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 November 2, 2009; First published October 1, 2009
Citation Information: J Clin Invest. 2009;119(11):3226-3235. https://doi.org/10.1172/JCI38374.
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Categories: 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 1

Schematic outline of adoptive immuno­therapy with lymphocytes extracted from liver allograft perfusate.

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Schematic outline of adoptive immuno­therapy with lymphocytes extracted ...
The therapy involved giving an intravenous injection of IL-2/OKT3–treated liver lymphocytes to LT recipients. The lymphocytes were extracted from the donor liver graft perfusate. After 3 days of culture with IL-2 (100 JRU/ml), the activated liver NK cell–enriched lymphocytes were administered to the LT recipients through venous circulation. OKT3 (1 μg/ml) was added to the culture medium 1 day before this administration in order to prevent GVHD.