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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4871-4877. Prepublished online as a Blood First Edition Paper on February 15, 2005; DOI 10.1182/blood-2004-10-3888. This Article Full Text (PDF) All Versions of this Article: 2004-10-3888v1 105/12/4871    most recent Alert me when this article is cited Alert me if a correction is posted 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 Karim, M. Articles by Bushell, A. R Search for Related Content PubMed PubMed Citation Articles by Karim, M. Articles by Bushell, A. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 7, 2004 Accepted February 8, 2005 CD25+CD4+ regulatory T cells generated by exposure to a model protein antigen prevent allograft rejection: antigen-specific re-activation in vivo is critical for bystander regulation Mahzuz Karim, Gang Feng, Kathryn J Wood, and Andrew R Bushell* Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom * Corresponding author; email: andrew.bushell{at}nds.ox.ac.uk. The importance of CD25+CD4+ regulatory T cells (Treg) in the control of immune responses is established, but their antigen specificity in vivo remains unclear. Understanding Treg specificity requirements will be important if their potential is to be developed for immunotherapy. Pre-treatment of recipient mice with donor alloantigen plus anti-CD4 antibody generates CD25+CD4+ Treg with the capacity to prevent skin allograft rejection in adoptive transfer recipients. Here we demonstrate that although this regulation can be antigen-specific, re-activation with the original tolerising alloantigen allows the Treg to suppress rejection of third party allografts. Aware of the limitations of alloantigen pre-treatment, we asked whether graft-protective Treg could be generated against unrelated, non-graft antigens. We demonstrate that bystander regulation also extends to CD25+CD4+ Treg generated in vivo by exposure to nominal antigens under anti-CD4 antibody cover. Providing these Treg are re-exposed to the tolerising antigens before adoptive transfer, they prevent the rejection of fully allogeneic skin grafts. That this might form the basis of a clinically relevant tolerance induction strategy is demonstrated by the fact that when combined with sub-therapeutic anti-CD8 antibody, Treg generated in response to non-graft antigens facilitate the acceptance of cardiac allografts in primary recipients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. R. Guerin, J. R. Prins, and S. A. Robertson Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum. Reprod. Update, September 1, 2009; 15(5): 517 - 535. [Abstract] [Full Text] [PDF] C. Becker, C. Taube, T. Bopp, C. Becker, K. Michel, J. Kubach, S. Reuter, N. Dehzad, M. F. Neurath, K. Reifenberg, et al. Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells Blood, August 6, 2009; 114(6): 1263 - 1269. [Abstract] [Full Text] [PDF] G. Vassalli, M.-E. 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