TY  - CONF
AU  - Jonić, Natalija
AU  - Koprivica, Ivan
AU  - Chatzigiannis, Christos
AU  - Tsiailanis, Antonis
AU  - Kyrkou, Stavroula
AU  - Tzakos, Eleftherios Paraskevas
AU  - Pavić, Aleksandar
AU  - Dimitrijević, Mirjana
AU  - Jovanović, Anđelina
AU  - Jovanović, Milan B.
AU  - Marinho, Sergio
AU  - Castro-Almeida, Ines
AU  - Otašević, Vesna
AU  - Moura-Alves, Pedro
AU  - Tzakos, Andreas
AU  - Stojanović, Ivana D.
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/7017
AB  - 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.
PB  - John Wiley and Sons
C3  - 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland
T1  - 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
IS  - 54
DO  - 10.1002/eji.202470200
SP  - 372
EP  - 373
ER  - 

@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"
}

Jonić, N., Koprivica, I., Chatzigiannis, C., Tsiailanis, A., Kyrkou, S., Tzakos, E. P., Pavić, A., Dimitrijević, M., Jovanović, A., Jovanović, M. B., Marinho, S., Castro-Almeida, I., Otašević, V., Moura-Alves, P., Tzakos, A.,& Stojanović, I. D.. (2024). 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. in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland
John Wiley and Sons.(54), 372-373.
https://doi.org/10.1002/eji.202470200

Jonić N, Koprivica I, Chatzigiannis C, Tsiailanis A, Kyrkou S, Tzakos EP, Pavić A, Dimitrijević M, Jovanović A, Jovanović MB, Marinho S, Castro-Almeida I, Otašević V, Moura-Alves P, Tzakos A, Stojanović ID. 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. in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland. 2024;(54):372-373.
doi:10.1002/eji.202470200 .

Jonić, Natalija, Koprivica, Ivan, Chatzigiannis, Christos, Tsiailanis, Antonis, Kyrkou, Stavroula, Tzakos, Eleftherios Paraskevas, Pavić, Aleksandar, Dimitrijević, Mirjana, Jovanović, Anđelina, Jovanović, Milan B., Marinho, Sergio, Castro-Almeida, Ines, Otašević, Vesna, Moura-Alves, Pedro, Tzakos, Andreas, Stojanović, Ivana D., "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" in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland, no. 54 (2024):372-373,
https://doi.org/10.1002/eji.202470200 . .

TY  - JOUR
AU  - Jonić, Natalija
AU  - Koprivica, Ivan
AU  - Chatzigiannis, Christos M.
AU  - Tsiailanis, Antonis D.
AU  - Kyrkou, Stavroula G
AU  - Tzakos, Eleftherios Paraskevas
AU  - Pavić, Aleksandar
AU  - Dimitrijević, Mirjana
AU  - Jovanović, Andjelina
AU  - Jovanović, Milan B.
AU  - Marinho, Sergio
AU  - Castro-Almeida, Ines
AU  - Otašević, Vesna
AU  - Moura-Alves, Pedro
AU  - Tzakos, Andreas G
AU  - Stojanović, Ivana D.
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6870
AB  - Aryl Hydrocarbon Receptor (AHR) ligands, upon binding, induce distinct gene expression profiles orchestrated by the AHR, leading to a spectrum of pro- or anti-inflammatory effects.
In this study, we designed, synthesized and evaluated three indole-containing potential AHR
ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were shown to
emit fluorescence in the near-infrared. Their AHR agonist activity was first predicted using in
silico docking studies, and then confirmed using AHR luciferase reporter cell lines. FluoAHRLs
were tested in vitro using mouse peritoneal macrophages and T lymphocytes to assess their
immunomodulatory properties. We then focused on AGT-5, as it illustrated the predominant
anti-inflammatory effects. Notably, AGT-5 demonstrated the ability to foster anti-inflammatory
regulatory T cells (Treg) while suppressing pro-inflammatory T helper (Th)17 cells in vitro. AGT-5
actively induced Treg differentiation from naïve CD4+ cells, and promoted Treg proliferation,
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and interleukin-10 (IL-10) production. The increase in IL-10 correlated with an upregulation of Signal Transducer and Activator
of Transcription 3 (STAT3) expression. Importantly, the Treg-inducing effect of AGT-5 was also
observed in human tonsil cells in vitro. AGT-5 showed no toxicity when applied to zebrafish
embryos and was therefore considered safe for animal studies. Following oral administration to
C57BL/6 mice, AGT-5 significantly upregulated Treg while downregulating pro-inflammatory Th1
cells in the mesenteric lymph nodes. Due to its fluorescent properties, AGT-5 could be visualized
both in vitro (during uptake by macrophages) and ex vivo (within the lamina propria of the
small intestine). These findings make AGT-5 a promising candidate for further exploration in the
treatment of inflammatory and autoimmune diseases.
PB  - Basel: MDPI
T2  - Molecules
T1  - Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells
IS  - 13
VL  - 29
DO  - 10.3390/molecules29132988
SP  - 2988
ER  - 

