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T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelop proteins control virus replication in mice

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Official URL:https://doi.org/10.1053/j.gastro.2013.04.047
PubMed:View item in PubMed
Creators Name:Krebs, K. and Boettinger, N. and Huang, L.R. and Chmielewski, M. and Arzberger, S. and Gasteiger, G. and Jaeger, C. and Schmitt, E. and Bohne, F. and Aichler, M. and Uckert, W. and Abken, H. and Heikenwalder, M. and Knolle, P. and Protzer, U.
Journal Title:Gastroenterology
Journal Abbreviation:Gastroenterology
Volume:145
Number:2
Page Range:456-465
Date:August 2013
Keywords:Immunotherapy, Chronic Hepatitis B, Hepatocellular Carcinoma, Adoptive T-Cell Therapy, Animals, Mice
Abstract:BACKGROUND & AIMS: Antiviral agents suppress hepatitis B virus (HBV) replication but do not clear the infection. A strong effector T-cell response is required to eradicate HBV, but this does not occur in patients with chronic infection. T cells might be directed toward virus-infected cells by expressing HBV-specific receptors, and thereby clear HBV and help to prevent development of liver cancer. In mice, we studied whether redirected T cells can engraft following adoptive transfer, without prior T-cell depletion, and whether the large amounts of circulating viral antigens inactivate the transferred T cells or lead to uncontrolled, immune-mediated damage. METHODS: CD8(+) T cells were isolated from mice and stimulated using an optimized protocol. Chimeric antigen receptors (CARs) that bind HBV envelope proteins (S-CAR) and activate T cells were expressed on the surface of cells using retroviral vectors. S-CAR-expressing CD8(+) T cells, which carried the marker CD45.1, were injected into CD45.2(+) HBV transgenic mice. We compared these mice with mice that received CD8(+) T cells induced by vaccination, cells that express a CAR without a proper signaling domain, or cells that express a CAR that does not bind HBV proteins (controls). RESULTS: CD8(+) T cells that expressed HBV-specific CARs recognized different HBV subtypes and were able to engraft and expand in immune-competent HBV transgenic mice. Following adoptive transfer, the S-CAR-expressing T cells localized to and functioned in the liver; they rapidly and efficiently controlled HBV replication, compared with controls, causing only transient liver damage. The large amount of circulating viral antigen did not impair or over-activate the S-CAR grafted T cells. CONCLUSION: T cells with a CAR specific for HBV envelop proteins localize to the livers of mice to reduce HBV replication, causing only transient liver damage. This immune-cell therapy might be developed for patients with chronic hepatitis B, regardless of their HLA-type.
ISSN:0016-5085
Publisher:Saunders / Elsevier (U.S.A.)
Item Type:Article

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