Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells

Ehud Hauben, Silvia Gregori, Elena Draghici, Barbara Migliavacca, Stefano Olivieri, Maximilian Woisetschläger, Maria Grazia Roncarolo

Research output: Contribution to journalArticle

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 (C57BI/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.

Original languageEnglish
Pages (from-to)1214-1222
Number of pages9
JournalBlood
Volume112
Issue number4
DOIs
Publication statusPublished - Aug 15 2008

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Transplantation Tolerance
Aryl Hydrocarbon Receptors
T-cells
Regulatory T-Lymphocytes
Dendritic Cells
Allografts
Grafts
Chemical activation
T-Lymphocytes
Transplantation (surgical)
Transplants
Cell Survival
Transplantation
Cells
Graft Rejection
Cell- and Tissue-Based Therapy
Islets of Langerhans
Oral Administration
Bone
B-Lymphocytes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Immunology
  • Hematology

Cite this

Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells. / Hauben, Ehud; Gregori, Silvia; Draghici, Elena; Migliavacca, Barbara; Olivieri, Stefano; Woisetschläger, Maximilian; Roncarolo, Maria Grazia.

In: Blood, Vol. 112, No. 4, 15.08.2008, p. 1214-1222.

Research output: Contribution to journalArticle

Hauben, Ehud ; Gregori, Silvia ; Draghici, Elena ; Migliavacca, Barbara ; Olivieri, Stefano ; Woisetschläger, Maximilian ; Roncarolo, Maria Grazia. / Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells. In: Blood. 2008 ; Vol. 112, No. 4. pp. 1214-1222.
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