@article{
author = "Jonić, Natalija and Koprivica, Ivan and Chatzigiannis, Christos M. and Tsiailanis, Antonis D. and Kyrkou, Stavroula G and Tzakos, Eleftherios Paraskevas and Pavić, Aleksandar and Dimitrijević, Mirjana and Jovanović, Andjelina and Jovanović, Milan B. and Marinho, Sergio and Castro-Almeida, Ines and Otašević, Vesna and Moura-Alves, Pedro and Tzakos, Andreas G and Stojanović, Ivana D.",
year = "2024",
abstract = "Aryl Hydrocarbon Receptor (AHR) ligands, upon binding, induce distinct gene expression profiles orchestrated by the AHR, leading to a spectrum of pro- or anti-inflammatory effects.
In this study, we designed, synthesized and evaluated three indole-containing potential AHR
ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were shown to
emit fluorescence in the near-infrared. Their AHR agonist activity was first predicted using in
silico docking studies, and then confirmed using AHR luciferase reporter cell lines. FluoAHRLs
were tested in vitro using mouse peritoneal macrophages and T lymphocytes to assess their
immunomodulatory properties. We then focused on AGT-5, as it illustrated the predominant
anti-inflammatory effects. Notably, AGT-5 demonstrated the ability to foster anti-inflammatory
regulatory T cells (Treg) while suppressing pro-inflammatory T helper (Th)17 cells in vitro. AGT-5
actively induced Treg differentiation from naïve CD4+ cells, and promoted Treg proliferation,
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and interleukin-10 (IL-10) production. The increase in IL-10 correlated with an upregulation of Signal Transducer and Activator
of Transcription 3 (STAT3) expression. Importantly, the Treg-inducing effect of AGT-5 was also
observed in human tonsil cells in vitro. AGT-5 showed no toxicity when applied to zebrafish
embryos and was therefore considered safe for animal studies. Following oral administration to
C57BL/6 mice, AGT-5 significantly upregulated Treg while downregulating pro-inflammatory Th1
cells in the mesenteric lymph nodes. Due to its fluorescent properties, AGT-5 could be visualized
both in vitro (during uptake by macrophages) and ex vivo (within the lamina propria of the
small intestine). These findings make AGT-5 a promising candidate for further exploration in the
treatment of inflammatory and autoimmune diseases.",
publisher = "Basel: MDPI",
journal = "Molecules",
title = "Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells",
number = "13",
volume = "29",
doi = "10.3390/molecules29132988",
pages = "2988"
}

Jonić, N., Koprivica, I., Chatzigiannis, C. M., Tsiailanis, A. D., Kyrkou, S. G., Tzakos, E. P., Pavić, A., Dimitrijević, M., Jovanović, A., Jovanović, M. B., Marinho, S., Castro-Almeida, I., Otašević, V., Moura-Alves, P., Tzakos, A. G.,& Stojanović, I. D.. (2024). Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells. in Molecules
Basel: MDPI., 29(13), 2988.
https://doi.org/10.3390/molecules29132988

Jonić N, Koprivica I, Chatzigiannis CM, Tsiailanis AD, Kyrkou SG, Tzakos EP, Pavić A, Dimitrijević M, Jovanović A, Jovanović MB, Marinho S, Castro-Almeida I, Otašević V, Moura-Alves P, Tzakos AG, Stojanović ID. Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells. in Molecules. 2024;29(13):2988.
doi:10.3390/molecules29132988 .

Jonić, Natalija, Koprivica, Ivan, Chatzigiannis, Christos M., Tsiailanis, Antonis D., Kyrkou, Stavroula G, Tzakos, Eleftherios Paraskevas, Pavić, Aleksandar, Dimitrijević, Mirjana, Jovanović, Andjelina, Jovanović, Milan B., Marinho, Sergio, Castro-Almeida, Ines, Otašević, Vesna, Moura-Alves, Pedro, Tzakos, Andreas G, Stojanović, Ivana D., "Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells" in Molecules, 29, no. 13 (2024):2988,
https://doi.org/10.3390/molecules29132988 . .