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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1214-1222. Prepublished online as a Blood First Edition Paper on June 11, 2008; DOI 10.1182/blood-2007-08-109843. This Article Full Text (PDF) All Versions of this Article: blood-2007-08-109843v1 112/4/1214    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 Hauben, E. Articles by Roncarolo, M. G. Search for Related Content PubMed PubMed Citation Articles by Hauben, E. Articles by Roncarolo, M. G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 30, 2007 Accepted April 20, 2008 Activation of the aryl hydrocarbon receptor promotes allograft specific tolerance through direct- and DC-mediated effects on regulatory T cells Ehud Hauben, Silvia Gregori, Elena Draghici, Barbara Migliavacca, Stefano Olivieri, Maximilian Woisetschlager, and Maria Grazia Roncarolo* San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milan, Italy Department of Pathology, San Raffaele Scientific Institute, Milan, Italy Department of Autoimmunity and Transplantation, Novartis Institute for Biomedical Research, Vienna, Austria Vita-Salute San Raffaele University, Milan, Italy * Corresponding author; email: m.roncarolo{at}hsr.it. VAF347 is a low molecular weight compound, which activates the aryl hydrocarbon receptor (AhR). Herein, we report that oral administration of a water-soluble derivative of VAF347 (VAG539) promotes long-term graft acceptance and active tolerance in Balb/c mice transplanted with MHC-mismatched pancreatic islet allografts. In vivo VAG539 treatment results in increased frequency of splenic CD4+ T cells expressing CD25 and Foxp3, markers associated with regulatory T (Tr) cells, and in vitro VAF347 treatment of splenic CD4+ T cells improved CD4+CD25+Foxp3+ T cell survival. Interestingly, transfer of CD11c+ DC, but not of CD4+ T or CD19+ B cells, from VAG539-treated long-term tolerant hosts into newly transplanted mice resulted in donor (C57Bl/6) specific graft acceptance and in a significantly higher frequency of splenic CD4+CD25+Foxp3+ Tr cells. Furthermore, the transfer of CD4+CD25+ T cells from these mice into newly transplanted mice promoted graft acceptance. Similarly, cell therapy with in vitro VAF347-treated bone marrow-derived mature DC prevented islet graft rejection, and reduced OVA-specific T cell responses in OVA-immunized mice. Collectively, our data indicate that AhR activation induces islet allograft specific tolerance through direct as well as DC-mediated effects on Tr cell survival and function. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Platzer, S. Richter, D. Kneidinger, D. Waltenberger, M. Woisetschlager, and H. Strobl Aryl Hydrocarbon Receptor Activation Inhibits In Vitro Differentiation of Human Monocytes and Langerhans Dendritic Cells J. Immunol., July 1, 2009; 183(1): 66 - 74. [Abstract] [Full Text] [PDF] B. Jux, S. Kadow, and C. Esser Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice J. Immunol., June 1, 2009; 182(11): 6709 - 6717. [Abstract] [Full Text] [PDF] B. P. Lawrence, M. S. Denison, H. Novak, B. A. Vorderstrasse, N. Harrer, W. Neruda, C. Reichel, and M. Woisetschlager Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound Blood, August 15, 2008; 112(4): 1158 - 1165. [Abstract] [Full Text] [PDF]

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