Pilipović, Ivan

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orcid::0000-0002-0642-3106
  • Pilipović, Ivan (86)

Author's Bibliography

Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development

Petrušić, Marija; Stojić-Vukanić, Zorica; Pilipović, Ivan; Kosec, Duško; Prijić, Ivana; Leposavić, Gordana

(Elsevier, 2023)

TY  - JOUR
AU  - Petrušić, Marija
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Prijić, Ivana
AU  - Leposavić, Gordana
PY  - 2023
UR  - http://intor.torlakinstitut.com/handle/123456789/633
AB  - The study was aimed to examine putative contribution of thymic involution to ageing-associated increase in susceptibility of Albino Oxford (AO) rats to the development of clinical EAE, and vice versa influence of the disease on the progression of thymic involution. To this end we examined (i) the parameters of thymocyte negative selection efficacy, the thymic generation of CD4+CD25+Foxp3+ T regulatory cells (Tregs) and thymic capacity to instruct/predetermine IL-17-producing T-cell differentiation, and thymopietic efficacy-associated accumulation of “inflammescent” cytotoxic CD28- T cells in the periphery, and (ii) the key underlying mechanisms in young and old non-immunised AO rats and their counterparts immunised for EAE (on the 16th day post-immunisation when the disease in old rats reached the plateau) using flow cytometry analysis and/or RT-qPCR. It was found that thymic involution impairs: (i) the efficacy of negative selection (by affecting thymocyte expression of CD90, negative regulator of selection threshold and the expression of thymic stromal cell integrity factors) and (ii) Treg generation (by diminishing expression of cytokines supporting their differentiation/maturation). Additionally, the results suggest that thymic involution facilitates CD8+ T-cell differentiation into IL-17-producing cells (previously linked to the development of clinical EAE in old AO rats). Furthermore, they confirmed that ageing-related decrease in thymic T-cell output (as indicated by diminished frequency of recent thymic emigrants in peripheral blood) resulted in the accumulation of CD28- T cells in peripheral blood and, upon immunisation, in the target organ. On the other hand, the development of EAE (most likely by increasing circulatory levels of proinflammatory cytokines) contributed to the decline in thymic output of T cells, including Tregs, and thereby to the progression/maintenance of clinical EAE. Thus, in AO rats thymic involution via multi-layered mechanisms may favour the development of clinically manifested autoimmunity, which, in turn, precipitates the thymus atrophy.
PB  - Elsevier
T2  - Experimental Gerontology
T1  - Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development
SP  - 112009
VL  - 171
DO  - 10.1016/j.exger.2022.112009
ER  - 
@article{
author = "Petrušić, Marija and Stojić-Vukanić, Zorica and Pilipović, Ivan and Kosec, Duško and Prijić, Ivana and Leposavić, Gordana",
year = "2023",
abstract = "The study was aimed to examine putative contribution of thymic involution to ageing-associated increase in susceptibility of Albino Oxford (AO) rats to the development of clinical EAE, and vice versa influence of the disease on the progression of thymic involution. To this end we examined (i) the parameters of thymocyte negative selection efficacy, the thymic generation of CD4+CD25+Foxp3+ T regulatory cells (Tregs) and thymic capacity to instruct/predetermine IL-17-producing T-cell differentiation, and thymopietic efficacy-associated accumulation of “inflammescent” cytotoxic CD28- T cells in the periphery, and (ii) the key underlying mechanisms in young and old non-immunised AO rats and their counterparts immunised for EAE (on the 16th day post-immunisation when the disease in old rats reached the plateau) using flow cytometry analysis and/or RT-qPCR. It was found that thymic involution impairs: (i) the efficacy of negative selection (by affecting thymocyte expression of CD90, negative regulator of selection threshold and the expression of thymic stromal cell integrity factors) and (ii) Treg generation (by diminishing expression of cytokines supporting their differentiation/maturation). Additionally, the results suggest that thymic involution facilitates CD8+ T-cell differentiation into IL-17-producing cells (previously linked to the development of clinical EAE in old AO rats). Furthermore, they confirmed that ageing-related decrease in thymic T-cell output (as indicated by diminished frequency of recent thymic emigrants in peripheral blood) resulted in the accumulation of CD28- T cells in peripheral blood and, upon immunisation, in the target organ. On the other hand, the development of EAE (most likely by increasing circulatory levels of proinflammatory cytokines) contributed to the decline in thymic output of T cells, including Tregs, and thereby to the progression/maintenance of clinical EAE. Thus, in AO rats thymic involution via multi-layered mechanisms may favour the development of clinically manifested autoimmunity, which, in turn, precipitates the thymus atrophy.",
publisher = "Elsevier",
journal = "Experimental Gerontology",
title = "Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development",
pages = "112009",
volume = "171",
doi = "10.1016/j.exger.2022.112009"
}
Petrušić, M., Stojić-Vukanić, Z., Pilipović, I., Kosec, D., Prijić, I.,& Leposavić, G.. (2023). Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development. in Experimental Gerontology
Elsevier., 171, 112009.
https://doi.org/10.1016/j.exger.2022.112009
Petrušić M, Stojić-Vukanić Z, Pilipović I, Kosec D, Prijić I, Leposavić G. Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development. in Experimental Gerontology. 2023;171:112009.
doi:10.1016/j.exger.2022.112009 .
Petrušić, Marija, Stojić-Vukanić, Zorica, Pilipović, Ivan, Kosec, Duško, Prijić, Ivana, Leposavić, Gordana, "Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development" in Experimental Gerontology, 171 (2023):112009,
https://doi.org/10.1016/j.exger.2022.112009 . .
2
2

Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis

Pilipović, Ivan; Stojić-Vukanić, Zorica; Leposavić, Gordana

(Elsevier, 2023)

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2023
UR  - http://intor.torlakinstitut.com/handle/123456789/663
AB  - This review summarizes recent findings related to the role of the sympathetic nervous system (SNS) in pathogenesis of multiple sclerosis (MS) and its commonly used experimental model – experimental autoimmune encephalomyelitis (EAE). They indicate that noradrenaline, the key end-point mediator of the SNS, acting through β-adrenoceptor, has a contributory role in the early stages of MS/EAE development. This stage is characterized by the SNS hyperactivity (increased release of noradrenaline) reflecting the net effect of different factors, such as the disease-associated inflammation, stress, vitamin D hypovitaminosis, Epstein-Barr virus infection and dysbiosis. Thus, the administration of propranolol, a non-selective β-adrenoceptor blocker, readily crossing the blood-brain barrier, to experimental rats before the autoimmune challenge and in the early (preclinical/prodromal) phase of the disease mitigates EAE severity. This phenomenon has been ascribed to the alleviation of neuroinflammation (due to attenuation of primarily microglial activation/proinflammatory functions) and the diminution of the magnitude of the primary CD4+ T-cell autoimmune response (the effect associated with impaired autoantigen uptake by antigen presenting cells and their migration into draining lymph nodes). The former is partly related to breaking of the catecholamine-dependent self-amplifying microglial feed-forward loop and the positive feedback loop between microglia and the SNS, leading to down-regulation of the SNS hyperactivity and its enhancing influence on microglial activation/proinflammatory functions and the magnitude of autoimmune response. The effects of propranolol are shown to be more prominent in male EAE animals, the phenomenon important as males (like men) are likely to develop clinically more severe disease. Thus, these findings could serve as a firm scientific background for formulation of a new sex-specific immune-intervention strategy for the early phases of MS (characterized by the SNS hyperactivity) exploiting anti-(neuro)inflammatory and immunomodulatory properties of propranolol and other relatively cheap and safe adrenergic drugs with similar therapeutic profile.
PB  - Elsevier
T2  - Pharmacology and Therapeutics
T1  - Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis
VL  - 243
DO  - 10.1016/j.pharmthera.2023.108358
ER  - 
@article{
author = "Pilipović, Ivan and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2023",
abstract = "This review summarizes recent findings related to the role of the sympathetic nervous system (SNS) in pathogenesis of multiple sclerosis (MS) and its commonly used experimental model – experimental autoimmune encephalomyelitis (EAE). They indicate that noradrenaline, the key end-point mediator of the SNS, acting through β-adrenoceptor, has a contributory role in the early stages of MS/EAE development. This stage is characterized by the SNS hyperactivity (increased release of noradrenaline) reflecting the net effect of different factors, such as the disease-associated inflammation, stress, vitamin D hypovitaminosis, Epstein-Barr virus infection and dysbiosis. Thus, the administration of propranolol, a non-selective β-adrenoceptor blocker, readily crossing the blood-brain barrier, to experimental rats before the autoimmune challenge and in the early (preclinical/prodromal) phase of the disease mitigates EAE severity. This phenomenon has been ascribed to the alleviation of neuroinflammation (due to attenuation of primarily microglial activation/proinflammatory functions) and the diminution of the magnitude of the primary CD4+ T-cell autoimmune response (the effect associated with impaired autoantigen uptake by antigen presenting cells and their migration into draining lymph nodes). The former is partly related to breaking of the catecholamine-dependent self-amplifying microglial feed-forward loop and the positive feedback loop between microglia and the SNS, leading to down-regulation of the SNS hyperactivity and its enhancing influence on microglial activation/proinflammatory functions and the magnitude of autoimmune response. The effects of propranolol are shown to be more prominent in male EAE animals, the phenomenon important as males (like men) are likely to develop clinically more severe disease. Thus, these findings could serve as a firm scientific background for formulation of a new sex-specific immune-intervention strategy for the early phases of MS (characterized by the SNS hyperactivity) exploiting anti-(neuro)inflammatory and immunomodulatory properties of propranolol and other relatively cheap and safe adrenergic drugs with similar therapeutic profile.",
publisher = "Elsevier",
journal = "Pharmacology and Therapeutics",
title = "Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis",
volume = "243",
doi = "10.1016/j.pharmthera.2023.108358"
}
Pilipović, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2023). Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis. in Pharmacology and Therapeutics
Elsevier., 243.
https://doi.org/10.1016/j.pharmthera.2023.108358
Pilipović I, Stojić-Vukanić Z, Leposavić G. Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis. in Pharmacology and Therapeutics. 2023;243.
doi:10.1016/j.pharmthera.2023.108358 .
Pilipović, Ivan, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis" in Pharmacology and Therapeutics, 243 (2023),
https://doi.org/10.1016/j.pharmthera.2023.108358 . .
2
3
2

Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis

Pilipović, Ivan; Stojić-Vukanić, Zorica; Leposavić, Gordana

(Elsevier, 2023)

