title: Early fetal gene delivery utilizes both central and peripheral mechanisms of tolerance induction.
abstract: OBJECTIVE
  We previously reported the induction of stable immune tolerance following direct injection of retroviral vectors into preimmune fetal sheep. In the present studies, we conduct detailed analysis of the thymus of recipients of in utero gene transfer (IUGT) to delineate the mechanism of the observed immune tolerance and assess the impact of recipient age on this process.
  
  
  METHODS
  Fetal sheep at varying gestational ages received the MSCV-NeoR-RFP retroviral vector. The thymus was then collected from these animals at 27 to 30 days postinjection and analyzed for evidence of transduction of key immunoregulatory thymic cells.
  
  
  RESULTS
  Our results reveal that both thymic epithelial cells (TEC), crucial for presentation of self-antigen during T-cell thymic selection, and the cells comprising the Hassall's corpuscles, which can present antigen directly and also instruct dendritic cells to induce the formation of CD4(+)CD25(+) T-regulatory cells in the thymus, were only efficiently transduced if IUGT was performed early in gestation.
  
  
  CONCLUSIONS
  Our findings thus demonstrate, for the first time, that early IUGT can potentially take advantage of multiple tolerogenic avenues in the fetus, transducing both TEC, which promote central tolerance, and Hassall's corpuscles, which induce formation of T regulatory cells that could act to maintain peripheral tolerance to the transgene products.
authors.affiliation: Department of Animal Biotechnology, University of Nevada, Reno, NV 89557-0104, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Colletti
authors.forename: Sean
authors.initials: S
authors.lastname: Lindstedt
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Park
authors.forename: Graça
authors.initials: G
authors.lastname: Almeida-Porada
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Porada
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D005333:Fetus / Q000166:cytology / Q000276:immunology*; D005822:Genetic Vectors; D005865:Gestational Age; D007108:Immune Tolerance / Q000235:genetics* / Q000276:immunology; D011247:Pregnancy; D012190:Retroviridae; D012756:Sheep; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology / Q000276:immunology; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics / Q000276:immunology*
chemical_list: D001324:Autoantigens