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Blood, 1 November 2006, Vol. 108, No. 9, pp. 2972-2978. Prepublished online as a Blood First Edition Paper on June 29, 2006; DOI 10.1182/blood-2006-03-010900. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-03-010900v1 108/9/2972    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Marodon, G. Articles by Klatzmann, D. Search for Related Content PubMed PubMed Citation Articles by Marodon, G. Articles by Klatzmann, D. Related Collections Immunobiology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors Gilles Marodon, Sylvain Fisson, Béatrice Levacher, Monique Fabre, Benoît L. Salomon, and David Klatzmann From the Université Pierre et Marie Curie-Paris6 (UPMC), UMR 7087, Hôpital de La Pitié-Salpêtrière, Paris, France; Centre National de la Recherche Scientifique (CNRS) UMR 7087, Hôpital de La Pitié-Salpêtrière, Paris, France; and Département de Pathologie, Université de Médecine Paris-Sud, Hopital Bicêtre, Le Kremlin-Bicêtre, France. Immune tolerance to self-antigens is established during lymphocyte differentiation in the thymus, but a simple means to induce antigen-specific tolerance in the thymus is still elusive. We show here that intrathymic injection of a lentiviral vector expressing the hemagglutinin antigen (HA) in TCR-HA transgenic mice resulted in negative selection of HA-specific effector T cells and sustained positive selection of HA-specific regulatory T cells (Tregs). This positive selection increased the number of HA-specific Tregs 10-fold and was comparable with the one observed in TCR-HA transgenic mice crossed with transgenic mice expressing HA under the control of the insulin promoter (Ins-HA). HA expression by radioresistant thymic epithelial cells was sufficient to drive Treg generation. Intrathymic injection of the lentiviral vector also resulted in an enrichment of HA-specific Tregs in peripheral lymphoid organs, which prevented diabetes induced in Ins-HA mice by transfer of HA-specific effector T cells. In this model, HA-specific Tregs inhibited effector T-cell division in pancreatic lymph nodes. Finally, we show that intrathymic injection of a lentiviral vector expressing preproinsulin-2 could reduce the occurrence of spontaneous diabetes in nonobese diabetic mice. Intrathymic gene transfer using lentiviral vectors thus offers new means to manipulate antigen-specific tolerance. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Yu, C. L. Haymaker, R. D. Divekar, J. S. Ellis, J. Hardaway, R. Jain, D. M. Tartar, C. M. Hoeman, J. A. Cascio, A. Ostermeier, et al. Fetal Exposure to High-Avidity TCR Ligand Enhances Expansion of Peripheral T Regulatory Cells J. Immunol., July 1, 2008; 181(1): 73 - 80. [Abstract] [Full Text] [PDF]

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