title: Evidence for contribution of CD4+ CD25+ regulatory T cells in maintaining immune tolerance to human factor IX following perinatal adenovirus vector delivery.
abstract: Following fetal or neonatal gene transfer in mice and other species immune tolerance of the transgenic protein is frequently observed; however the underlying mechanisms remain largely undefined. In this study fetal and neonatal BALB/c mice received adenovirus vector to deliver human factor IX (hFIX) cDNA. The long-term tolerance of hFIX was robust in the face of immune challenge with hFIX protein and adjuvant but was eliminated by simultaneous administration of anti-CD25+ antibody. Naive irradiated BALB/c mice which had received lymphocytes from donors immunised with hFIX developed anti-hFIX antibodies upon immune challenge. Cotransplantation with CD4+CD25+ cells isolated from neonatally tolerized donors decreased the antibody response. In contrast, cotransplantation with CD4+CD25- cells isolated from the same donors increased the antibody response. These data provide evidence that immune tolerance following perinatal gene transfer is maintained by a CD4+CD25+ regulatory population.
authors.affiliation: Gene Transfer Technology Group, University College London, 86-96 Chenies Mews, London WC1E 6HXZ, UK.
authors.forename: Megha S
authors.initials: MS
authors.lastname: Nivsarkar
authors.affiliation: Gene Transfer Technology Group, University College London, 86-96 Chenies Mews, London WC1E 6HXZ, UK.
authors.forename: Suzanne M K
authors.initials: SM
authors.lastname: Buckley
authors.affiliation: Institute of Cancer & Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Parker
authors.affiliation: Gene Transfer Technology Group, University College London, 86-96 Chenies Mews, London WC1E 6HXZ, UK.
authors.forename: Dany
authors.initials: D
authors.lastname: Perocheau
authors.affiliation: Stem Cell Group, Cardiovascular & Cell Sciences Research Institute, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Tristan R
authors.initials: TR
authors.lastname: McKay
authors.affiliation: Department of Pharmacology, School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Ahad A
authors.initials: AA
authors.lastname: Rahim
authors.affiliation: Molecular and Cellular Immunology, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Howe
authors.affiliation: Gene Transfer Technology Group, University College London, 86-96 Chenies Mews, London WC1E 6HXZ, UK ; Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D005164:Factor IX / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000906:Antibodies; D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D005164:Factor IX