BALB/c mice show impaired hepatic tolerogenic response following AAV gene transfer to the liver.
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.
Breous
Ekaterina
E
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Somanathan
Suryanarayan
S
Wilson
James M
JM
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D000229:Dependovirus / Q000276:immunology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D008099:Liver / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods
D000956:Antigens, Viral