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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.
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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
ISSN (print) / ISBN
0016-5085
e-ISSN
1528-0012
Zeitschrift
Gastroenterology
Quellenangaben
Band: 145,
Heft: 2,
Seiten: 456-465
Verlag
Elsevier
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed