@conference{
author = "Jonić, Natalija and Koprivica, Ivan and Chatzigiannis, Christos and Tsiailanis, Antonis and Kyrkou, Stavroula and Tzakos, Eleftherios Paraskevas and Pavić, Aleksandar and Dimitrijević, Mirjana and Jovanović, Anđelina and Jovanović, Milan B. and Marinho, Sergio and Castro-Almeida, Ines and Otašević, Vesna and Moura-Alves, Pedro and Tzakos, Andreas and Stojanović, Ivana D.",
year = "2024",
abstract = "Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by an imbalance between pathogenic CD4+ and
CD8+ lymphocytes on one side and regulatory T cells (Treg) on the other. Activating Treg and/or tolerogenic dendritic
cells (tolDC) through various methods has shown benefits in animal models of T1D. Both cell types express high levels
of the aryl hydrocarbon receptor (AHR), and AHR activation is typically associated with enhanced tolDC and Treg
functionality. In this study, the novel fluorescent indole-containing compound AGT-5 was investigated for its potential
to act as an AHR ligand and modulate immune cells both in vitro and in vivo. Through in silico docking analysis, AGT-
5 demonstrated the ability to bind AHR, and its agonistic effects were confirmed using the reporter Caco-2 cell line.
Additionally, due to its fluorescent properties, AGT-5 was visualized in macrophages in vitro and in the small intestine
lamina propria ex vivo after oral administration using confocal microscopy. AGT-5 exhibited no toxicity towards murine
macrophages and human tonsillar cells. Moreover, tests on zebrafish embryos revealed no nephrotoxicity, hepatotoxicity,
or cardiotoxicity. Utilizing an ADME virtual platform it was confirmed that AGT-5 possesses drug-like characteristics.
Subsequently, AGT-5 was orally administered to C57BL/6 mice that had received low doses of streptozotocin to induce
T1D. Treatment with AGT-5 commencing from the first day of T1D induction and lasting for 20 days effectively
prevented immune cell infiltration into the pancreas, preserved insulin production, and halted the progression of T1D.
AGT-5 achieved this by promoting tolDC and Treg activity along the gut-pancreatic lymph node-pancreas axis.
Mechanistically, AGT-5 upregulated indoleamine 2,3-dioxygenase 1 in tolDC and enhanced ATP-degrading enzyme
expression on Treg, thereby promoting immunosuppressive action. The positive outcomes seen in T1D animals suggest
that AGT-5 holds promise for a potential treatment for inflammatory conditions that can benefit from stimulation of the
regulatory arm of the immune response.",
publisher = "John Wiley and Sons",
journal = "7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland",
title = "A novel aryl hydrocarbon receptor ligand inhibits the development of Type 1 diabetes by enhancing the function of tolerogenic dendritic cells and regulatory T cells",
number = "54",
doi = "10.1002/eji.202470200",
pages = "372-373"
}