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 Transplantation

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

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 6

Adoptive immunotherapy with IL-2/OKT3–treated liver lymphocytes induced the production of IFN-γ in the LT recipients.

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Adoptive immunotherapy with IL-2/OKT3–treated liver lymphocytes induced ...
At 14 days after LT, the number of IFN-γ–secreting cells in the peripheral blood of LT recipients treated with the adoptive immunotherapy (+) with IL-2/OKT3–treated liver lymphocytes, including NK and NKT cells, was significantly higher than that in the peripheral blood of untreated LT recipients (–). Histograms represent the proportion (percentage) of IFN-γ–positive cells among the mononuclear cells obtained from the peripheral blood of the immunotherapy (n = 4) and control group (n = 4) LT recipients. Dotted lines represent negative control staining with isotype-matched mAbs. Horizontal lines indicate the gated portion of lymphocytes. Data are presented as mean ± SEM. Histogram profiles shown are representative of 4 independent experiments. Statistical analyses were performed using the Mann-Whitney U test. *P < 0.05 for immunotherapy group versus control group.