期刊
HUMAN GENE THERAPY
卷 18, 期 3, 页码 185-194出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2007.001
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资金
- NHLBI NIH HHS [P01-HL-059407] Funding Source: Medline
- NIDDK NIH HHS [P30-DK-47757-PILOT, P30-DK-47757] Funding Source: Medline
Liver toxicity observed in a clinical trial of adeno-associated virus serotype 2 ( AAV2) delivered systemically to patients with hemophilia was ascribed to killing of vector-transduced hepatocytes by capsid-specific T cells. This study evaluated the biology of T cell activation in response to AAV capsids in murine models. CD8(+) T cell epitopes were mapped to capsids from AAV2, AAV7, and AAV8. A tetramer generated in response to a dominant capsid epitope in BALB/c mice was shared between these AAV serotypes. Administration of AAV2 vector resulted in the activation of capsid-specific CD8(+) T cells as evidenced by binding to tetramer and production of capsid-induced interferon-gamma expression; this was not observed with the AAV7 and AAV8 vectors. CD8(+) T cells specific to AAV2 capsids demonstrate functional cytolytic activity in vivo to peptide-loaded target cells. The frequency of capsid-specific T cells was much higher in liver than in blood or spleen. The performance of liver-directed AAV-mediated gene transfer was not diminished in animals with high levels of preexisting capsid-specific T cells. We conclude that cross-presentation of AAV capsids does result in activation of cytotoxic T lymphocytes ( CTLs) in a serotype-specific manner; however, there is no evidence that vector-transduced hepatocytes are targets for CTL effector activity.
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