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2023
UR  - http://intor.torlakinstitut.com/handle/123456789/657
AB  - This review summarizes recent findings related to the role of the sympathetic nervous system (SNS) in pathogenesis of multiple sclerosis (MS) and its commonly used experimental model – experimental autoimmune encephalomyelitis (EAE). They indicate that noradrenaline, the key end-point mediator of the SNS, acting through β-adrenoceptor, has a contributory role in the early stages of MS/EAE development. This stage is characterized by the SNS hyperactivity (increased release of noradrenaline) reflecting the net effect of different factors, such as the disease-associated inflammation, stress, vitamin D hypovitaminosis, Epstein-Barr virus infection and dysbiosis. Thus, the administration of propranolol, a non-selective β-adrenoceptor blocker, readily crossing the blood-brain barrier, to experimental rats before the autoimmune challenge and in the early (preclinical/prodromal) phase of the disease mitigates EAE severity. This phenomenon has been ascribed to the alleviation of neuroinflammation (due to attenuation of primarily microglial activation/proinflammatory functions) and the diminution of the magnitude of the primary CD4+ T-cell autoimmune response (the effect associated with impaired autoantigen uptake by antigen presenting cells and their migration into draining lymph nodes). The former is partly related to breaking of the catecholamine-dependent self-amplifying microglial feed-forward loop and the positive feedback loop between microglia and the SNS, leading to down-regulation of the SNS hyperactivity and its enhancing influence on microglial activation/proinflammatory functions and the magnitude of autoimmune response. The effects of propranolol are shown to be more prominent in male EAE animals, the phenomenon important as males (like men) are likely to develop clinically more severe disease. Thus, these findings could serve as a firm scientific background for formulation of a new sex-specific immune-intervention strategy for the early phases of MS (characterized by the SNS hyperactivity) exploiting anti-(neuro)inflammatory and immunomodulatory properties of propranolol and other relatively cheap and safe adrenergic drugs with similar therapeutic profile.
PB  - Elsevier
T2  - Pharmacology and Therapeutics
T1  - Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis
VL  - 243
DO  - 10.1016/j.pharmthera.2023.108358
ER  - 
@article{
author = "Pilipović, Ivan and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2023",
abstract = "This review summarizes recent findings related to the role of the sympathetic nervous system (SNS) in pathogenesis of multiple sclerosis (MS) and its commonly used experimental model – experimental autoimmune encephalomyelitis (EAE). They indicate that noradrenaline, the key end-point mediator of the SNS, acting through β-adrenoceptor, has a contributory role in the early stages of MS/EAE development. This stage is characterized by the SNS hyperactivity (increased release of noradrenaline) reflecting the net effect of different factors, such as the disease-associated inflammation, stress, vitamin D hypovitaminosis, Epstein-Barr virus infection and dysbiosis. Thus, the administration of propranolol, a non-selective β-adrenoceptor blocker, readily crossing the blood-brain barrier, to experimental rats before the autoimmune challenge and in the early (preclinical/prodromal) phase of the disease mitigates EAE severity. This phenomenon has been ascribed to the alleviation of neuroinflammation (due to attenuation of primarily microglial activation/proinflammatory functions) and the diminution of the magnitude of the primary CD4+ T-cell autoimmune response (the effect associated with impaired autoantigen uptake by antigen presenting cells and their migration into draining lymph nodes). The former is partly related to breaking of the catecholamine-dependent self-amplifying microglial feed-forward loop and the positive feedback loop between microglia and the SNS, leading to down-regulation of the SNS hyperactivity and its enhancing influence on microglial activation/proinflammatory functions and the magnitude of autoimmune response. The effects of propranolol are shown to be more prominent in male EAE animals, the phenomenon important as males (like men) are likely to develop clinically more severe disease. Thus, these findings could serve as a firm scientific background for formulation of a new sex-specific immune-intervention strategy for the early phases of MS (characterized by the SNS hyperactivity) exploiting anti-(neuro)inflammatory and immunomodulatory properties of propranolol and other relatively cheap and safe adrenergic drugs with similar therapeutic profile.",
publisher = "Elsevier",
journal = "Pharmacology and Therapeutics",
title = "Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis",
volume = "243",
doi = "10.1016/j.pharmthera.2023.108358"
}
Pilipović, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2023). Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis. in Pharmacology and Therapeutics
Elsevier., 243.
https://doi.org/10.1016/j.pharmthera.2023.108358
Pilipović I, Stojić-Vukanić Z, Leposavić G. Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis. in Pharmacology and Therapeutics. 2023;243.
doi:10.1016/j.pharmthera.2023.108358 .
Pilipović, Ivan, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis" in Pharmacology and Therapeutics, 243 (2023),
https://doi.org/10.1016/j.pharmthera.2023.108358 . .
2
3
2

Supplementary information for the article: Pilipović, I.; Stojić-Vukanić, Z.; Prijić, I.; Jasnić, N.; Đorđević, J.; Leposavić, G. β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. Cellular and Molecular Neurobiology 2022. https://doi.org/10.1007/s10571-022-01246-z

Pilipović, Ivan; Stojić-Vukanić, Zorica; Prijić, Ivana; Jasnić, Nebojša; Đorđević, Jelena; Leposavić, Gordana

(Springer, 2022)

TY  - DATA
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Jasnić, Nebojša
AU  - Đorđević, Jelena
AU  - Leposavić, Gordana
PY  - 2022
UR  - http://intor.torlakinstitut.com/handle/123456789/649
PB  - Springer
T2  - Cellular and Molecular Neurobiology
T1  - Supplementary information for the article:
Pilipović, I.; Stojić-Vukanić, Z.; Prijić, I.; Jasnić, N.; Đorđević, J.; Leposavić, G. β-Adrenoceptor
Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual
Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. Cellular
and Molecular Neurobiology 2022. https://doi.org/10.1007/s10571-022-01246-z
UR  - https://hdl.handle.net/21.15107/rcub_intor_649
ER  - 
@misc{
author = "Pilipović, Ivan and Stojić-Vukanić, Zorica and Prijić, Ivana and Jasnić, Nebojša and Đorđević, Jelena and Leposavić, Gordana",
year = "2022",
publisher = "Springer",
journal = "Cellular and Molecular Neurobiology",
title = "Supplementary information for the article:
Pilipović, I.; Stojić-Vukanić, Z.; Prijić, I.; Jasnić, N.; Đorđević, J.; Leposavić, G. β-Adrenoceptor
Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual
Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. Cellular
and Molecular Neurobiology 2022. https://doi.org/10.1007/s10571-022-01246-z",
url = "https://hdl.handle.net/21.15107/rcub_intor_649"
}
Pilipović, I., Stojić-Vukanić, Z., Prijić, I., Jasnić, N., Đorđević, J.,& Leposavić, G.. (2022). Supplementary information for the article:
Pilipović, I.; Stojić-Vukanić, Z.; Prijić, I.; Jasnić, N.; Đorđević, J.; Leposavić, G. β-Adrenoceptor
Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual
Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. Cellular
and Molecular Neurobiology 2022. https://doi.org/10.1007/s10571-022-01246-z. in Cellular and Molecular Neurobiology
Springer..
https://hdl.handle.net/21.15107/rcub_intor_649
Pilipović I, Stojić-Vukanić Z, Prijić I, Jasnić N, Đorđević J, Leposavić G. Supplementary information for the article:
Pilipović, I.; Stojić-Vukanić, Z.; Prijić, I.; Jasnić, N.; Đorđević, J.; Leposavić, G. β-Adrenoceptor
Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual
Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. Cellular
and Molecular Neurobiology 2022. https://doi.org/10.1007/s10571-022-01246-z. in Cellular and Molecular Neurobiology. 2022;.
https://hdl.handle.net/21.15107/rcub_intor_649 .
Pilipović, Ivan, Stojić-Vukanić, Zorica, Prijić, Ivana, Jasnić, Nebojša, Đorđević, Jelena, Leposavić, Gordana, "Supplementary information for the article:
Pilipović, I.; Stojić-Vukanić, Z.; Prijić, I.; Jasnić, N.; Đorđević, J.; Leposavić, G. β-Adrenoceptor
Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual
Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. Cellular
and Molecular Neurobiology 2022. https://doi.org/10.1007/s10571-022-01246-z" in Cellular and Molecular Neurobiology (2022),
https://hdl.handle.net/21.15107/rcub_intor_649 .

β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males

Pilipović, Ivan; Stojić-Vukanić, Zorica; Prijić, Ivana; Jasnić, Nebojša; Đorđević, Jelena; Leposavić, Gordana

(Springer, 2022)

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Jasnić, Nebojša
AU  - Đorđević, Jelena
AU  - Leposavić, Gordana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4198
UR  - http://intor.torlakinstitut.com/handle/123456789/622
AB  - Our previous studies showed more severe experimental autoimmune encephalomyelitis (EAE) in male compared with female adult rats, and moderating effect of propranolol-induced β-adrenoceptor blockade on EAE in females, the effect associated with transcriptional stimulation of Nrf2/HO-1 axis in spinal cord microglia. This study examined putative sexual dimor- phism in propranolol action on EAE severity. Propranolol treatment beginning from the onset of clinical EAE mitigated EAE severity in rats of both sexes, but to a greater extent in males exhibiting higher noradrenaline levels and myeloid cell β 2 -adrenoceptor expression in spinal cord. This correlated with more prominent stimulatory effects of propranolol not only on CX3CL1/CX3CR1/Nrf2/HO-1 cascade, but also on Stat3/Socs3 signaling axis in spinal cord microglia/myeloid cells (mirrored in the decreased Stat3 and the increased Socs3 expression) from male rats compared with their female counterparts. Propranolol diminished the frequency of activated cells among microglia, increased their phagocyting/endocyting capacity, and shifted cytokine secretory profile of microglia/blood-borne myeloid cells towards an anti-inflammatory/neuroprotective phenotype. Additionally, it downregulated the expression of chemokines (CCL2, CCL19/21) driving T-cell/monocyte traf- ficking into spinal cord. Consequently, in propranolol-treated rats fewer activated CD4+ T cells and IL-17+ T cells, including CD4+IL17+ cells coexpressing IFN-γ/GM-CSF, were recovered from spinal cord of propranolol-treated rats compared with sex-matched saline-injected controls. All the effects of propranolol were more prominent in males. The study as a whole disclosed that sexual dimorphism in multiple molecular mechanisms implicated in EAE development may be responsible for greater severity of EAE in male rats and sexually dimorphic action of substances affecting them.
PB  - Springer
T2  - Cellular and Molecular Neurobiology
T1  - β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males
DO  - 10.1007/s10571-022-01246-z
ER  - 
@article{
author = "Pilipović, Ivan and Stojić-Vukanić, Zorica and Prijić, Ivana and Jasnić, Nebojša and Đorđević, Jelena and Leposavić, Gordana",
year = "2022",
abstract = "Our previous studies showed more severe experimental autoimmune encephalomyelitis (EAE) in male compared with female adult rats, and moderating effect of propranolol-induced β-adrenoceptor blockade on EAE in females, the effect associated with transcriptional stimulation of Nrf2/HO-1 axis in spinal cord microglia. This study examined putative sexual dimor- phism in propranolol action on EAE severity. Propranolol treatment beginning from the onset of clinical EAE mitigated EAE severity in rats of both sexes, but to a greater extent in males exhibiting higher noradrenaline levels and myeloid cell β 2 -adrenoceptor expression in spinal cord. This correlated with more prominent stimulatory effects of propranolol not only on CX3CL1/CX3CR1/Nrf2/HO-1 cascade, but also on Stat3/Socs3 signaling axis in spinal cord microglia/myeloid cells (mirrored in the decreased Stat3 and the increased Socs3 expression) from male rats compared with their female counterparts. Propranolol diminished the frequency of activated cells among microglia, increased their phagocyting/endocyting capacity, and shifted cytokine secretory profile of microglia/blood-borne myeloid cells towards an anti-inflammatory/neuroprotective phenotype. Additionally, it downregulated the expression of chemokines (CCL2, CCL19/21) driving T-cell/monocyte traf- ficking into spinal cord. Consequently, in propranolol-treated rats fewer activated CD4+ T cells and IL-17+ T cells, including CD4+IL17+ cells coexpressing IFN-γ/GM-CSF, were recovered from spinal cord of propranolol-treated rats compared with sex-matched saline-injected controls. All the effects of propranolol were more prominent in males. The study as a whole disclosed that sexual dimorphism in multiple molecular mechanisms implicated in EAE development may be responsible for greater severity of EAE in male rats and sexually dimorphic action of substances affecting them.",
publisher = "Springer",
journal = "Cellular and Molecular Neurobiology",
title = "β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males",
doi = "10.1007/s10571-022-01246-z"
}
Pilipović, I., Stojić-Vukanić, Z., Prijić, I., Jasnić, N., Đorđević, J.,& Leposavić, G.. (2022). β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. in Cellular and Molecular Neurobiology
Springer..
https://doi.org/10.1007/s10571-022-01246-z
Pilipović I, Stojić-Vukanić Z, Prijić I, Jasnić N, Đorđević J, Leposavić G. β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. in Cellular and Molecular Neurobiology. 2022;.
doi:10.1007/s10571-022-01246-z .
Pilipović, Ivan, Stojić-Vukanić, Zorica, Prijić, Ivana, Jasnić, Nebojša, Đorđević, Jelena, Leposavić, Gordana, "β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males" in Cellular and Molecular Neurobiology (2022),
https://doi.org/10.1007/s10571-022-01246-z . .
3
2

Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases

Stojić-Vukanić, Zorica; Pilipović, Ivan; Arsenović-Ranin, Nevena; Dimitrijević, Mirjana; Leposavić, Gordana

(Elsevier B.V., 2021)

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Arsenović-Ranin, Nevena
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3946
UR  - http://intor.torlakinstitut.com/handle/123456789/624
AB  - The incidence of multiple sclerosis (MS) and susceptibility of animals to experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model of MS, decrease with aging. Generally, autoimmune diseases develop as the ultimate outcome of an imbalance between damaging immune responses against self and regulatory immune responses (keeping the former under control). Thus, in this review the age-related changes possibly underlying this balance were discussed. Specifically, considering the central role of T cells in MS/EAE, the impact of aging on overall functional capacity (reflecting both overall count and individual functional cell properties) of self-reactive conventional T cells (Tcons) and FoxP3+ regulatory T cells (Tregs), as the most potent immunoregulatory/suppressive cells, was analyzed, as well. The analysis encompasses three distinct compartments: thymus (the primary lymphoid organ responsible for the elimination of self-reactive T cells – negative selection and the generation of Tregs, compensating for imperfections of the negative selection), peripheral blood/lymphoid tissues (“afferent” compartment), and brain/spinal cord tissues (“target” compartment). Given that the incidence of MS and susceptibility of animals to EAE are greater in women/females than in age-matched men/males, sex as independent variable was also considered. In conclusion, with aging, sex-specific alterations in the balance of self-reactive Tcons/Tregs are likely to occur not only in the thymus/”afferent” compartment, but also in the “target” compartment, reflecting multifaceted changes in both T-cell types. Their in depth understanding is important not only for envisaging effects of aging, but also for designing interventions to slow-down aging without any adverse effect on incidence of autoimmune diseases.
PB  - Elsevier B.V.
T2  - Immunology Letters
T1  - Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases
EP  - 59
SP  - 42
VL  - 239
DO  - 10.1016/j.imlet.2021.08.003
ER  - 
@article{
author = "Stojić-Vukanić, Zorica and Pilipović, Ivan and Arsenović-Ranin, Nevena and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2021",
abstract = "The incidence of multiple sclerosis (MS) and susceptibility of animals to experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model of MS, decrease with aging. Generally, autoimmune diseases develop as the ultimate outcome of an imbalance between damaging immune responses against self and regulatory immune responses (keeping the former under control). Thus, in this review the age-related changes possibly underlying this balance were discussed. Specifically, considering the central role of T cells in MS/EAE, the impact of aging on overall functional capacity (reflecting both overall count and individual functional cell properties) of self-reactive conventional T cells (Tcons) and FoxP3+ regulatory T cells (Tregs), as the most potent immunoregulatory/suppressive cells, was analyzed, as well. The analysis encompasses three distinct compartments: thymus (the primary lymphoid organ responsible for the elimination of self-reactive T cells – negative selection and the generation of Tregs, compensating for imperfections of the negative selection), peripheral blood/lymphoid tissues (“afferent” compartment), and brain/spinal cord tissues (“target” compartment). Given that the incidence of MS and susceptibility of animals to EAE are greater in women/females than in age-matched men/males, sex as independent variable was also considered. In conclusion, with aging, sex-specific alterations in the balance of self-reactive Tcons/Tregs are likely to occur not only in the thymus/”afferent” compartment, but also in the “target” compartment, reflecting multifaceted changes in both T-cell types. Their in depth understanding is important not only for envisaging effects of aging, but also for designing interventions to slow-down aging without any adverse effect on incidence of autoimmune diseases.",
publisher = "Elsevier B.V.",
journal = "Immunology Letters",
title = "Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases",
pages = "59-42",
volume = "239",
doi = "10.1016/j.imlet.2021.08.003"
}
Stojić-Vukanić, Z., Pilipović, I., Arsenović-Ranin, N., Dimitrijević, M.,& Leposavić, G.. (2021). Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases. in Immunology Letters
Elsevier B.V.., 239, 42-59.
https://doi.org/10.1016/j.imlet.2021.08.003
Stojić-Vukanić Z, Pilipović I, Arsenović-Ranin N, Dimitrijević M, Leposavić G. Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases. in Immunology Letters. 2021;239:42-59.
doi:10.1016/j.imlet.2021.08.003 .
Stojić-Vukanić, Zorica, Pilipović, Ivan, Arsenović-Ranin, Nevena, Dimitrijević, Mirjana, Leposavić, Gordana, "Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases" in Immunology Letters, 239 (2021):42-59,
https://doi.org/10.1016/j.imlet.2021.08.003 . .
1

Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.; Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6), 2312–2331. https://doi.org/10.1007/s10753-020-01302-0.

Dimitrijević, Mirjana; Arsenović-Ranin, Nevena; Bufan, Biljana; Nacka-Aleksić, Mirjana; Kosec, Duško; Pilipović, Ivan; Kotur-Stevuljević, Jelena; Simić, Ljubica; Sopta, Jelena; Leposavić, Gordana

(Springer, 2020)

