Tolerance Induction to Cytoplasmic β-Galactosidase by Hepatic AAV Gene Transfer — Implications for Antigen Presentation and Immunotoxicity

• DOI: 10.1371/journal.pone.0006376
• Publication Date: 2009-08-03T22:34:13Z
• Authors: Ashley T. Martino; Sushrusha Nayak; Brad E. Hoffman; Mario Cooper; Gongxian Liao; David M. Markusic; Barry J. Byrne; Cox Terhorst; Roland W. Herzog
• Keywords: Adoptive Cell Transfer

Background Hepatic gene transfer, in particular using adeno-associated viral (AAV) vectors, has been shown to induce immune tolerance several protein antigens. This approach exploited animal models of inherited deficiency for systemic delivery therapeutic proteins. Adequate levels transgene expression hepatocytes a suppressive T cell response, thereby promoting tolerance. study addresses the question whether AAV transfer can cytoplasmic protein. Major Findings AAV-2 vector-mediated hepatic β-galactosidase (β-gal) was performed competent mice, followed by secondary β-gal with E1/E3-deleted adenoviral Ad-LacZ vector provoke severe immunotoxic response. Transgene from ∼2% almost completely protected inflammatory responses against β-gal, eliminated antibody formation, and significantly reduced adenovirus-induced hepatotoxicity. Consequently, ∼10% continued express 45 days after time point when control mice had lost all derived expression. Suppression infiltration liver damage linked specific not seen Ad-GFP. A combination adoptive studies flow cytometric analyses demonstrated induction Treg that actively suppressed CD8+ amplified spleen upon transfer. Conclusions These data demonstrate does require product neo-antigen few provide long-term suppression immunotoxicity.