Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice
Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice
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DOI：
10.1172/jci38374
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发表时间：
2009-11-01
影响因子：
15.9
通讯作者：
Ohdan, Hideki
中科院分区：
文献类型：
--
作者：
Ohira, Masahiro;Ishiyama, Kohei;Ohdan, Hideki
HCV感染者进行肝移植后，病毒载量不可避免地超过移植前的水平。这种现象反映了用于防止移植肝脏排斥的免疫抑制药物对控制 HCV 复制的宿主效应免疫反应的抑制。在这里，我们描述了一种过继免疫治疗方法，使用从同种异体肝移植物灌注液中提取的淋巴细胞（本文称为同种异体肝移植物衍生的淋巴细胞），其中包括大量的NK/NKT细胞，尽管处于免疫抑制环境，但在HCV感染的肝移植受者中仍能产生抗HCV反应。该疗法包括在肝移植后 3 天向患者静脉注射经过 IL-2 和 CD3 特异性 mAb OKT3 处理的肝同种异体移植物衍生的淋巴细胞。肝移植后第一个月，接受免疫治疗的受者血清中HCV RNA滴度明显低于未接受免疫治疗的受者血清中的HCV RNA滴度。我们进一步在人肝细胞嵌合小鼠中探索了这些观察结果，其中小鼠肝细胞被人肝细胞取代。这些小鼠在接种HCV感染的人血清后，必然会出现HCV感染。然而，注射用IL-2/OKT3处理过的人肝源性淋巴细胞可以完全预防HCV感染。此外，一项使用含有基因组 HCV 复制子的肝细胞的体外研究表明，IFN-γ 分泌细胞在这种抗 HCV 反应中发挥着关键作用。因此，我们的研究提出了我们认为抑制 HCV 感染的肝移植受者中 HCV 复制的新范例。
After liver transplantation in HCV-infected patients, the virus load inevitably exceeds pre-transplantation levels. This phenomenon reflects suppression of the host-effector immune responses that control HCV replication by the immunosuppressive drugs used to prevent rejection of the transplanted liver. Here, we describe an adoptive immunotherapy approach, using lymphocytes extracted from liver allograft perfusate (termed herein liver allograft-derived lymphocytes), which includes an abundance of NK/NKT cells that mounted an anti-HCV response in HCV-infected liver transplantation recipients, despite the immunosuppressive environment. This therapy involved intravenously injecting patients 3 days after liver transplantation with liver allograft-derived lymphocytes treated with IL-2 and the CD3-specific mAb OKT3. During the first month after liver transplantation, the HCV RNA titers in the sera of recipients who received immunotherapy were markedly lower than those in the sera of recipients who did not receive immunotherapy. We further explored these observations in human hepatocyte-chimeric mice, in which mouse hepatocytes were replaced by human hepatocytes. These mice unfailingly developed HCV infections after inoculation with HCV-infected human serum. However, injection of human liver-derived lymphocytes treated with IL-2/OKT3 completely prevented HCV infection. Furthermore, an in vitro study using genomic HCV replicon-containing hepatic cells revealed that IFN-gamma-secreting cells played a pivotal role in such anti-HCV responses. Thus, our study presents what we believe to be a novel paradigm for the inhibition of HCV replication in HCV-infected liver transplantation recipients.