TY  - DATA
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Kotur-Stevuljević, Jelena
AU  - Simić, Ljubica
AU  - Sopta, Jelena
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/647
AB  - Supplementary Fig. 1 Sex differences in the clinical and histological presentation of CIA. (a) A line graph indicates daily arthritic score  (mean ± SEM) from the 12th to the 39th day post-immunization (d.p.i.) in male (n = 9) and female (n = 10) CIA rats.  Mann–Whitney U test: * p ≤ 0.05, from the 17th to the 39th d.p.i. (b) Line graph indicates daily arthritic score  (mean ± SEM) from the 13th to the 21st day post-immunization (d.p.i.) in male and female CIA rats. Mann–Whitney U test: n = 8 rats/sex. * p ≤ 0.05.  Photographs show representative arthritic joints (arrows) of hind paws from male and female CIA rats.  (c) Photomicrographs of HE-stained sections of paraffin-embedded joints from male and female CIA rats show replacement  of the normal bone marrow cell populations by inflammatory cells. In females, numerous multinuclear giant cells (red arrows)  are present as opposed to male CIA rats. Original magnification × 400. The bar indicates 100 μm (PNG 2723 kb) Supplementary Fig. 2 Fluorescence minus one controls for flow cytometry analysis of CD11b/CCR2/CX3CR1 staining of splenocytes.  For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single  antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without anti-CX3CR1 or anti-CCR2  Abs within CD11b+ splenocytes (gated as shown in Fig. 3) isolated from CIA rats on the 21st day post-immunization (PNG 98 kb). Supplementary Fig. 3 Fluorescence minus one controls for flow cytometry analysis of CD11b/CD43/CCR2/CX3CR1 staining of peripheral blood cells.  For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single  antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without (upper) CD43 mAb within  CD11b+ peripheral blood cells (gated as shown in Fig. 4a) and (lower) anti-CX3CR1 or anti-CCR2 Abs within CD11b+CD43+  peripheral blood cells isolated from CIA rats on the 21st day post-immunization (PNG 157 kb). Supplementary Fig. 4 Sex differences in the activation of Th cells, Th17 cell function, and frequency of CD40+CD11b+ antigen presenting cells in  draining lymph nodes from CIA rats, popliteal draining lymph nodes (DLNs) were retrieved from male and female CIA rats on the  21st day post-immunization. (a) Scatter plots with bar indicate the frequencies of activated Th cells (CD25+Foxp3-CD4+) and  Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats and the concentration of IL-17 in supernatants of collagen type  II-stimulated and unstimulated (medium) DLN cell cultures from male and female rats (see MATERIAL AND METHODS).  Linear graph shows the correlation between the frequency of activated Th cells (CD25+Foxp3-CD4+) and the frequency of  Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats. Pearson’s r value is shown in the graph. (b) Representative flow  cytometry dot plots show (upper) CD11b staining and (lower) CD40 vs CD11b staining of DLN cells from male and female rats.  Number indicates percent in the region. Scatter plots with bar indicate the frequency and the number of (upper) CD11b+ cells  and (lower) CD40+CD11b+ cells in DLNs of male and female rats. The Number indicates percent in the region. Results are  expressed as mean ± SEM. (c) The linear graph shows the correlation between the frequency of activated Th cells  (CD25+Foxp3-CD4+) and the frequency of CD40+CD11b+ cells in DLNs from CIA rats. Pearson’s r value is shown in the graph.  n = 8 rats/sex. * p ≤ 0.05, ** p ≤ 0.01, and *** p ≤ 0.001 (PNG 590 kb). Supplementary Fig. 5 Gating strategy for activated Th cells and Th17 cells, popliteal draining lymph nodes (DLNs) were retrieved from CIA rats on  the 21st day post-immunization. Flow cytometry dot plots show gating strategy for (a) activated The cells (CD25+Foxp3-CD4+)  and (b) Th17 cells (IL-17+CD4+TCRαβ+) (PNG 101 kb).
PB  - Springer
T2  - Inflammation
T1  - Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0.
EP  - 2331
IS  - 6
SP  - 2312
VL  - 43
UR  - https://hdl.handle.net/21.15107/rcub_intor_647
ER  - 
@misc{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Bufan, Biljana and Nacka-Aleksić, Mirjana and Kosec, Duško and Pilipović, Ivan and Kotur-Stevuljević, Jelena and Simić, Ljubica and Sopta, Jelena and Leposavić, Gordana",
year = "2020",
abstract = "Supplementary Fig. 1 Sex differences in the clinical and histological presentation of CIA. (a) A line graph indicates daily arthritic score  (mean ± SEM) from the 12th to the 39th day post-immunization (d.p.i.) in male (n = 9) and female (n = 10) CIA rats.  Mann–Whitney U test: * p ≤ 0.05, from the 17th to the 39th d.p.i. (b) Line graph indicates daily arthritic score  (mean ± SEM) from the 13th to the 21st day post-immunization (d.p.i.) in male and female CIA rats. Mann–Whitney U test: n = 8 rats/sex. * p ≤ 0.05.  Photographs show representative arthritic joints (arrows) of hind paws from male and female CIA rats.  (c) Photomicrographs of HE-stained sections of paraffin-embedded joints from male and female CIA rats show replacement  of the normal bone marrow cell populations by inflammatory cells. In females, numerous multinuclear giant cells (red arrows)  are present as opposed to male CIA rats. Original magnification × 400. The bar indicates 100 μm (PNG 2723 kb) Supplementary Fig. 2 Fluorescence minus one controls for flow cytometry analysis of CD11b/CCR2/CX3CR1 staining of splenocytes.  For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single  antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without anti-CX3CR1 or anti-CCR2  Abs within CD11b+ splenocytes (gated as shown in Fig. 3) isolated from CIA rats on the 21st day post-immunization (PNG 98 kb). Supplementary Fig. 3 Fluorescence minus one controls for flow cytometry analysis of CD11b/CD43/CCR2/CX3CR1 staining of peripheral blood cells.  For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single  antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without (upper) CD43 mAb within  CD11b+ peripheral blood cells (gated as shown in Fig. 4a) and (lower) anti-CX3CR1 or anti-CCR2 Abs within CD11b+CD43+  peripheral blood cells isolated from CIA rats on the 21st day post-immunization (PNG 157 kb). Supplementary Fig. 4 Sex differences in the activation of Th cells, Th17 cell function, and frequency of CD40+CD11b+ antigen presenting cells in  draining lymph nodes from CIA rats, popliteal draining lymph nodes (DLNs) were retrieved from male and female CIA rats on the  21st day post-immunization. (a) Scatter plots with bar indicate the frequencies of activated Th cells (CD25+Foxp3-CD4+) and  Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats and the concentration of IL-17 in supernatants of collagen type  II-stimulated and unstimulated (medium) DLN cell cultures from male and female rats (see MATERIAL AND METHODS).  Linear graph shows the correlation between the frequency of activated Th cells (CD25+Foxp3-CD4+) and the frequency of  Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats. Pearson’s r value is shown in the graph. (b) Representative flow  cytometry dot plots show (upper) CD11b staining and (lower) CD40 vs CD11b staining of DLN cells from male and female rats.  Number indicates percent in the region. Scatter plots with bar indicate the frequency and the number of (upper) CD11b+ cells  and (lower) CD40+CD11b+ cells in DLNs of male and female rats. The Number indicates percent in the region. Results are  expressed as mean ± SEM. (c) The linear graph shows the correlation between the frequency of activated Th cells  (CD25+Foxp3-CD4+) and the frequency of CD40+CD11b+ cells in DLNs from CIA rats. Pearson’s r value is shown in the graph.  n = 8 rats/sex. * p ≤ 0.05, ** p ≤ 0.01, and *** p ≤ 0.001 (PNG 590 kb). Supplementary Fig. 5 Gating strategy for activated Th cells and Th17 cells, popliteal draining lymph nodes (DLNs) were retrieved from CIA rats on  the 21st day post-immunization. Flow cytometry dot plots show gating strategy for (a) activated The cells (CD25+Foxp3-CD4+)  and (b) Th17 cells (IL-17+CD4+TCRαβ+) (PNG 101 kb).",
publisher = "Springer",
journal = "Inflammation",
title = "Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0.",
pages = "2331-2312",
number = "6",
volume = "43",
url = "https://hdl.handle.net/21.15107/rcub_intor_647"
}
Dimitrijević, M., Arsenović-Ranin, N., Bufan, B., Nacka-Aleksić, M., Kosec, D., Pilipović, I., Kotur-Stevuljević, J., Simić, L., Sopta, J.,& Leposavić, G.. (2020). Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0.. in Inflammation
Springer., 43(6), 2312-2331.
https://hdl.handle.net/21.15107/rcub_intor_647
Dimitrijević M, Arsenović-Ranin N, Bufan B, Nacka-Aleksić M, Kosec D, Pilipović I, Kotur-Stevuljević J, Simić L, Sopta J, Leposavić G. Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0.. in Inflammation. 2020;43(6):2312-2331.
https://hdl.handle.net/21.15107/rcub_intor_647 .
Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Bufan, Biljana, Nacka-Aleksić, Mirjana, Kosec, Duško, Pilipović, Ivan, Kotur-Stevuljević, Jelena, Simić, Ljubica, Sopta, Jelena, Leposavić, Gordana, "Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0." in Inflammation, 43, no. 6 (2020):2312-2331,
https://hdl.handle.net/21.15107/rcub_intor_647 .

Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

Dimitrijević, Mirjana; Arsenović-Ranin, Nevena; Kosec, Duško; Bufan, Biljana; Nacka-Aleksić, Mirjana; Pilipović, Ivan; Leposavić, Gordana

(Nature Publishing Group, London, 2020)

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/554
AB  - The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki-67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higher Tfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-gamma /IL-4 production ratio was shifted towards IFN-gamma. Consistently, the serum IgG2a(b)/IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.
PB  - Nature Publishing Group, London
T2  - Scientific Reports
T1  - Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis
IS  - 1
VL  - 10
DO  - 10.1038/s41598-020-58127-y
ER  - 
@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Kosec, Duško and Bufan, Biljana and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Leposavić, Gordana",
year = "2020",
abstract = "The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki-67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higher Tfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-gamma /IL-4 production ratio was shifted towards IFN-gamma. Consistently, the serum IgG2a(b)/IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.",
publisher = "Nature Publishing Group, London",
journal = "Scientific Reports",
title = "Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis",
number = "1",
volume = "10",
doi = "10.1038/s41598-020-58127-y"
}
Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2020). Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis. in Scientific Reports
Nature Publishing Group, London., 10(1).
https://doi.org/10.1038/s41598-020-58127-y
Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis. in Scientific Reports. 2020;10(1).
doi:10.1038/s41598-020-58127-y .
Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis" in Scientific Reports, 10, no. 1 (2020),
https://doi.org/10.1038/s41598-020-58127-y . .
10
25
12
24

Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats

Dimitrijević, Mirjana; Arsenović-Ranin, Nevena; Bufan, Biljana; Nacka-Aleksić, Mirjana; Kosec, Duško; Pilipović, Ivan; Kotur-Stevuljević, Jelena; Simić, Ljubica; Sopta, Jelena; Leposavić, Gordana

(Springer/Plenum Publishers, New York, 2020)

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Kotur-Stevuljević, Jelena
AU  - Simić, Ljubica
AU  - Sopta, Jelena
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/543
AB  - Monocytes' plasticity has an important role in the development of rheumatoid arthritis (RA), an autoimmune disease exhibiting greater prevalence in women. Contribution of this phenomenon to sex bias in RA severity was investigated in rat collagen-induced arthritis (CIA) model of RA. The greater severity of CIA in females (exhibiting signs of bone resorption) was accompanied by the higher blood level of advanced oxidation protein products and a more pro-oxidant profile. Consistently, in females, the greater density of giant multinuclear cells (monocytes/macrophages and osteoclasts) in inflamed joint tissue was found. This correlated with the higher frequencies of CCR2- and CX3CR1- expressing cells (precursors of inflammatory monocytes/macrophages and osteoclasts) among CD11b+ splenocytes. This in conjunction with the enhanced migratory capacity of CD11b+ monocytic cells in females compared with males could be linked with the higher frequencies of CCR2+CX3CR1-CD43(low)CD11b+ and CCR2-CX3CR1+CD43(hi)CD11b+ cells (corresponding to "classical" and "non-classical" monocytes, respectively) and the greater density of CD68+ cells (monocytes/macrophages and osteoclast precursors/osteoclasts) in blood and inflamed paws from female rats, respectively. Consistently, the higher levels of GM-CSF, TNF-alpha and IL-6, IL-1 beta (driving Th17 cell differentiation), and IL-17 followed by the lower level of IL-10 were measured in inflamed paw cultures from female compared with male rats. To the greater IL-17 production (associated with enhanced monocyte immigration and differentiation into osteoclasts) most likely contributed augmented Th17 cell generation in the lymph nodes draining arthritic joints from female compared with male rats. Overall, the study suggests the sex-specific contribution of monocytic lineage cells to CIA, and possibly RA development.
PB  - Springer/Plenum Publishers, New York
T2  - Inflammation
T1  - Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats
EP  - 2331
IS  - 6
SP  - 2312
VL  - 43
DO  - 10.1007/s10753-020-01302-0
ER  - 
@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Bufan, Biljana and Nacka-Aleksić, Mirjana and Kosec, Duško and Pilipović, Ivan and Kotur-Stevuljević, Jelena and Simić, Ljubica and Sopta, Jelena and Leposavić, Gordana",
year = "2020",
abstract = "Monocytes' plasticity has an important role in the development of rheumatoid arthritis (RA), an autoimmune disease exhibiting greater prevalence in women. Contribution of this phenomenon to sex bias in RA severity was investigated in rat collagen-induced arthritis (CIA) model of RA. The greater severity of CIA in females (exhibiting signs of bone resorption) was accompanied by the higher blood level of advanced oxidation protein products and a more pro-oxidant profile. Consistently, in females, the greater density of giant multinuclear cells (monocytes/macrophages and osteoclasts) in inflamed joint tissue was found. This correlated with the higher frequencies of CCR2- and CX3CR1- expressing cells (precursors of inflammatory monocytes/macrophages and osteoclasts) among CD11b+ splenocytes. This in conjunction with the enhanced migratory capacity of CD11b+ monocytic cells in females compared with males could be linked with the higher frequencies of CCR2+CX3CR1-CD43(low)CD11b+ and CCR2-CX3CR1+CD43(hi)CD11b+ cells (corresponding to "classical" and "non-classical" monocytes, respectively) and the greater density of CD68+ cells (monocytes/macrophages and osteoclast precursors/osteoclasts) in blood and inflamed paws from female rats, respectively. Consistently, the higher levels of GM-CSF, TNF-alpha and IL-6, IL-1 beta (driving Th17 cell differentiation), and IL-17 followed by the lower level of IL-10 were measured in inflamed paw cultures from female compared with male rats. To the greater IL-17 production (associated with enhanced monocyte immigration and differentiation into osteoclasts) most likely contributed augmented Th17 cell generation in the lymph nodes draining arthritic joints from female compared with male rats. Overall, the study suggests the sex-specific contribution of monocytic lineage cells to CIA, and possibly RA development.",
publisher = "Springer/Plenum Publishers, New York",
journal = "Inflammation",
title = "Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats",
pages = "2331-2312",
number = "6",
volume = "43",
doi = "10.1007/s10753-020-01302-0"
}
Dimitrijević, M., Arsenović-Ranin, N., Bufan, B., Nacka-Aleksić, M., Kosec, D., Pilipović, I., Kotur-Stevuljević, J., Simić, L., Sopta, J.,& Leposavić, G.. (2020). Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. in Inflammation
Springer/Plenum Publishers, New York., 43(6), 2312-2331.
https://doi.org/10.1007/s10753-020-01302-0
Dimitrijević M, Arsenović-Ranin N, Bufan B, Nacka-Aleksić M, Kosec D, Pilipović I, Kotur-Stevuljević J, Simić L, Sopta J, Leposavić G. Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. in Inflammation. 2020;43(6):2312-2331.
doi:10.1007/s10753-020-01302-0 .
Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Bufan, Biljana, Nacka-Aleksić, Mirjana, Kosec, Duško, Pilipović, Ivan, Kotur-Stevuljević, Jelena, Simić, Ljubica, Sopta, Jelena, Leposavić, Gordana, "Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats" in Inflammation, 43, no. 6 (2020):2312-2331,
https://doi.org/10.1007/s10753-020-01302-0 . .
3
1
3

Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Pilipović, Ivan; Stojić-Vukanić, Zorica; Prijić, Ivana; Leposavić, Gordana

(Frontiers Media Sa, Lausanne, 2020)

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/571
AB  - The role of stress effector systems in the initiation and progression of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model of MS, has strongly been suggested. To corroborate this notion, alterations in activity of the sympathoadrenal and sympathoneural axes of sympathoadrenal system (a major communication pathway between the central nervous system and the immune system), mirrored in altered release of their end-point mediators (adrenaline and noradrenaline, respectively), are shown to precede (in MS) and/or occur during development of MS and EAE in response to immune cell activation (in early phase of disease) and disease-related damage of sympathoadrenal system neurons and their projections (in late phase of disease). To add to the complexity, innate immunity cells and T-lymphocytes synthesize noradrenaline that may be implicated in a local autocrine/paracrine self-amplifying feed-forward loop to enhance myeloid-cell synthesis of proinflammatory cytokines and inflammatory injury. Furthermore, experimental manipulations targeting noradrenaline/adrenaline action are shown to influence clinical outcome of EAE, in a disease phase-specific manner. This is partly related to the fact that virtually all types of cells involved in the instigation and progression of autoimmune inflammation and target tissue damage in EAE/MS express functional adrenoceptors. Although catecholamines exert majority of immunomodulatory effects through beta(2)-adrenoceptor, a role for alpha-adrenoceptors in EAE pathogenesis has also been indicated. In this review, we summarize all aforementioned aspects of immunopathogenetic action of catecholamines in EAE/MS as possibly important for designing new strategies targeting their action to prevent/mitigate autoimmune neuroinflammation and tissue damage.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Endocrinology
T1  - Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis
VL  - 10
DO  - 10.3389/fendo.2019.00921
ER  - 
@article{
author = "Pilipović, Ivan and Stojić-Vukanić, Zorica and Prijić, Ivana and Leposavić, Gordana",
year = "2020",
abstract = "The role of stress effector systems in the initiation and progression of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model of MS, has strongly been suggested. To corroborate this notion, alterations in activity of the sympathoadrenal and sympathoneural axes of sympathoadrenal system (a major communication pathway between the central nervous system and the immune system), mirrored in altered release of their end-point mediators (adrenaline and noradrenaline, respectively), are shown to precede (in MS) and/or occur during development of MS and EAE in response to immune cell activation (in early phase of disease) and disease-related damage of sympathoadrenal system neurons and their projections (in late phase of disease). To add to the complexity, innate immunity cells and T-lymphocytes synthesize noradrenaline that may be implicated in a local autocrine/paracrine self-amplifying feed-forward loop to enhance myeloid-cell synthesis of proinflammatory cytokines and inflammatory injury. Furthermore, experimental manipulations targeting noradrenaline/adrenaline action are shown to influence clinical outcome of EAE, in a disease phase-specific manner. This is partly related to the fact that virtually all types of cells involved in the instigation and progression of autoimmune inflammation and target tissue damage in EAE/MS express functional adrenoceptors. Although catecholamines exert majority of immunomodulatory effects through beta(2)-adrenoceptor, a role for alpha-adrenoceptors in EAE pathogenesis has also been indicated. In this review, we summarize all aforementioned aspects of immunopathogenetic action of catecholamines in EAE/MS as possibly important for designing new strategies targeting their action to prevent/mitigate autoimmune neuroinflammation and tissue damage.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Endocrinology",
title = "Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis",
volume = "10",
doi = "10.3389/fendo.2019.00921"
}
Pilipović, I., Stojić-Vukanić, Z., Prijić, I.,& Leposavić, G.. (2020). Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. in Frontiers in Endocrinology
Frontiers Media Sa, Lausanne., 10.
https://doi.org/10.3389/fendo.2019.00921
Pilipović I, Stojić-Vukanić Z, Prijić I, Leposavić G. Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. in Frontiers in Endocrinology. 2020;10.
doi:10.3389/fendo.2019.00921 .
Pilipović, Ivan, Stojić-Vukanić, Zorica, Prijić, Ivana, Leposavić, Gordana, "Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis" in Frontiers in Endocrinology, 10 (2020),
https://doi.org/10.3389/fendo.2019.00921 . .
2
4
1
4

Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia

Pilipović, Ivan; Stojić-Vukanić, Zorica; Prijić, Ivana; Jasnić, Nebojša; Leposavić, Gordana

(Academic Press Inc Elsevier Science, San Diego, 2020)

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Jasnić, Nebojša
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/561
AB  - Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point mediator, in modulation of microglial phenotypic and functional properties in rat EAE model was examined. The study showed that noradrenaline acting in neurocrine and autocrine/paracrine way might influence microglia during EAE. Propranolol treatment over the effector phase moderated EAE course. This was associated with the increased proportion of microglia expressing CX3CR1, the key molecule in their immunomodulatory/neuroprotective action, and up regulation of CX3CR1 downstream Nrf2 gene. This correlated with the increased heme oxygenase-1 (HO-1) expression and phagocytic capacity of microglia, and their phenotypic changes mirrored in increased proportion of CD163- and CD83-expressing cells. The enhanced HO-1 expression was linked with the decreased proportion of microglial cells expressing IL-1 beta and IL-23, and possibly IL-6, followed by increased proportion of IL-10 expressing microglia, and downregulated MCP-1/CCL2 expression. Consistently, spinal cord infiltration with blood-borne myeloid and CD4 + T cells, as well as CD4 + T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17 + cells co-producing IFN-gamma and GM-CSF were decreased in propranolol-treated rats compared with saline-injected controls. The in vitro investigations of the effects of noradrenaline on microglia showed that noradrenaline through beta-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests beta-adrenoceptor-mediated neuroinflammation-promoting role of noradrenaline in EAE via modulation of microglial Nrf2 expression, and thereby forms the basis for further translational pharmacological research to improve multiple sclerosis therapy.
PB  - Academic Press Inc Elsevier Science, San Diego
T2  - Neurobiology of Disease
T1  - Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia
VL  - 134
DO  - 10.1016/j.nbd.2019.104665
ER  - 
@article{
author = "Pilipović, Ivan and Stojić-Vukanić, Zorica and Prijić, Ivana and Jasnić, Nebojša and Leposavić, Gordana",
year = "2020",
abstract = "Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point mediator, in modulation of microglial phenotypic and functional properties in rat EAE model was examined. The study showed that noradrenaline acting in neurocrine and autocrine/paracrine way might influence microglia during EAE. Propranolol treatment over the effector phase moderated EAE course. This was associated with the increased proportion of microglia expressing CX3CR1, the key molecule in their immunomodulatory/neuroprotective action, and up regulation of CX3CR1 downstream Nrf2 gene. This correlated with the increased heme oxygenase-1 (HO-1) expression and phagocytic capacity of microglia, and their phenotypic changes mirrored in increased proportion of CD163- and CD83-expressing cells. The enhanced HO-1 expression was linked with the decreased proportion of microglial cells expressing IL-1 beta and IL-23, and possibly IL-6, followed by increased proportion of IL-10 expressing microglia, and downregulated MCP-1/CCL2 expression. Consistently, spinal cord infiltration with blood-borne myeloid and CD4 + T cells, as well as CD4 + T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17 + cells co-producing IFN-gamma and GM-CSF were decreased in propranolol-treated rats compared with saline-injected controls. The in vitro investigations of the effects of noradrenaline on microglia showed that noradrenaline through beta-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests beta-adrenoceptor-mediated neuroinflammation-promoting role of noradrenaline in EAE via modulation of microglial Nrf2 expression, and thereby forms the basis for further translational pharmacological research to improve multiple sclerosis therapy.",
publisher = "Academic Press Inc Elsevier Science, San Diego",
journal = "Neurobiology of Disease",
title = "Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia",
volume = "134",
doi = "10.1016/j.nbd.2019.104665"
}
Pilipović, I., Stojić-Vukanić, Z., Prijić, I., Jasnić, N.,& Leposavić, G.. (2020). Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia. in Neurobiology of Disease
Academic Press Inc Elsevier Science, San Diego., 134.
https://doi.org/10.1016/j.nbd.2019.104665
Pilipović I, Stojić-Vukanić Z, Prijić I, Jasnić N, Leposavić G. Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia. in Neurobiology of Disease. 2020;134.
doi:10.1016/j.nbd.2019.104665 .
Pilipović, Ivan, Stojić-Vukanić, Zorica, Prijić, Ivana, Jasnić, Nebojša, Leposavić, Gordana, "Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia" in Neurobiology of Disease, 134 (2020),
https://doi.org/10.1016/j.nbd.2019.104665 . .
15
7
16

Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment

Nacka-Aleksić, Mirjana; Stojić-Vukanić, Zorica; Pilipović, Ivan; Blagojević, Veljko; Kotur-Stevuljević, Jelena; Leposavić, Gordana

(Pergamon-Elsevier Science Ltd, Oxford, 2020)

TY  - JOUR
AU  - Nacka-Aleksić, Mirjana
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Blagojević, Veljko
AU  - Kotur-Stevuljević, Jelena
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/555
AB  - The study examined the influence of sex on the alterations occurring with ageing in rat lymph node (LN) T cell compartment. In female and male rats the decrease in LN T cell counts was followed by a shift in CD4+/CD8+ T cell ratio towards CD8+ T cells, which was more prominent in males than in females. With ageing, in both major LN T cell subpopulations naive (recent thymic emigrants and mature naive cells) to memory/activated T cell ratio shifted to the side of memory/activated cells in female, and particularly in male rats. The frequency of regulatory CD25+Foxp3+ cells increased among LN CD4+/CD8+ T cells with ageing, reflecting, at least partly, an enhanced conversion of effector T cells into regulatory cells. This was also more prominent in male rats. The more prounounced increase in LN oxidative damage and the expression levels of proinflammatory cytokines in male rats with ageing, most likely contributed to the greater frequency of proinflammatory, replicatively senescent CD28- cells expressing CD11b (innate cell marker), among T cells of old male rats compared with age matched females. The increase in LN oxidation/proinflammatory state with ageing was also consistent with the accumulation of exhausted PD-1(high) cells among T lymphocytes, particularly prominent among CD8+ T cells from male rats. Finally, by calculating a summary score for the key ageing-relevant parameters (an ageing index), a faster development of the deleterious changes in the T cell compartment occurring with ageing was confirmed in male rat LNs. Additionally, the study pointed to indices of LN T cell compartment ageing which correlate with those in peripheral blood.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Experimental Gerontology
T1  - Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment
VL  - 142
DO  - 10.1016/j.exger.2020.111140
ER  - 
@article{
author = "Nacka-Aleksić, Mirjana and Stojić-Vukanić, Zorica and Pilipović, Ivan and Blagojević, Veljko and Kotur-Stevuljević, Jelena and Leposavić, Gordana",
year = "2020",
abstract = "The study examined the influence of sex on the alterations occurring with ageing in rat lymph node (LN) T cell compartment. In female and male rats the decrease in LN T cell counts was followed by a shift in CD4+/CD8+ T cell ratio towards CD8+ T cells, which was more prominent in males than in females. With ageing, in both major LN T cell subpopulations naive (recent thymic emigrants and mature naive cells) to memory/activated T cell ratio shifted to the side of memory/activated cells in female, and particularly in male rats. The frequency of regulatory CD25+Foxp3+ cells increased among LN CD4+/CD8+ T cells with ageing, reflecting, at least partly, an enhanced conversion of effector T cells into regulatory cells. This was also more prominent in male rats. The more prounounced increase in LN oxidative damage and the expression levels of proinflammatory cytokines in male rats with ageing, most likely contributed to the greater frequency of proinflammatory, replicatively senescent CD28- cells expressing CD11b (innate cell marker), among T cells of old male rats compared with age matched females. The increase in LN oxidation/proinflammatory state with ageing was also consistent with the accumulation of exhausted PD-1(high) cells among T lymphocytes, particularly prominent among CD8+ T cells from male rats. Finally, by calculating a summary score for the key ageing-relevant parameters (an ageing index), a faster development of the deleterious changes in the T cell compartment occurring with ageing was confirmed in male rat LNs. Additionally, the study pointed to indices of LN T cell compartment ageing which correlate with those in peripheral blood.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Experimental Gerontology",
title = "Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment",
volume = "142",
doi = "10.1016/j.exger.2020.111140"
}
Nacka-Aleksić, M., Stojić-Vukanić, Z., Pilipović, I., Blagojević, V., Kotur-Stevuljević, J.,& Leposavić, G.. (2020). Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment. in Experimental Gerontology
Pergamon-Elsevier Science Ltd, Oxford., 142.
https://doi.org/10.1016/j.exger.2020.111140
Nacka-Aleksić M, Stojić-Vukanić Z, Pilipović I, Blagojević V, Kotur-Stevuljević J, Leposavić G. Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment. in Experimental Gerontology. 2020;142.
doi:10.1016/j.exger.2020.111140 .
Nacka-Aleksić, Mirjana, Stojić-Vukanić, Zorica, Pilipović, Ivan, Blagojević, Veljko, Kotur-Stevuljević, Jelena, Leposavić, Gordana, "Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment" in Experimental Gerontology, 142 (2020),
https://doi.org/10.1016/j.exger.2020.111140 . .
2
2
2

Age and sex determine CD4+T cell stimulatory and polarizing capacity of rat splenic dendritic cells

Stojić-Vukanić, Zorica; Pilipović, Ivan; Bufan, Biljana; Stojanović, Marija; Leposavić, Gordana

(Springer, New York, 2020)

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Bufan, Biljana
AU  - Stojanović, Marija
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/560
AB  - The study investigated influence of sex and age on splenic myeloid dendritic cells (DCs) from Dark Agouti rats. Freshly isolated DCs from young males exhibited less mature phenotype and greater endocytic capacity compared with those from age-matched females. Upon LPS stimulation in vitro they were less potent in stimulating allogeneic CD4+ cells in mixed leukocyte reaction (MLR), due to lower expression of MHC II, and greater NO and IL-10 production. In accordance with higher TGF-beta production, young male rat DCs were less potent in stimulating IL-17 production in MLR than those from young females. Irrespective of sex, endocytic capacity and responsiveness of DCs to LPS stimulation in culture, judging by their allostimulatory capacity in MLR decreased with age, reflecting decline in MHC II surface density followed by their greater NO production; the effects more prominent in females. Additionally, compared with LPS-stimulated DCs from young rats, those from sex-matched aged rats were more potent in stimulating IL-10 production in MLR, whereas capacity of DCs from aged female and male rats to stimulate IL-17 production remained unaltered and decreased, respectively. This reflected age-related shift in IL-6/TGF-beta production level ratio in LPS-stimulated DC cultures towards TGF-beta, and sex-specific age-related remodeling CD4+ cell cytokine pathways. Additionally, compared with LPS-stimulated DCs from young rats, those cells from sex-matched aged rats were less potent in stimulating IFN-gamma production in MLR, the effect particularly prominent in MLRs encompassing male rat DCs. The study showed that stimulatory and polarizing capacity of DCs depends on rat sex and age.
PB  - Springer, New York
T2  - Biogerontology
T1  - Age and sex determine CD4+T cell stimulatory and polarizing capacity of rat splenic dendritic cells
EP  - 107
IS  - 1
SP  - 83
VL  - 21
DO  - 10.1007/s10522-019-09845-y
ER  - 
@article{
author = "Stojić-Vukanić, Zorica and Pilipović, Ivan and Bufan, Biljana and Stojanović, Marija and Leposavić, Gordana",
year = "2020",
abstract = "The study investigated influence of sex and age on splenic myeloid dendritic cells (DCs) from Dark Agouti rats. Freshly isolated DCs from young males exhibited less mature phenotype and greater endocytic capacity compared with those from age-matched females. Upon LPS stimulation in vitro they were less potent in stimulating allogeneic CD4+ cells in mixed leukocyte reaction (MLR), due to lower expression of MHC II, and greater NO and IL-10 production. In accordance with higher TGF-beta production, young male rat DCs were less potent in stimulating IL-17 production in MLR than those from young females. Irrespective of sex, endocytic capacity and responsiveness of DCs to LPS stimulation in culture, judging by their allostimulatory capacity in MLR decreased with age, reflecting decline in MHC II surface density followed by their greater NO production; the effects more prominent in females. Additionally, compared with LPS-stimulated DCs from young rats, those from sex-matched aged rats were more potent in stimulating IL-10 production in MLR, whereas capacity of DCs from aged female and male rats to stimulate IL-17 production remained unaltered and decreased, respectively. This reflected age-related shift in IL-6/TGF-beta production level ratio in LPS-stimulated DC cultures towards TGF-beta, and sex-specific age-related remodeling CD4+ cell cytokine pathways. Additionally, compared with LPS-stimulated DCs from young rats, those cells from sex-matched aged rats were less potent in stimulating IFN-gamma production in MLR, the effect particularly prominent in MLRs encompassing male rat DCs. The study showed that stimulatory and polarizing capacity of DCs depends on rat sex and age.",
publisher = "Springer, New York",
journal = "Biogerontology",
title = "Age and sex determine CD4+T cell stimulatory and polarizing capacity of rat splenic dendritic cells",
pages = "107-83",
number = "1",
volume = "21",
doi = "10.1007/s10522-019-09845-y"
}
Stojić-Vukanić, Z., Pilipović, I., Bufan, B., Stojanović, M.,& Leposavić, G.. (2020). Age and sex determine CD4+T cell stimulatory and polarizing capacity of rat splenic dendritic cells. in Biogerontology
Springer, New York., 21(1), 83-107.
https://doi.org/10.1007/s10522-019-09845-y
Stojić-Vukanić Z, Pilipović I, Bufan B, Stojanović M, Leposavić G. Age and sex determine CD4+T cell stimulatory and polarizing capacity of rat splenic dendritic cells. in Biogerontology. 2020;21(1):83-107.
doi:10.1007/s10522-019-09845-y .
Stojić-Vukanić, Zorica, Pilipović, Ivan, Bufan, Biljana, Stojanović, Marija, Leposavić, Gordana, "Age and sex determine CD4+T cell stimulatory and polarizing capacity of rat splenic dendritic cells" in Biogerontology, 21, no. 1 (2020):83-107,
https://doi.org/10.1007/s10522-019-09845-y . .
1
1
1

Propranolol reduced severity of eae by increasing the Expression of Nrf2 in microglia

Pilipović, Ivan; Prijić, Ivana; Stojić-Vukanić, Zorica; Leposavić, Gordana

(Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, 2019)

