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T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice.
Gastroenterology 145, 456-465 (2013)
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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
Scopus
Cited By
Cited By
Altmetric
12.821
2.684
130
140
Anmerkungen
Besondere Publikation
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Immunotherapy ; Chronic Hepatitis B ; Hepatocellular Carcinoma ; Adoptive T-cell Therapy; Bone-marrow-transplantation ; Closed Circular Dna ; Surface-antigen ; Infected Hepatocytes ; Viral Clearance ; Kupffer Cells ; Liver-injury ; In-vitro ; Il-12 ; Effector
Sprache
englisch
Veröffentlichungsjahr
2013
HGF-Berichtsjahr
2013
ISSN (print) / ISBN
0016-5085
e-ISSN
1528-0012
Zeitschrift
Gastroenterology
Quellenangaben
Band: 145,
Heft: 2,
Seiten: 456-465
Verlag
Elsevier
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Virology (VIRO)
Research Unit Analytical Pathology (AAP)
Institute of Pathology (PATH)
Research Unit Analytical Pathology (AAP)
Institute of Pathology (PATH)
POF Topic(s)
30203 - Molecular Targets and Therapies
30205 - Bioengineering and Digital Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30205 - Bioengineering and Digital Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er)
Immune Response and Infection
Enabling and Novel Technologies
Enabling and Novel Technologies
PSP-Element(e)
G-502700-003
G-500390-001
G-500300-001
G-502700-004
G-500390-001
G-500300-001
G-502700-004
PubMed ID
23639914
WOS ID
WOS:000322630600035
Scopus ID
84880582625
Erfassungsdatum
2013-05-10