Date: Monday, June 3, 2019
Session Time: 2:30pm-4:00pm
Presentation Time: 2:30pm-2:42pm
Location: Room 311
*Purpose: The aryl hydrocarbon receptor (AHR) has been shown to have a central role in the ability of dendritic cells (DCs) to direct differentiation of Tregs from naïve T cells. Targeting the AHR with intraperitoneal, oral or inhaled ligands prolongs survival of murine skin grafts. Recently, it has been shown that nanoparticles (NPs) loaded with a ligand of the AHR have been shown to promote the generation of Tregs by DCs and reduce disease in murine models of EAE and diabetes. We propose the use of these tolerogenic nanoparticles in models of allogenic transplant as a novel method of targeted immunosuppression via the AHR.
*Methods: PLA/PEG NPs approximately 50 nm in size were manufactured and loaded with ITE, an AHR ligand, and peptide antigen to the alpha chain of I-E (Eα-peptide) or ovalbumin to evaluate for antigen-specific response. BMDCs generated from AHR+/- and AHR-/- mice were exposed to free ITE, NP-ITE, NP-peptide/ITE. Cells were evaluated for uptake into DCs by flow cytometric analysis of Cy5.5-labeling of NP, and ability to activate AHR determined by RT-PCR expression of CYP1A1 and IDO1. DCs isolated from OT-II splenocytes were generated and exposed for 4 days to ova, NP-Ova, NP-Ova/ITE for evaluation of proliferative response and effect on cytokine production of IL-17 and IFN𝜸;. NPs were utilized in-vivo by injecting CFSE-labeled OT-II splenocytes IV into B6 mice, treating the following day with ova peptide or NP, and performing flow cytometric analysis of proliferation after 3 days.
*Results: BMDCs cultured with NP-Ea/ITE had reliable uptake of NPs by CD11c+ cells and a subsequent 4-6 fold increase in CYP1A1 expression of AHR+/- mice over untreated control. OT-II splenocytes incubated with NP-Ova or NP-Ova/ITE had markedly suppressed generation of IL-17 or IFN𝜸; compared to exposure to ova peptide alone. In-vivo experiments demonstrated significant reduction in proliferation of NP-Ova/ITE treated mice compared to NP-Ova treated mice.
*Conclusions: Nanoparticles containing the AHR ligand ITE have been generated and used in preliminary experiments demonstrating the ability to be taken up by dendritic cells and activate the AHR. This leads to a decrease inflammatory cytokines IL-17 and IFN𝜸; upon antigen stimulation in-vitro and decrease proliferative response to stimulation in-vivo.
To cite this abstract in AMA style:Janek K, Fechner J, Gong S, Wang Y, Mezrich J. Tolerogenic Nanoparticles Targeting the Aryl Hydrocarbon Receptor [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/tolerogenic-nanoparticles-targeting-the-aryl-hydrocarbon-receptor/. Accessed July 13, 2020.
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