德国慕尼黑工业大学Ulrike Protzer访谈

 

　　编者按：慢性乙型肝炎（CHB）是一种危害人类健康的难治性疾病。感染HBV后，机体的免疫系统不能及时、有效、彻底地清除病毒导致乙型肝炎的免疫耐受，被认为是乙型肝炎慢性化的一个主要机制。免疫耐受主要有宿主和病毒两方面的因素，而宿主免疫功能紊乱是其主要原因。因此，重新定向患者自身的T细胞免疫，打破HBV感染后的免疫耐受状态，是治疗CHB的关键所在。在第51届EASL年会上，德国慕尼黑工业大学病毒系主任Ulrike Protzer教授在一场关于“乙型肝炎免疫治疗”的研讨会中进行了专题报告。会后，针对T细胞重新定向技术这一话题，Protzer教授接受了《国际肝病》的采访。

 

　　《国际肝病》：在慢性乙型肝炎患者中，针对HBV的T细胞免疫起到什么作用？

 

　　Protzer教授：慢性乙型肝炎患者的T细胞应答能力往往极低，即使能够检出T细胞应答，也是单一特异性的，并且应答范围较窄，而不是所希望的范围较广的应答。慢性乙型肝炎患者体内大量T细胞的表型为耗竭型，这一T细胞应答显然不足以控制HBV。

 

　　Prof. Protzer: Patients with chronic hepatitis B usually have a very low T-cell response. If detected, it is monospecific and narrow in focus rather than the preferred broad response. A lot of the T-cells have an exhausted T-cell phenotype. This T-cell response is apparently not good enough to control the virus.

 

　　《国际肝病》：针对HBV的T细胞免疫的新型生物标志物对预后和抗病毒治疗的应答具有预测价值吗？

 

　　Protzer教授：非常可惜，目前尚无可以反映针对HBV的T细胞免疫的新型生物标志物。这是非常重要的研究领域，确实需要投入更多的研究工作，因为尚无与抗病毒治疗应答以及T细胞应答相关的标志物。由于T细胞数量很少，对其检测非常困难。退一万步讲，即使我们可以检测T细胞，所检测到的T细胞也没有预测性。

 

　　Prof. Protzer: Unfortunately, there is not. I think this is an important field where we really need to put in more research effort because there is no correlation marker of response to antiviral therapies and existing T-cells. Since the T-cells are so low in number, they are very hard to measure and that is one of the reasons the correlation is bad. But even when we can measure them, they are not the ones that can be predictive, so there is no predictive marker.

 

　　《国际肝病》：有什么临床试验表明重定向T细胞用于慢性乙型肝炎免疫治疗的安全性和效果吗？

 

　　Protzer教授：有不同策略可以激活T细胞：首先，我们可以应用治疗性疫苗特异性激活HBV核心和聚合酶特异性T细胞；其次，我们可以应用调定点抑制剂增强这些应答；第三，我们可以重新定向T细胞，即应用受体移植T细胞，或者应用结合至T细胞的抗体 ，将T细胞重定向至HBV感染的肝细胞。

 

　　Prof.  Protzer: There are different approaches to activating T-cells. You could have a therapeutic vaccine which would specifically activate HBV core and polymerase specific T-cells. You could use checkpoint inhibitors and strengthen those responses. Or you could redirect the T-cells. For redirection, you can either graft the T-cells with a receptor, or you can use antibodies that bind the T-cell to the infected cell and bring the two together.

 

　　《国际肝病》：随着将来有更加强效的抗病毒药物和包括重定向T细胞的免疫疗法可用，我们可以期待有机会在全球范围内消灭HBV吗？

 

　　Protzer教授：迄今为止，只有一例病例报告介绍了重定向T细胞治疗慢性乙型肝炎的临床应用，不过研究显示非常安全。此外尚无相关的临床试验报道。不过，有一些临床试验正在计划进行。目前，其他一些临床试验显示，将来自具有抗HBV免疫力供者的干细胞移植给患有慢性乙型肝炎的淋巴瘤或白血病患者，治疗非常安全，并且过继转输的T细胞有效清除了受者的HBV感染。这算是意外的发现。

 

　　将来我们有机会在全球范围内消灭HBV，但仍需要在两个方面进行努力：首先，需要保证有效实施乙肝疫苗的普遍接种，以预防新的感染；其次，需要针对已经感染的患者给予治疗，希望将来研发出治愈乙型肝炎的方法。

 

　　Prof. Protzer: So far there are no trials. I know there are trials being planned but otherwise we have only seen a case report on this treatment, which was safe. Clinical trials have been done with stem cell transplantation where the stem cells from an HBV-immune donor were transplanted into a patient who had lymphoma or leukemia and needed that stem cell transplant but who also had chronic hepatitis B. In those cases, the adaptive transfer of T-cells was, on one hand, safe, and on the other hand, efficacious because it eliminated the HBV infection.

 

　　I hope we will be able to but I think we need to be working in two directions. First, we need to ensure the vaccine is efficiently established to prevent new infections. And then we need to be targeting those who already have an infection and developing the cure that we obviously currently don’t have at the moment.