Ohashi K, Marion P L, Nakai H, Meuse L, Cullen J M, Bordier B B, Schwall R, Greenberg H B, Glenn J S, Kay M A
Program in Human Gene Therapy, Department of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Nat Med. 2000 Mar;6(3):327-31. doi: 10.1038/73187.
Persistence of hepatocytes transplanted into the same or related species has been established. The long-term engraftment of human hepatocytes into rodents would be useful for the study of human viral hepatitis, where it might allow the species, technical and size limitations of the current animal models to be overcome. Although transgenic mice expressing the hepatitis B virus (HBV) genome produce infectious virus in their serum, the viral life cycle is not complete, in that the early stages of viral binding and entry into hepatocytes and production of an episomal transcriptional DNA template do not occur. As for hepatitis delta virus (HDV), another cause of liver disease, no effective therapy exists to eradicate infection, and it remains resistant even to recent regimens that have considerably changed the treatment of HBV (ref. 13). Here, we demonstrate long-term engraftment of primary human hepatocytes transplanted in a matrix under the kidney capsule of mice with administration of an agonistic antibody against c-Met. These mice were susceptible to HBV infection and completion of the viral life cycle. In addition, we demonstrate super-infection of the HBV-infected mice with HDV. Our results describe a new xenotransplant model that allows study of multiple aspects of human hepatitis viral infections, and may enhance studies of human liver diseases.
已证实移植到同一物种或相关物种体内的肝细胞能够持续存在。将人类肝细胞长期植入啮齿动物体内，对于人类病毒性肝炎的研究将大有裨益，因为这可能克服当前动物模型在物种、技术和规模方面的局限性。虽然表达乙型肝炎病毒（HBV）基因组的转基因小鼠在其血清中产生传染性病毒，但其病毒生命周期并不完整，因为病毒结合、进入肝细胞以及产生游离转录DNA模板的早期阶段并未发生。至于另一种肝病病因丁型肝炎病毒（HDV），目前尚无根除感染的有效疗法，即使是对最近显著改变了HBV治疗方案的疗法，它仍具有抗性（参考文献13）。在此，我们证明了在给予抗c-Met激动性抗体的情况下，原代人类肝细胞在小鼠肾包膜下的基质中移植后能够长期存活。这些小鼠易受HBV感染且病毒生命周期完整。此外，我们还证明了HDV对HBV感染小鼠的超感染。我们的研究结果描述了一种新的异种移植模型，该模型能够对人类肝炎病毒感染的多个方面进行研究，并可能加强对人类肝脏疾病的研究。
