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. IntroductionLiver failure and hepatocellular carcinoma (HCC) due to chronic hepatitis C infection are the most common indications for liver transplantation (LT), and the incidences of both have been projected to increase further in the future. Recurrent HCV infection of the allograft is universal, occurs immediately after LT, and is associated with accelerated progression to cirrhosis, graft loss, and death (1, 2). This reflects the suppression of those host-effector immune responses that usually control HCV replication, suggesting that the immunosuppressive environment may play a major role in the rapid progression of recurrent HCV infection after LT (3, 4). Further, the immunosuppressive condition described above is considered to increase the incidence of cancer recurrence after LT in HCC patients. We recently proposed the novel strategy of adjuvant immunotherapy for preventing the recurrence of HCC after LT; this immunotherapy involves intravenously injecting LT recipients with activated liver allograft-derived NK cells (5, 6). Since the immunosuppressive regimen currently used after LT reduces the adaptive immune components but effectively maintains the innate components of cellular immunity (7-9), the augmenta-

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

“…In addition to their antitumor activity, NK cells might exert antiviral activity (4,44,45). Although the precise role of NK cells in this context requires further clarification (4,46), NK and NKT cells from liver allograft perfusates, infused after liver transplantation, reduced HCV RNA serum titers (47), suggesting that the application of expanded NK cells in this context is worthy of further study.…”

Strategies to reduce hepatitis C virus recurrence after liver transplantation

“…Activated liver allograftderived NK cells were isolated from the perfusate (IL-2 stimulated and anti-CD3 monoclonal antibody treated to deplete T cells), and injected intravenously into the transplant recipient. Early data from the pilot study reported lower HCV RNA titers at one month post-transplant, but the effect was transient [94] . Augmentation of the NK cell response, which plays a pivotal role in innate immunity, may be an alternative approach to preventing HCV recurrence and is an area of active research [95] .…”

Prevention of hepatitis C recurrence after liver transplantation: An update

“…The enhancement of the natural killer cellular response that plays a pivotal role in innate immunity may be a promising immunotherapeutic approach, also in the prevention of HCV recurrence post-LT [121] . Ohira et al [122] report an interesting immunotherapeutic approach for preventing post-transplant HCV recurrence, based on adoptive transfer of interleukin 2 (IL-2)/anti-CD3 monoclonal antibody (OKT3)-treated liver allograft-derived lymphocyte pools enriched in natural killer and natural killer T cells.…”