BALB/c mice show impaired hepatic tolerogenic response following AAV gene transfer to the liver

Mol Ther. 2010 Apr;18(4):766-74. doi: 10.1038/mt.2009.301. Epub 2010 Jan 12.


Following adeno-associated virus (AAV) gene transfer to the liver, both C57BL/6 and BALB/c mice show long-term expression of nonself transgene antigens along with the absence of a transgene-specific immune response. However, in this study, we report that despite the equal ability to induce T-cell tolerance to vector-encoded antigens, the underlying mechanisms are entirely different in these two strains. We have previously shown that in C57BL/6 mice, cytotoxic T lymphocyte (CTL) responses to systemic AAV-delivered antigens are suppressed by combined actions of hepatic regulatory T cells (Tregs), Kupffer cells, and hepatic suppressive cytokines. In stark contrast, our present findings reveal that such tolerogenic response is not induced in the liver of BALB/c mice systemically administered with AAV. As a result, these mice fail to suppress a transgene-specific CTL response induced by a strong immunogenic challenge and express dramatically reduced levels of AAV-encoded antigen. Interestingly, there was active B-cell tolerance to the transgene antigen, which was mediated by splenic Tregs. We conclude that lack of tolerance induction in the liver renders BALB/c mice susceptible to CTL-mediated clearance of transduced hepatocytes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Viral / immunology
  • B-Lymphocytes / immunology
  • Dependovirus / immunology*
  • Gene Transfer Techniques
  • Genetic Vectors / immunology
  • Immune Tolerance / genetics*
  • Liver / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Spleen / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / immunology
  • Transduction, Genetic / methods


  • Antigens, Viral