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Adoptive immunotherapy with liver allograft–derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice
Masahiro Ohira, … , Kazuaki Chayama, Hideki Ohdan
Masahiro Ohira, … , Kazuaki Chayama, Hideki Ohdan
Published October 1, 2009
Citation Information: J Clin Invest. 2009;119(11):3226-3235. https://doi.org/10.1172/JCI38374.
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Research Article Article has an altmetric score of 12

Adoptive immunotherapy with liver allograft–derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice

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Abstract

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-γ–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.

Authors

Masahiro Ohira, Kohei Ishiyama, Yuka Tanaka, Marlen Doskali, Yuka Igarashi, Hirotaka Tashiro, Nobuhiko Hiraga, Michio Imamura, Naoya Sakamoto, Toshimasa Asahara, Kazuaki Chayama, Hideki Ohdan

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Figure 7

Adoptive immunotherapy with IL-2/OKT3–treated liver lymphocytes prevented HCV infection in human hepatocyte–chimeric mice.

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Adoptive immunotherapy with IL-2/OKT3–treated liver lymphocytes prevente...
(A) Human hepatocyte–chimeric mice were intravenously injected with human serum samples positive for HCV genotype 1b. Two weeks after injecting the infected serum, the mice were intraperitoneally inoculated with IL-2/OKT3–treated liver lymphocytes (20 × 106 cells/mouse; n = 6) for adoptive immunotherapy. When indicated, anti-human IFN-γ mAb was injected intraperitoneally 1 day before the immunotherapy (n = 4). Intraperitoneal injection of recombinant human IFN-γ (rhIFN-γ) was commenced at 2 weeks after injecting the infected serum (n = 5). The untreated mice served as controls (n = 6). The dot plots represent serum HCV RNA titers in each chimeric mouse 4 weeks after the injecting the infected serum. Statistical analyses were performed using the Mann-Whitney U test. *P < 0.01 for immunotherapy group versus control group. (B) The lines represent serial changes in human serum albumin levels in the sera of the mice indicated above. Data are presented as mean ± SEM. (C) IL-2/OKT3–treated liver lymphocytes (20 × 106 cells/mouse) were intraperitoneally inoculated 4 weeks after the injection with the infected serum (n = 5) for adoptive immunotherapy. Intraperitoneal injection of recombinant human IFN-γ was commenced 4 weeks after the injecting the infected serum (n = 9). The untreated mice served as controls (n = 9). The dot plots represent serum HCV RNA titers in each chimeric mouse 6 weeks after injection with the infected serum.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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