Abstract:
:As efficient and less toxic virus-derived gene therapy vectors are developed, a pressing problem is to avoid immune response to the therapeutic gene product. Secreted therapeutic proteins potentially represent a special problem, as they are readily available to professional antigen-presenting cells throughout the body. Some studies suggest that immunity to serum proteins can be avoided in some mouse strains by using tissue-specific promoters. Here we show that expression of human alpha1-antitrypsin (AAT) was nonimmunogenic in the immune-responsive strain C3H/HeJ, when expressed from helper-dependent (HD) vectors using ubiquitous as well as tissue-specific promoters. Coadministration of less immunogenic HD vectors with an immunogenic first-generation vector failed to immunize, suggesting immune suppression rather than immune stealth. Indeed, mice primed with HD vectors were tolerant to immune challenge with hAAT emulsified in complete Freund's adjuvant. Such animals developed high-titer antibodies to coemulsified human serum albumin, showing that tolerance was antigen specific. AAT-specific T cell responses were depressed in tolerized animals, suggesting that tolerance affects both T and B cells. These results are consistent with models of high-dose tolerance of B cells and certain other suppressive mechanisms, and suggest that a high level of expression from HD vectors can be sufficient to induce specific immune tolerance to serum proteins.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Cerullo V,McCormack W,Seiler M,Mane V,Cela R,Clarke C,Rodgers JR,Lee Bdoi
10.1089/hum.2006.036subject
Has Abstractpub_date
2007-12-01 00:00:00pages
1215-24issue
12eissn
1043-0342issn
1557-7422journal_volume
18pub_type
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journal_title:Human gene therapy
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journal_title:Human gene therapy
pub_type: 杂志文章
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journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.2-171
更新日期:1997-01-20 00:00:00
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pub_type: 杂志文章
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更新日期:1998-09-20 00:00:00
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journal_title:Human gene therapy
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更新日期:2019-06-01 00:00:00
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