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Type: Journal article
Title: Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell–mediated effects on regulatory T cells
Author: Hauben, E.
Gregori, S.
Draghici, E.
Migliavacca, B.
Olivieri, S.
Woisetschlager, M.
Roncarolo, M.
Citation: Blood, 2008; 112(4):1214-1222
Publisher: Amer Soc Hematology
Issue Date: 2008
ISSN: 0006-4971
Statement of
Ehud Hauben, Silvia Gregori, Elena Draghici, Barbara Migliavacca, Stefano Olivieri, Maximilian Woisetschläger, and Maria Grazia Roncarolo
Abstract: 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 that receive a transplant of 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+ dendritic cells (DCs), but not of CD4+ T or CD19+ B cells, from VAG539-treated long-term tolerant hosts into mice that recently underwent transplantation 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 mice that recently underwent transplantation promoted graft acceptance. Similarly, cell therapy with in vitro VAF347-treated bone marrow–derived mature DCs 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.
Keywords: Dendritic Cells; Animals; Mice; Pyrimidines; Receptors, Aryl Hydrocarbon; Islets of Langerhans Transplantation; Cell Survival; Transplantation Tolerance; Graft Survival; T-Lymphocytes, Regulatory
Rights: © 2008 by The American Society of Hematology
RMID: 0020114685
DOI: 10.1182/blood-2007-08-109843
Appears in Collections:Surgery publications

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