Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection
Janine Kah, … , Antonio Bertoletti, Maura Dandri
Janine Kah, … , Antonio Bertoletti, Maura Dandri
Published July 24, 2017
Citation Information: J Clin Invest. 2017;127(8):3177-3188. https://doi.org/10.1172/JCI93024.
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Research Article Immunology Infectious disease

Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection

Abstract

Adoptive transfer of T cells engineered to express a hepatitis B virus–specific (HBV-specific) T cell receptor (TCR) may supplement HBV-specific immune responses in chronic HBV patients and facilitate HBV control. However, the risk of triggering unrestrained proliferation of permanently engineered T cells raises safety concerns that have hampered testing of this approach in patients. The aim of the present study was to generate T cells that transiently express HBV-specific TCRs using mRNA electroporation and to assess their antiviral and pathogenetic activity in vitro and in HBV-infected human liver chimeric mice. We assessed virological and gene-expression changes using quantitative reverse-transcriptase PCR (qRT-PCR), immunofluorescence, and Luminex technology. HBV-specific T cells lysed HBV-producing hepatoma cells in vitro. In vivo, 3 injections of HBV-specific T cells caused progressive viremia reduction within 12 days of treatment in animals reconstituted with haplotype-matched hepatocytes, whereas viremia remained stable in mice receiving irrelevant T cells redirected toward hepatitis C virus–specific TCRs. Notably, increases in alanine aminotransferase levels, apoptotic markers, and human inflammatory cytokines returned to pretreatment levels within 9 days after the last injection. T cell transfer did not trigger inflammation in uninfected mice. These data support the feasibility of using mRNA electroporation to engineer HBV TCR–redirected T cells in patients with chronic HBV infection.

Authors

Janine Kah, Sarene Koh, Tassilo Volz, Erica Ceccarello, Lena Allweiss, Marc Lütgehetmann, Antonio Bertoletti, Maura Dandri

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Figure 2

mRNA HBV–specific TCR–electroporated T cells show antiviral efficacy in vivo.

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mRNA HBV–specific TCR–electroporated T cells show antiviral efficacy in ...
(A) Schematic representation of the experiment performed to assess the effect of 1 single injection of electroporated effector T cells in high viremic mice reconstituted with haplotype-matched hepatocytes. (B) Viremia changes relative to baseline levels determined after 4 and 6 days in individual mice upon 1 injection of mRNA HBV s183–TCR T cells (n = 5) and in untreated controls (n = 2). (C) ALT levels determined in HBV-infected and uninfected mice receiving a single injection of effector T cells. (D) Schematic representation of the experiment performed to assess the antiviral effect of multiple injections of electroporated effector T cells in high viremic mice reconstituted either with haplotype-matched (n = 3) or -mismatched (n = 3) human hepatocytes and in comparison with mice that were left untreated (n = 3). (E) Median viremia changes determined within each group depicted in D and relative to baseline levels determined in individual mice upon 3 injections of mRNA HBV s183–TCR T cells. Blood was taken 4, 8, and 12 days after the first T cell injection. (F) Median changes in levels of circulating HBeAg were determined by ELISA in all animal groups. BL, baseline.