TY  - CONF
AU  - Lazarević, Milica
AU  - Stegnjaić, Goran
AU  - Stanisavljević, Suzana
AU  - Nikolovski, Neda
AU  - Momčilović, Miljana
AU  - Dimitrijević, Mirjana
AU  - Fraser, Graeme L
AU  - Miljković, Đorđe
AU  - Jevtić, Bojan
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/7021
AB  - Innate lymphoid cells type 3 (ILC3) play a central role in maintaining intestinal homeostasis and regulating the balance between effector T cell populations and regulatory T cells (Treg) in the gut milieu. Dysregulation of this balance, which is strongly influenced by the gut microbiota and dietary components, is associated with autoimmune diseases such as multiple sclerosis (MS). Intestinal ILC3 are activated by dietary compounds like short-chain fatty acids (SCFA), which are produced by gut bacteria. SCFA, acting via the free fatty acid receptor 2 (FFAR2), stimulate ILC3 proliferation, IL-22 and IL-2 production in the small intestine. The secretion of IL-22 by ILC3 supports the integrity of the intestinal barrier and the balance of the immune system, while IL-2 enhances the activity of Treg and thus improves immune regulation in the intestine.
In this study, the efficacy of a FFAR2 agonist - Cpd1 as evaluated in a mouse model of chronic experimental autoimmune encephalomyelitis (EAE). Treatment with Cpd1 efficiently ameliorated EAE and showed significant attenuation of CNS inflammation and lessened infiltration of immune cells into the spinal cord. Flow cytometric analysis of immune cells in the spinal cord showed that the number of CD4+ T cells, Th1, and Th17 cells decreased with Cpd1 treatment. In addition, Cpd1 treatment in EAE mice led to changes in the composition of immune cells in the lamina propria of the small intestine, which was characterized by an increased proportion of Treg and IL-22-producing ILC3 and a decrease in IL-17-
expressing ILC3, while there was no difference in the proportion of IL-2-producing ILC3 cells between Cpd1-treated and control mice. Consistent with this, Cpd1 treatment also altered the composition of the microbiota in the EAE model. In summary, these data indicate that activation of immune-regulatory, gut-resident ILC3 cells by FFAR2 agonists modulates the autoimmune response local to the small intestine as well as in distal tissues such as the spinal cord. These findings highlight the potential therapeutic use of FFAR2 agonists in the treatment of autoimmune diseases.
PB  - John Wiley and Sons
C3  - 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland
T1  - Pharmacological activation of free fatty acid receptor 2 in intestinal type 3 innate lymphoid cells ameliorates experimental autoimmune encephalomyelitis
DO  - 10.1002/eji.202470200
SP  - 23
ER  - 

@conference{
author = "Lazarević, Milica and Stegnjaić, Goran and Stanisavljević, Suzana and Nikolovski, Neda and Momčilović, Miljana and Dimitrijević, Mirjana and Fraser, Graeme L and Miljković, Đorđe and Jevtić, Bojan",
year = "2024",
abstract = "Innate lymphoid cells type 3 (ILC3) play a central role in maintaining intestinal homeostasis and regulating the balance between effector T cell populations and regulatory T cells (Treg) in the gut milieu. Dysregulation of this balance, which is strongly influenced by the gut microbiota and dietary components, is associated with autoimmune diseases such as multiple sclerosis (MS). Intestinal ILC3 are activated by dietary compounds like short-chain fatty acids (SCFA), which are produced by gut bacteria. SCFA, acting via the free fatty acid receptor 2 (FFAR2), stimulate ILC3 proliferation, IL-22 and IL-2 production in the small intestine. The secretion of IL-22 by ILC3 supports the integrity of the intestinal barrier and the balance of the immune system, while IL-2 enhances the activity of Treg and thus improves immune regulation in the intestine.
In this study, the efficacy of a FFAR2 agonist - Cpd1 as evaluated in a mouse model of chronic experimental autoimmune encephalomyelitis (EAE). Treatment with Cpd1 efficiently ameliorated EAE and showed significant attenuation of CNS inflammation and lessened infiltration of immune cells into the spinal cord. Flow cytometric analysis of immune cells in the spinal cord showed that the number of CD4+ T cells, Th1, and Th17 cells decreased with Cpd1 treatment. In addition, Cpd1 treatment in EAE mice led to changes in the composition of immune cells in the lamina propria of the small intestine, which was characterized by an increased proportion of Treg and IL-22-producing ILC3 and a decrease in IL-17-
expressing ILC3, while there was no difference in the proportion of IL-2-producing ILC3 cells between Cpd1-treated and control mice. Consistent with this, Cpd1 treatment also altered the composition of the microbiota in the EAE model. In summary, these data indicate that activation of immune-regulatory, gut-resident ILC3 cells by FFAR2 agonists modulates the autoimmune response local to the small intestine as well as in distal tissues such as the spinal cord. These findings highlight the potential therapeutic use of FFAR2 agonists in the treatment of autoimmune diseases.",
publisher = "John Wiley and Sons",
journal = "7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland",
title = "Pharmacological activation of free fatty acid receptor 2 in intestinal type 3 innate lymphoid cells ameliorates experimental autoimmune encephalomyelitis",
doi = "10.1002/eji.202470200",
pages = "23"
}

