Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells.
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.
San Raffaele Telethon Institute for Gene Therapy, HSR-TIGET, Milan, Italy.
Ehud
E
Hauben
Silvia
S
Gregori
Elena
E
Draghici
Barbara
B
Migliavacca
Stefano
S
Olivieri
Maximilian
M
Woisetschläger
Maria Grazia
MG
Roncarolo
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D051379:Mice; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D023001:Transplantation Tolerance
D011743:Pyrimidines; D018336:Receptors, Aryl Hydrocarbon; C509596:VAF347