的多种人HBV-T细胞反应是衰竭的，包括抗原呈递（树突状细胞）、先天性免疫反应（IFN通路和NK灭活）和适应性T细胞和B细胞衰竭。
 

临床上成功控制慢性HBV感染尚有许多挑战，但是近期的研究提供了证据支持慢性乙型肝炎在未来是可治愈的观点。第一，HBV感染在接近90%的成年患者身上通过自身免疫反应得到了成功控制，而超过90%的获得性HBV患儿会发展成慢性感染。第二，应用PEG-IFN-α长期治疗能使接近10%的慢性乙肝患者HBsAg转为阴性，表明应用免疫疗法治愈慢性HBV感染是可能的。第三，免疫供体提供骨髓从而进行骨髓移植能够完全治愈慢性HBV感染。第四，HBsAg疫苗可以在超过95%的人群中产生抗HBV中和抗体。最后，ALT水平升高、HBV定量降低表明患者的免疫反应得到改善，通常比免疫反应较弱的患者对抗病毒治疗的反应更好。
 

此外，现已证明HBsAg血清转换与HBV特异性T细胞反应改善紧密相关。目前的抗病毒治疗可以成功控制HBV的复制，能够诱导一些慢性HBV感染患者出现血清转换。同时，免疫治疗的目的应该集中于激发HBV特异性T细胞反应，进而降低HBsAg。迄今，基础和临床证据表明这种疾病在未来会被治愈。
 

原文阅读》》》Hepatic T Cells in HBV Pathogenesis and Immune Therapeutic Strategies
 

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, liver cirrhosis,  and hepatocellular carcinoma in humans. HBV itself is usually regarded as a non-cytopathic virus. The pathogenesis of HBV infection is considered, at least in part, to be due to T-cell responses directed against HBV antigens. In particular, the role of adaptive T cell immune exhaustion in HBV infection is well understood.

Firstly, HBV infection induces liver inflammation and fibrosis, which is associated with a disorder of the T cell response including the Th17, Treg, and NK cells within the liver. Secondly, the persistent HBV replication and high levels of viral proteins, in particular HBsAg, may  persistently  suppress  the immune responses against HBV through manipulating several key checkpoints, such as regulatory T cells, immune inhibitory cytokines (IL-10  and  TGF-β)  as  well  as inhibitory molecules (PD-1, Tim-3 and CTLA-4); however, it remains unknown how this process develops. Thirdly, in chronic HBV infection, more and more evidence indicates that the multiple human HBV-T cell responses against HBV are exhausted, including  antigen  presentation (dendritic cells), innate immune responses (IFN pathway and NK inactivation), and adaptive T and B exhaustions.
 

There are many challenges in the successful control of chronic HBV infection in the clinic, but recent studies have provided the evidence to support the notion that chronic hepatitis B could be curable in the future. Firstly, HBV infection is successfully controlled by natural immune responses in approximately 90% of adult infections, while more than 90% of infants with HBV acquirement will develop a chronic infection.  Secondly,  long-term therapy with PEG-IFN-α potentially leads to nearly 10% HBsAg loss in CHB patients, which indicates that it is possible to cure chronic HBV infections with immunotherapy. Thirdly, bone marrow transplantation from an immune donor could complete the cure of a chronic HBV infection. Fourthly, an HBsAg vaccine potentially induces anti- HBV neutralized antibodies in more than 95% of the population. Finally, the patients with improved immune responses indicated by high ALT levels and low HBV load usually display a better responsiveness to antiviral treatment than those patients with poor immune responses. 
 

In addition, HBsAg seroconversion has also been demonstrated to be closely linked with the improvement of HBV-specific T cell responses. Current  antiviral  treatment  can successfully control the HBV replication, and can induce HBeAg seroconversion in some patients with chronic HBV infection. Therefore, the purpose of immune therapy should be focused on boosting the HBV-specific T cell response to further decrease HBsAg. Hence, basic and clinical evidence indicates the disease should be curable in the future.