Lazarević, M., Stegnjaić, G., Stanisavljević, S., Nikolovski, N., Momčilović, M., Dimitrijević, M., Fraser, G. L., Miljković, Đ.,& Jevtić, B.. (2024). Pharmacological activation of free fatty acid receptor 2 in intestinal type 3 innate lymphoid cells ameliorates experimental autoimmune encephalomyelitis. in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland
John Wiley and Sons., 23.
https://doi.org/10.1002/eji.202470200

Lazarević M, Stegnjaić G, Stanisavljević S, Nikolovski N, Momčilović M, Dimitrijević M, Fraser GL, Miljković Đ, Jevtić B. Pharmacological activation of free fatty acid receptor 2 in intestinal type 3 innate lymphoid cells ameliorates experimental autoimmune encephalomyelitis. in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland. 2024;:23.
doi:10.1002/eji.202470200 .

Lazarević, Milica, Stegnjaić, Goran, Stanisavljević, Suzana, Nikolovski, Neda, Momčilović, Miljana, Dimitrijević, Mirjana, Fraser, Graeme L, Miljković, Đorđe, Jevtić, Bojan, "Pharmacological activation of free fatty acid receptor 2 in intestinal type 3 innate lymphoid cells ameliorates experimental autoimmune encephalomyelitis" in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland (2024):23,
https://doi.org/10.1002/eji.202470200 . .

TY  - CONF
AU  - Jonić, Natalija
AU  - Koprivica, Ivan
AU  - Mićanović, Dragica
AU  - Saksida, Tamara
AU  - Jevtić, Bojan
AU  - Fraser, Graeme L
AU  - Miljković, Đorđe
AU  - Stojanović, Ivana D.
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/7023
AB  - Type 1 diabetes (T1D) is a chronic autoimmune disease that usually develops in early childhood. The recent market approval of the anti-CD3 monoclonal antibody (teplizumab) is a major advance in protecting at-risk patients from the onset  of T1D . In addition to the presence of autoantibodies, T1D-prone individuals exhibit alteration in the gut microbiota and the intestinal immune response. As intestinal epithelial and immune cells express receptors for free fatty acids (FFAR), and it was shown that stimulation of FFAR2 can down-regulate inflammation during Crohn’s disease, we have tested the efficacy of the novel agonist for FFAR2 (Cpd1) in the prevention of T1D induced by five injections of low-dose of streptozotocin in C57BL/6 mice. Oral application of Cpd1 (applied from the 1st day of T1D induction for 20 days in total) resulted in a significant reduction of T1D incidence and lowered mean glycemia levels in the treated mice. Accordingly, these mice had lower insulitis in the pancreas and higher insulin production. Ex vivo analysis on the 8th day post T1D induction showed higher proportions of innate lymphoid cell type 3 (ILC3) that produced IL-2 within the small intestine (SI) lamina propria of Cpd1-treated mice. The increase in IL-2 correlated with  higher Treg proportions detected on day 12 in the SI lamina propria. Similar findings were observed in NOD mice, a spontaneous T1D model, treated with Cpd1 on a daily basis (from 8 weeks until 12 weeks of age). Cpd1 increased the presence of ILC3 in the SI lamina propria of NOD mice, and more specifically, the proportion of Nkp46− ILC3. In total, these results demonstrate that Cpd1 increased the population of ILC3 and Treg by activating FFAR2, thereby modulating the anti-inflammatory immune response and protecting the pancreas from the imposed damage.
PB  - John Wiley and Sons
C3  - 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland
T1  - Novel FFAR2 agonist prevents development of type 1 diabetes in C57BL/6 mice
DO  - 10.1002/eji.202470200
SP  - 1210
ER  - 

