Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection
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Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. / Kah, Janine; Koh, Sarene; Volz, Tassilo; Ceccarello, Erica; Allweiss, Lena; Lütgehetmann, Marc; Bertoletti, Antonio; Dandri, Maura.
in: J CLIN INVEST, Jahrgang 127, Nr. 8, 01.08.2017, S. 3177-3188.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection
AU - Kah, Janine
AU - Koh, Sarene
AU - Volz, Tassilo
AU - Ceccarello, Erica
AU - Allweiss, Lena
AU - Lütgehetmann, Marc
AU - Bertoletti, Antonio
AU - Dandri, Maura
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1172/JCI93024
DO - 10.1172/JCI93024
M3 - SCORING: Journal article
C2 - 28737510
VL - 127
SP - 3177
EP - 3188
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 8
ER -