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J Clin Invest. 2017 Aug 1;127(8):3177-3188. doi: 10.1172/JCI93024. Epub 2017 Jul 24.

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

Author information

1
I. Medical Department, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2
Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
3
Lion TCR Pte. Ltd., Singapore.
4
Emerging Infectious Diseases Programme, Duke-NUS Medical School, Singapore.
5
Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
6
German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Hamburg, Germany.

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.

PMID:
28737510
PMCID:
PMC5531408
DOI:
10.1172/JCI93024
[Indexed for MEDLINE]
Free PMC Article

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