@conference{
author = "Jonić, Natalija and Koprivica, Ivan and Mićanović, Dragica and Saksida, Tamara and Jevtić, Bojan and Fraser, Graeme L and Miljković, Đorđe and Stojanović, Ivana D.",
year = "2024",
abstract = "Type 1 diabetes (T1D) is a chronic autoimmune disease that usually develops in early childhood. The recent market approval of the anti-CD3 monoclonal antibody (teplizumab) is a major advance in protecting at-risk patients from the onset  of T1D . In addition to the presence of autoantibodies, T1D-prone individuals exhibit alteration in the gut microbiota and the intestinal immune response. As intestinal epithelial and immune cells express receptors for free fatty acids (FFAR), and it was shown that stimulation of FFAR2 can down-regulate inflammation during Crohn’s disease, we have tested the efficacy of the novel agonist for FFAR2 (Cpd1) in the prevention of T1D induced by five injections of low-dose of streptozotocin in C57BL/6 mice. Oral application of Cpd1 (applied from the 1st day of T1D induction for 20 days in total) resulted in a significant reduction of T1D incidence and lowered mean glycemia levels in the treated mice. Accordingly, these mice had lower insulitis in the pancreas and higher insulin production. Ex vivo analysis on the 8th day post T1D induction showed higher proportions of innate lymphoid cell type 3 (ILC3) that produced IL-2 within the small intestine (SI) lamina propria of Cpd1-treated mice. The increase in IL-2 correlated with  higher Treg proportions detected on day 12 in the SI lamina propria. Similar findings were observed in NOD mice, a spontaneous T1D model, treated with Cpd1 on a daily basis (from 8 weeks until 12 weeks of age). Cpd1 increased the presence of ILC3 in the SI lamina propria of NOD mice, and more specifically, the proportion of Nkp46− ILC3. In total, these results demonstrate that Cpd1 increased the population of ILC3 and Treg by activating FFAR2, thereby modulating the anti-inflammatory immune response and protecting the pancreas from the imposed damage.",
publisher = "John Wiley and Sons",
journal = "7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland",
title = "Novel FFAR2 agonist prevents development of type 1 diabetes in C57BL/6 mice",
doi = "10.1002/eji.202470200",
pages = "1210"
}

Jonić, N., Koprivica, I., Mićanović, D., Saksida, T., Jevtić, B., Fraser, G. L., Miljković, Đ.,& Stojanović, I. D.. (2024). Novel FFAR2 agonist prevents development of type 1 diabetes in C57BL/6 mice. in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland
John Wiley and Sons., 1210.
https://doi.org/10.1002/eji.202470200

Jonić N, Koprivica I, Mićanović D, Saksida T, Jevtić B, Fraser GL, Miljković Đ, Stojanović ID. Novel FFAR2 agonist prevents development of type 1 diabetes in C57BL/6 mice. in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland. 2024;:1210.
doi:10.1002/eji.202470200 .

Jonić, Natalija, Koprivica, Ivan, Mićanović, Dragica, Saksida, Tamara, Jevtić, Bojan, Fraser, Graeme L, Miljković, Đorđe, Stojanović, Ivana D., "Novel FFAR2 agonist prevents development of type 1 diabetes in C57BL/6 mice" in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland (2024):1210,
https://doi.org/10.1002/eji.202470200 . .

TY  - JOUR
AU  - Lazarević, Milica
AU  - Stegnjaić, Goran
AU  - Jevtić, Bojan
AU  - Despotović, Sanja
AU  - Ignjatović, Đurđica
AU  - Stanisavljević, Suzana
AU  - Nikolovski, Neda
AU  - Momčilović, Miljana
AU  - Fraser, Graeme L
AU  - Dimitrijević, Mirjana
AU  - Miljković, Đorđe
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6501
AB  - Experimental autoimmune encephalomyelitis (EAE) induced in inbred rodents, i.e., genetically identical animals kept under identical environmental conditions, shows variable clinical outcomes. We investigated such variations of EAE in Dark Agouti rats immunized with spinal cord homogenate and identified four groups: lethal, severe, moderate, and mild, at day 28 post immunization. Higher numbers of CD4+ T cells, helper T cells type 1 (Th1) and 17 (Th17) in particular, were detected in the spinal cord of the severe group in comparison with the moderate group. In addition, increased proportion of Th1 and Th17 cells, and heightened levels of interferon (IFN)-γ and interleukin (IL)-6 were detected in the small intestine lamina propria of the severe group. A selective agonist of free fatty acid receptor type 2 (Ffar2) applied orally in the inductive phase of EAE shifted the distribution of the disease outcomes towards milder forms. This effect was paralleled with potentiation of intestinal innate lymphoid cells type 3 (ILC3) regulatory properties, and diminished Th1 and Th17 cell response in the lymph nodes draining the site of immunization. Our results suggest that different clinical outcomes in DA rats are under determinative influence of intestinal ILC3 activity during the inductive phase of EAE.
PB  - Springer Nature
T2  - Journal of Neuroinflammation
T1  - Increased regulatory activity of intestinal innate lymphoid cells type 3 (ILC3) prevents experimental autoimmune encephalomyelitis severity
VL  - 21
DO  - 10.1186/s12974-024-03017-7
SP  - 26
ER  - 

