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This Article Full Text Full Text (PDF) 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 Bracy, J. L. Articles by Iacomini, J. Search for Related Content PubMed PubMed Citation Articles by Bracy, J. L. Articles by Iacomini, J. Related Collections Immunobiology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 November 2000, Vol. 96, No. 9, pp. 3008-3015 GENE THERAPY Induction of B-cell tolerance by retroviral gene therapy Jennifer L. Bracy and John Iacomini From the Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA. The primary immunologic barrier to overcome before clinical xenotransplantation can be successful is rejection mediated by preformed natural antibodies in the host, directed toward a single carbohydrate epitope Gal1-3Gal1-4GlcNAc-R (Gal) present on porcine tissue, encoded for by the enzyme glucosyltransferase UDP galactose:-D-galactosyl-1,4-N-acetyl-D-glucosaminide (1-3)galactosyltransferase (EC 2.4.1.151) or simply GT. Although we have shown previously that a gene therapy approach could be used to prevent production of natural antibodies specific for Gal, the ability to induce and maintain tolerance after rigorous antigen challenge would be required if similar approaches are to be used clinically. Here, we demonstrate in GT knockout mice (GT0 mice), which, like humans, contain in their serum antibodies that bind Gal, that the efficient transduction and expression of a retrovirally transduced GT gene in bone marrow-derived cells induces stable long-term tolerance to the Gal epitope. GT0 mice reconstituted with GT-transduced bone marrow cells were unable to produce antibodies that bind Gal after extensive immunization with pig cells. Furthermore, using ELISPOT assays, we were unable to detect the presence of B cells that produce Gal reactive antibodies after immunization, suggesting that such B cells were eliminated from the immunologic repertoire after gene therapy. Interestingly, after tolerance to Gal is induced by gene therapy, the antiporcine non-Gal humoral response changes from a predominantly IgM to an IgG response. This suggests that once the natural antibody barrier is eliminated by the induction of tolerance, the antipig response changes to a typical T-cell-dependent response involving isotype switching. Thus, gene therapy approaches may be used to overcome immunologic responses leading to xenograft rejection, and similar gene therapy approaches could be used to overcome autoimmunity. © 2000 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Benatuil, J. Kaye, N. Cretin, J. G. Godwin, A. Cariappa, S. Pillai, and J. Iacomini Ig Knock-In Mice Producing Anti-Carbohydrate Antibodies: Breakthrough of B Cells Producing Low Affinity Anti-Self Antibodies J. Immunol., March 15, 2008; 180(6): 3839 - 3848. [Abstract] [Full Text] [PDF] C. Tian, M. J. I. Ansari, J. Paez-Cortez, J. Bagley, J. Godwin, M. Donnarumma, M. H. Sayegh, and J. 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