Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer.
Immune responses to the therapeutic gene product are a potentially serious complication in treatment of genetic disease by gene therapy. Induction and maintenance of immunologic hypo-responsiveness to the therapeutic antigen is therefore critical to the success of gene-based treatment of inherited protein deficiency. Here, we demonstrate induction of antigen-specific CD4+ T-cell tolerance to a secreted transgene product (ovalbumin, ova) in ova-specific T-cell receptor (TCR) transgenic mice by hepatic adeno-associated virus (AAV)-mediated gene transfer. Transduced mice maintained stable circulating ova levels without evidence of an immune response. Lymph node cells and splenocytes were hypo-responsive to ova as early as day 10 after gene transfer. Numbers of TCR+CD4+ cells were reduced in secondary lymphoid organs and in the thymus by 1 to 2 months after vector administration. The remaining TCR+CD4+ cell population was anergic to ova antigen in vitro and enriched for CD25+ cells. These data provide direct evidence that transgene expression following in vivo viral gene transfer can induce CD4+ T-cell tolerance to the transgene product, involving anergy and deletion mechanisms.
Dobrzynski
Eric
E
The Children's Hospital of Philadelphia, Abramson Research Center 302, 34th St and Civic Center Blvd, Philadelphia, PA 19104, USA.
Mingozzi
Federico
F
Liu
Yi-Lin
YL
Bendo
Elisabeth
E
Cao
Ou
O
Wang
Lixin
L
Herzog
Roland W
RW
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002645:Chickens; D017635:Clonal Anergy / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D007108:Immune Tolerance; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology
C111390:OVA 323-339; D010446:Peptide Fragments; D010047:Ovalbumin