The Aryl Hydrocarbon Receptor (AHR) is a cytosolic transcription factor with numerous endogenous and xenobiotic ligands playing a key role in a number of cellular processes especially immune cell function and development. Differential effects of AHR ligands upon CD4 naïve Tcell development has been described with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inducing regulatory Tcells while FICZ promotes Th17 responses. Prior work demonstrated prolongation of graft survival in a fully mismatched skin allograft model (Balb/c donor to C57BL/6 recipient) with intraperitoneal administration of TCDD and early rejection with FICZ treatment. In the present work we demonstrate prolonged graft survival in a minor mismatch allograft model (C57BL/6 Male to Female) with dietary supplementation with the AHR ligand, Indole-3-Carbinol (I3C). C57BL/6 female mice were maintained on semi-purified base (SPB) diet deficient of AHR-ligands or SPB diet with I3C supplementation (3ppm) for 3wks prior to transplant and for the duration of the model. AHR-mediated graft survival was correlated to decreases in IFNγ producing Graft Infiltrating lymphocytes. Animals maintained on SPB diet demonstrated a loss of intestinal Treg, Innate Lymphoid Cells type 3, and γδ Tcells. However, I3C supplementation led to maintenance of these mucosal immune cell populations as measured by Flow cytometry. Conversely, maintenance of animals on the AHR-deficient SPB diet led to accelerated graft rejection (Median GST of 46 vs 15.5days p<0.05). These findings were AHR-dependent as AHR null animals were found to not only reject grafts earlier than WT counterparts but were not responsive to I3C supplementation (Median GST, AHR null on SPB vs I3C diet were 17 vs 15.5 days respectively). Interestingly, animals null for the AHR-dependent cytokine IL22 (IL22KO) were found to have a significantly increased rate of graft rejection similar to AHR null animals compared with WT counterparts (19d vs 46d respectively). Splenocytes isolated from animals on either SPB or I3C diets were collected and cultured in vitro with exposure to HY peptide. ELISA performed on the supernatants demonstrated a decrease in IFNγ and TNFa production in those animals maintained on I3C vs SPB diet. While the underlying mechanism remains unclear, these data suggest a role for activation of the mucosal immune system via AHR stimulation and dietary AHR ligands play a novel regulatory role in modulating systemic immune responses.

CITATION INFORMATION: Afrazi A., Owens L., Fechner J., O'Driscoll C., Mezrich J. Prolongation of Skin Allograft Survival through Dietary Supplementation of Ayrl Hydrocarbon Receptor Ligands Am J Transplant. 2017;17 (suppl 3).

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