@article{
author = "Lazarević, Milica and Stegnjaić, Goran and Jevtić, Bojan and Despotović, Sanja and Ignjatović, Đurđica and Stanisavljević, Suzana and Nikolovski, Neda and Momčilović, Miljana and Fraser, Graeme L and Dimitrijević, Mirjana and Miljković, Đorđe",
year = "2024",
abstract = "Experimental autoimmune encephalomyelitis (EAE) induced in inbred rodents, i.e., genetically identical animals kept under identical environmental conditions, shows variable clinical outcomes. We investigated such variations of EAE in Dark Agouti rats immunized with spinal cord homogenate and identified four groups: lethal, severe, moderate, and mild, at day 28 post immunization. Higher numbers of CD4+ T cells, helper T cells type 1 (Th1) and 17 (Th17) in particular, were detected in the spinal cord of the severe group in comparison with the moderate group. In addition, increased proportion of Th1 and Th17 cells, and heightened levels of interferon (IFN)-γ and interleukin (IL)-6 were detected in the small intestine lamina propria of the severe group. A selective agonist of free fatty acid receptor type 2 (Ffar2) applied orally in the inductive phase of EAE shifted the distribution of the disease outcomes towards milder forms. This effect was paralleled with potentiation of intestinal innate lymphoid cells type 3 (ILC3) regulatory properties, and diminished Th1 and Th17 cell response in the lymph nodes draining the site of immunization. Our results suggest that different clinical outcomes in DA rats are under determinative influence of intestinal ILC3 activity during the inductive phase of EAE.",
publisher = "Springer Nature",
journal = "Journal of Neuroinflammation",
title = "Increased regulatory activity of intestinal innate lymphoid cells type 3 (ILC3) prevents experimental autoimmune encephalomyelitis severity",
volume = "21",
doi = "10.1186/s12974-024-03017-7",
pages = "26"
}

Lazarević, M., Stegnjaić, G., Jevtić, B., Despotović, S., Ignjatović, Đ., Stanisavljević, S., Nikolovski, N., Momčilović, M., Fraser, G. L., Dimitrijević, M.,& Miljković, Đ.. (2024). Increased regulatory activity of intestinal innate lymphoid cells type 3 (ILC3) prevents experimental autoimmune encephalomyelitis severity. in Journal of Neuroinflammation
Springer Nature., 21, 26.
https://doi.org/10.1186/s12974-024-03017-7

Lazarević M, Stegnjaić G, Jevtić B, Despotović S, Ignjatović Đ, Stanisavljević S, Nikolovski N, Momčilović M, Fraser GL, Dimitrijević M, Miljković Đ. Increased regulatory activity of intestinal innate lymphoid cells type 3 (ILC3) prevents experimental autoimmune encephalomyelitis severity. in Journal of Neuroinflammation. 2024;21:26.
doi:10.1186/s12974-024-03017-7 .

Lazarević, Milica, Stegnjaić, Goran, Jevtić, Bojan, Despotović, Sanja, Ignjatović, Đurđica, Stanisavljević, Suzana, Nikolovski, Neda, Momčilović, Miljana, Fraser, Graeme L, Dimitrijević, Mirjana, Miljković, Đorđe, "Increased regulatory activity of intestinal innate lymphoid cells type 3 (ILC3) prevents experimental autoimmune encephalomyelitis severity" in Journal of Neuroinflammation, 21 (2024):26,
https://doi.org/10.1186/s12974-024-03017-7 . .