TY  - CONF
AU  - Pilipović, Ivan
AU  - Prijić, Ivana
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/854
AB  - Sympathetic dysfunction was proposed to participate in development of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). This may be linked with findings indicating that noradrenaline, the key sympathetic end-point mediator, through β- adrenoceptor exerts immunomodulatory action. Considering importance of the target tissue for the clinical outcome of EAE, the study investigated the effects of propranolol, a non-selective β- adrenoceptor blocker, on the disease severity in Dark Agouti rats. Administration of propranolol over the effector phase of EAE substantially moderated neurological symptoms of the disease. This correlated with the increased proportion of spinal cord microglia expressing CX3CR1, the crucial neuroinflammation-limiting molecule, and upregulated expression of Nrf2, the key CX3CR1 downstream target gene. Additionally, in spinal cord of propranolol-administered rats the expression of heme-oxigenase 1, Nrf2 target gene, was upregulated. Consequently, microglia from propranolol-administered rats, exhibited increased proportion of IL-10–expressing cells, but decreased those of IL-1β– and IL-23–expressing ones. Propranolol also downregulated the IL-6 and MCP-1/CCL2 expression in spinal cord. Furthermore, propranolol affecting CXCR1/Nrf2 signaling pathway enhanced microglial phagocytic/endocytic capacity and surface expression of anti-inflammatory CD163/CD83 markers. Results from in vitro pharmacological study examining influence of noradrenaline/propranolol on functional properties of microglia showed that microglia synthesize noradrenaline, which, in turn, through β-adrenoceptor, downregulated their Nrf2 expression, in a CX3CR1-independent manner. In accordance with microglial shift towards a more anti-inflammatory profile, in spinal cord of propranolol- administered rats was found: i) decreased infiltration with blood-borne myeloid and CD4+ T cells, and ii) reduced CD4+ T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17+ cells co-producing IFN-y and GM-CSF. The study suggests a neuroinflammation-promoting role for central noradrenaline in EAE, via β-adrenoceptor– mediated modulation of microglial Nrf2 expression. Thus, it points out to a putative target for future translational pharmacological research to optimize multiple sclerosis therapy.
PB  - Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade
PB  - Immunological Society of Serbia
C3  - Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019
T1  - Propranolol reduced severity of eae by increasing the Expression of Nrf2 in microglia
EP  - 69
SP  - 69
UR  - https://hdl.handle.net/21.15107/rcub_intor_854
ER  - 
@conference{
author = "Pilipović, Ivan and Prijić, Ivana and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2019",
abstract = "Sympathetic dysfunction was proposed to participate in development of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). This may be linked with findings indicating that noradrenaline, the key sympathetic end-point mediator, through β- adrenoceptor exerts immunomodulatory action. Considering importance of the target tissue for the clinical outcome of EAE, the study investigated the effects of propranolol, a non-selective β- adrenoceptor blocker, on the disease severity in Dark Agouti rats. Administration of propranolol over the effector phase of EAE substantially moderated neurological symptoms of the disease. This correlated with the increased proportion of spinal cord microglia expressing CX3CR1, the crucial neuroinflammation-limiting molecule, and upregulated expression of Nrf2, the key CX3CR1 downstream target gene. Additionally, in spinal cord of propranolol-administered rats the expression of heme-oxigenase 1, Nrf2 target gene, was upregulated. Consequently, microglia from propranolol-administered rats, exhibited increased proportion of IL-10–expressing cells, but decreased those of IL-1β– and IL-23–expressing ones. Propranolol also downregulated the IL-6 and MCP-1/CCL2 expression in spinal cord. Furthermore, propranolol affecting CXCR1/Nrf2 signaling pathway enhanced microglial phagocytic/endocytic capacity and surface expression of anti-inflammatory CD163/CD83 markers. Results from in vitro pharmacological study examining influence of noradrenaline/propranolol on functional properties of microglia showed that microglia synthesize noradrenaline, which, in turn, through β-adrenoceptor, downregulated their Nrf2 expression, in a CX3CR1-independent manner. In accordance with microglial shift towards a more anti-inflammatory profile, in spinal cord of propranolol- administered rats was found: i) decreased infiltration with blood-borne myeloid and CD4+ T cells, and ii) reduced CD4+ T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17+ cells co-producing IFN-y and GM-CSF. The study suggests a neuroinflammation-promoting role for central noradrenaline in EAE, via β-adrenoceptor– mediated modulation of microglial Nrf2 expression. Thus, it points out to a putative target for future translational pharmacological research to optimize multiple sclerosis therapy.",
publisher = "Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Immunological Society of Serbia",
journal = "Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019",
title = "Propranolol reduced severity of eae by increasing the Expression of Nrf2 in microglia",
pages = "69-69",
url = "https://hdl.handle.net/21.15107/rcub_intor_854"
}
Pilipović, I., Prijić, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2019). Propranolol reduced severity of eae by increasing the Expression of Nrf2 in microglia. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019
Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade., 69-69.
https://hdl.handle.net/21.15107/rcub_intor_854
Pilipović I, Prijić I, Stojić-Vukanić Z, Leposavić G. Propranolol reduced severity of eae by increasing the Expression of Nrf2 in microglia. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019. 2019;:69-69.
https://hdl.handle.net/21.15107/rcub_intor_854 .
Pilipović, Ivan, Prijić, Ivana, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Propranolol reduced severity of eae by increasing the Expression of Nrf2 in microglia" in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019 (2019):69-69,
https://hdl.handle.net/21.15107/rcub_intor_854 .

Sexual dimorphism in thymic senescence

Nacka-Aleksić, Mirjana; Pilipović, Ivan; Kotur-Stevuljević, Jelena; Leposavić, Gordana

(Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, 2019)

TY  - CONF
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Kotur-Stevuljević, Jelena
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/855
AB  - The study showed sexual dimorphism in the kinetics of thymic involution in Dark Agouti rats, so in 24-month-old males prominent thymic fibro-adipose degeneration was found, whereas fibrous changes dominated in thymi of age-matched females. This dimorphism reflected sex-specific constellation of age-related alterations in the expression of the key proadipogenic factors (xanthine oxidase-induced PPARy, STAT3, the transcription factor controlling PPARy downstream adipocyte- differentiation-related gene expression, and IL-6) and TGF-β, the key pro-fibrinogenic factor. The age-related epithelial-mesenchymal transition in thymi of Dark Agouti rats was accompanied by decline in thymopoiesis mirrored in decrease in the frequency of the most mature CD4+CD8-/CD4-CD8+ TCRaβhigh thymocytes and CD4+ and CD8+ recent thymic emigrants in peripheral blood (PB). This was more prominent in males than in females. Irrespective of sex, differentiation/maturation “block” leading to accumulation of the least mature CD45RC+CD2-CD4-CD8- thymocytes, accompanied by decline in the frequency of descendant double positive (DP) TCRaβ- ones was observed with aging. This was followed by opposing changes in the efficacy of positive/negative selection in males and females, which was related to sex-specific alterations in thymic expression of Nur77, a nuclear receptor involved in negative selection, and surface density of CD90 (negative regulator of thymocyte-selection threshold) on thymocytes undergoing selection. Moreover, compared with old females, in age-matched males CD4+CD8-/CD4-CD8+ TCRaβhigh thymocyte ratio was shifted towards the latter. However, CD4+/CD8+ ratio in PB was skewed towards CD8+ T cells in both sexes. Irrespective of sex, with aging the frequency of CD4+CD25+Foxp3+ thymocytes diminished, but that of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in PB increased, most likely due to enhanced expansion of “induced” Tregs. Collectively, the study i) indicates necessity of sex-specific approaches in designing thymus-rejuvenating strategies and ii) warns that changes in the PB T-cell compartment do not necessarily reflect sex-based differences in T-cell generation in thymus.
PB  - Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade
PB  - Immunological Society of Serbia
C3  - Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019
T1  - Sexual dimorphism in thymic senescence
EP  - 85
SP  - 85
UR  - https://hdl.handle.net/21.15107/rcub_intor_855
ER  - 
@conference{
author = "Nacka-Aleksić, Mirjana and Pilipović, Ivan and Kotur-Stevuljević, Jelena and Leposavić, Gordana",
year = "2019",
abstract = "The study showed sexual dimorphism in the kinetics of thymic involution in Dark Agouti rats, so in 24-month-old males prominent thymic fibro-adipose degeneration was found, whereas fibrous changes dominated in thymi of age-matched females. This dimorphism reflected sex-specific constellation of age-related alterations in the expression of the key proadipogenic factors (xanthine oxidase-induced PPARy, STAT3, the transcription factor controlling PPARy downstream adipocyte- differentiation-related gene expression, and IL-6) and TGF-β, the key pro-fibrinogenic factor. The age-related epithelial-mesenchymal transition in thymi of Dark Agouti rats was accompanied by decline in thymopoiesis mirrored in decrease in the frequency of the most mature CD4+CD8-/CD4-CD8+ TCRaβhigh thymocytes and CD4+ and CD8+ recent thymic emigrants in peripheral blood (PB). This was more prominent in males than in females. Irrespective of sex, differentiation/maturation “block” leading to accumulation of the least mature CD45RC+CD2-CD4-CD8- thymocytes, accompanied by decline in the frequency of descendant double positive (DP) TCRaβ- ones was observed with aging. This was followed by opposing changes in the efficacy of positive/negative selection in males and females, which was related to sex-specific alterations in thymic expression of Nur77, a nuclear receptor involved in negative selection, and surface density of CD90 (negative regulator of thymocyte-selection threshold) on thymocytes undergoing selection. Moreover, compared with old females, in age-matched males CD4+CD8-/CD4-CD8+ TCRaβhigh thymocyte ratio was shifted towards the latter. However, CD4+/CD8+ ratio in PB was skewed towards CD8+ T cells in both sexes. Irrespective of sex, with aging the frequency of CD4+CD25+Foxp3+ thymocytes diminished, but that of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in PB increased, most likely due to enhanced expansion of “induced” Tregs. Collectively, the study i) indicates necessity of sex-specific approaches in designing thymus-rejuvenating strategies and ii) warns that changes in the PB T-cell compartment do not necessarily reflect sex-based differences in T-cell generation in thymus.",
publisher = "Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Immunological Society of Serbia",
journal = "Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019",
title = "Sexual dimorphism in thymic senescence",
pages = "85-85",
url = "https://hdl.handle.net/21.15107/rcub_intor_855"
}
Nacka-Aleksić, M., Pilipović, I., Kotur-Stevuljević, J.,& Leposavić, G.. (2019). Sexual dimorphism in thymic senescence. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019
Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade., 85-85.
https://hdl.handle.net/21.15107/rcub_intor_855
Nacka-Aleksić M, Pilipović I, Kotur-Stevuljević J, Leposavić G. Sexual dimorphism in thymic senescence. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019. 2019;:85-85.
https://hdl.handle.net/21.15107/rcub_intor_855 .
Nacka-Aleksić, Mirjana, Pilipović, Ivan, Kotur-Stevuljević, Jelena, Leposavić, Gordana, "Sexual dimorphism in thymic senescence" in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019 (2019):85-85,
https://hdl.handle.net/21.15107/rcub_intor_855 .

Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells

Dimitrijević, Mirjana; Arsenović-Ranin, Nevena; Kosec, Duško; Bufan, Biljana; Nacka-Aleksić, Mirjana; Pilipović, Ivan; Leposavić, Gordana

(Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, 2019)

TY  - CONF
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/856
AB  - Collagen-induced arthritis (CIA) is a well-established experimental model mimicking many immunopathogenic and clinical aspects of rheumatoid arthritis (RA), including sexual dimorphism in the clinical presentation. Our previous study showed that a more severe disease in female compared with male rats correlated with more robust Th17 response reflecting sexual dimorphism in Th17/Treg axis plasticity. Given that autoantibodies play a significant role in the immunopathogenesis of RA and CIA, in the present study the germinal center (GC) reaction in the lymph nodes draining inflamed joints and adjacent tissue (dLNs) was examined for putative sexual dimorphism. Female rats mounted greater serum collagen II-specific IgG response than their male counterparts. This dimorphism correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki67+ cells among dLN B cells was higher in females than in males. This was associated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higher Tfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL- 21/27, the key cytokines involved in Tfh cell generation and help to B cells. Additionally, in collagen II-stimulated female rat dLN cell cultures, IFN-γ/IL-4 ratio was shifted towards IFN-γ. Consistently, serum ratio between pathogenic IgG2a and protective IgG1 collagen II-specific antibodies was shifted towards the former in females. Thus, the study suggests that targeting T/B cell interactions should be considered in further translation research aimed to design sex-specific therapies for RA.
PB  - Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade
PB  - Immunological Society of Serbia
C3  - Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019
T1  - Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells
EP  - 106
SP  - 106
UR  - https://hdl.handle.net/21.15107/rcub_intor_856
ER  - 
@conference{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Kosec, Duško and Bufan, Biljana and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Leposavić, Gordana",
year = "2019",
abstract = "Collagen-induced arthritis (CIA) is a well-established experimental model mimicking many immunopathogenic and clinical aspects of rheumatoid arthritis (RA), including sexual dimorphism in the clinical presentation. Our previous study showed that a more severe disease in female compared with male rats correlated with more robust Th17 response reflecting sexual dimorphism in Th17/Treg axis plasticity. Given that autoantibodies play a significant role in the immunopathogenesis of RA and CIA, in the present study the germinal center (GC) reaction in the lymph nodes draining inflamed joints and adjacent tissue (dLNs) was examined for putative sexual dimorphism. Female rats mounted greater serum collagen II-specific IgG response than their male counterparts. This dimorphism correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki67+ cells among dLN B cells was higher in females than in males. This was associated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higher Tfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL- 21/27, the key cytokines involved in Tfh cell generation and help to B cells. Additionally, in collagen II-stimulated female rat dLN cell cultures, IFN-γ/IL-4 ratio was shifted towards IFN-γ. Consistently, serum ratio between pathogenic IgG2a and protective IgG1 collagen II-specific antibodies was shifted towards the former in females. Thus, the study suggests that targeting T/B cell interactions should be considered in further translation research aimed to design sex-specific therapies for RA.",
publisher = "Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Immunological Society of Serbia",
journal = "Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019",
title = "Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells",
pages = "106-106",
url = "https://hdl.handle.net/21.15107/rcub_intor_856"
}
Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2019). Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019
Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade., 106-106.
https://hdl.handle.net/21.15107/rcub_intor_856
Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019. 2019;:106-106.
https://hdl.handle.net/21.15107/rcub_intor_856 .
Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells" in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019 (2019):106-106,
https://hdl.handle.net/21.15107/rcub_intor_856 .

Propranolol Impairs Primary Immune Responses in Rat Experimental Autoimmune Encephalomyelitis

Pilipović, Ivan; Vujnović, Ivana; Petrović, Raisa; Stojić-Vukanić, Zorica; Leposavić, Gordana

(Karger, Basel, 2019)

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Vujnović, Ivana
AU  - Petrović, Raisa
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/541
AB  - Objective: We examined the effect of beta-adrenoceptor (AR) blockade in the preclinical phase of experimental autoimmune encephalomyelitis (EAE), the most commonly used model of multiple sclerosis, on the development of primary CD4+ T-cell responses in draining lymph nodes (dLNs). Methods: CD11b+ cell migration to dLNs, CD4+ T-cell activation/proliferation, and IL-17+ CD4+ (Th17) cell numbers in dLN and spinal cord (SC) were examined in male and female Dark Agouti rats using flow cytometry analysis. Results: Irrespective of sex, in propranolol-treated (PT) rats, migration of CD11b+ antigen-presenting cells from the site of immunization to dLNs was impaired compared with saline-treated controls and consequently the frequency of all CD11b+ cells in dLNs and activated cells among them, too. This correlated with decreased expression of CCL19/21 transcripts in dLNs. Consistently, the frequency of activated/proliferating cells among dLN CD4+ T cells was reduced in PT rats. Additionally, propranolol reduced the number of Th17 cells in dLNs and SC. Consistently, male and female PT rats exhibited a decreased incidence of EAE and prolonged duration of the asymptomatic disease phase. Conclusion: This study suggests that sympathetic dysregulation is involved in the outbreak of clinical EAE. (C) 2019 S. Karger AG, Basel
PB  - Karger, Basel
T2  - Neuroimmunomodulation
T1  - Propranolol Impairs Primary Immune Responses in Rat Experimental Autoimmune Encephalomyelitis
EP  - 138
IS  - 3
SP  - 129
VL  - 26
DO  - 10.1159/000500094
ER  - 
@article{
author = "Pilipović, Ivan and Vujnović, Ivana and Petrović, Raisa and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2019",
abstract = "Objective: We examined the effect of beta-adrenoceptor (AR) blockade in the preclinical phase of experimental autoimmune encephalomyelitis (EAE), the most commonly used model of multiple sclerosis, on the development of primary CD4+ T-cell responses in draining lymph nodes (dLNs). Methods: CD11b+ cell migration to dLNs, CD4+ T-cell activation/proliferation, and IL-17+ CD4+ (Th17) cell numbers in dLN and spinal cord (SC) were examined in male and female Dark Agouti rats using flow cytometry analysis. Results: Irrespective of sex, in propranolol-treated (PT) rats, migration of CD11b+ antigen-presenting cells from the site of immunization to dLNs was impaired compared with saline-treated controls and consequently the frequency of all CD11b+ cells in dLNs and activated cells among them, too. This correlated with decreased expression of CCL19/21 transcripts in dLNs. Consistently, the frequency of activated/proliferating cells among dLN CD4+ T cells was reduced in PT rats. Additionally, propranolol reduced the number of Th17 cells in dLNs and SC. Consistently, male and female PT rats exhibited a decreased incidence of EAE and prolonged duration of the asymptomatic disease phase. Conclusion: This study suggests that sympathetic dysregulation is involved in the outbreak of clinical EAE. (C) 2019 S. Karger AG, Basel",
publisher = "Karger, Basel",
journal = "Neuroimmunomodulation",
title = "Propranolol Impairs Primary Immune Responses in Rat Experimental Autoimmune Encephalomyelitis",
pages = "138-129",
number = "3",
volume = "26",
doi = "10.1159/000500094"
}
Pilipović, I., Vujnović, I., Petrović, R., Stojić-Vukanić, Z.,& Leposavić, G.. (2019). Propranolol Impairs Primary Immune Responses in Rat Experimental Autoimmune Encephalomyelitis. in Neuroimmunomodulation
Karger, Basel., 26(3), 129-138.
https://doi.org/10.1159/000500094
Pilipović I, Vujnović I, Petrović R, Stojić-Vukanić Z, Leposavić G. Propranolol Impairs Primary Immune Responses in Rat Experimental Autoimmune Encephalomyelitis. in Neuroimmunomodulation. 2019;26(3):129-138.
doi:10.1159/000500094 .
Pilipović, Ivan, Vujnović, Ivana, Petrović, Raisa, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Propranolol Impairs Primary Immune Responses in Rat Experimental Autoimmune Encephalomyelitis" in Neuroimmunomodulation, 26, no. 3 (2019):129-138,
https://doi.org/10.1159/000500094 . .
6
3
6

Noradrenaline through beta-adrenoceptor contributes to sexual dimorphism in primary CD4+T-cell response in DA rat EAE model?

Vujnović, Ivana; Pilipović, Ivan; Jasnić, Nebojša; Petrović, Raisa; Blagojević, Veljko; Arsenović-Ranin, Nevena; Stojić-Vukanić, Zorica; Đorđević, Jelena; Leposavić, Gordana

(Academic Press Inc Elsevier Science, San Diego, 2019)

TY  - JOUR
AU  - Vujnović, Ivana
AU  - Pilipović, Ivan
AU  - Jasnić, Nebojša
AU  - Petrović, Raisa
AU  - Blagojević, Veljko
AU  - Arsenović-Ranin, Nevena
AU  - Stojić-Vukanić, Zorica
AU  - Đorđević, Jelena
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/539
AB  - Males exhibit stronger sympathetic nervous system (SNS) activity, but weaker primary CD4 + T-cell (auto) immune responses. To test the role of catecholamines, major end-point SNS mediators, in this dimorphism, influence of propranolol (beta-adrenoceptor blocker) on mitogen/neuroantigen-stimulated CD4 + T cells from female and male EAE rat draining lymph node (dLN) cell cultures was examined. Male rat dLNs exhibited higher noradrenaline concentration and frequency of beta(2)-adrenoceptor-expressing CD4 + T lymphocytes and antigen presenting cells. Propranolol, irrespective of exogenous noradrenaline presence, more prominently augmented IL-2 production and proliferation of CD4 + lymphocytes in male than female rat dLN cell cultures. In neuroantigen-stimulated dLN cells of both sexes propranolol increased IL-1 beta and IL-23/p19 expression and IL-17 + CD4 + cell frequency, but enhanced IL-17 production only in male rat CD4 + lymphocytes, thereby abrogating sexual dimorphism in IL-17 concentration observed in propranolol-free cultures. Thus, beta-adrenoceptor-mediated signalling may contribute to sex bias in rat IL-17-producing cell secretory capacity.
PB  - Academic Press Inc Elsevier Science, San Diego
T2  - Cellular Immunology
T1  - Noradrenaline through beta-adrenoceptor contributes to sexual dimorphism in primary CD4+T-cell response in DA rat EAE model?
EP  - 57
SP  - 48
VL  - 336
DO  - 10.1016/j.cellimm.2018.12.009
ER  - 
@article{
author = "Vujnović, Ivana and Pilipović, Ivan and Jasnić, Nebojša and Petrović, Raisa and Blagojević, Veljko and Arsenović-Ranin, Nevena and Stojić-Vukanić, Zorica and Đorđević, Jelena and Leposavić, Gordana",
year = "2019",
abstract = "Males exhibit stronger sympathetic nervous system (SNS) activity, but weaker primary CD4 + T-cell (auto) immune responses. To test the role of catecholamines, major end-point SNS mediators, in this dimorphism, influence of propranolol (beta-adrenoceptor blocker) on mitogen/neuroantigen-stimulated CD4 + T cells from female and male EAE rat draining lymph node (dLN) cell cultures was examined. Male rat dLNs exhibited higher noradrenaline concentration and frequency of beta(2)-adrenoceptor-expressing CD4 + T lymphocytes and antigen presenting cells. Propranolol, irrespective of exogenous noradrenaline presence, more prominently augmented IL-2 production and proliferation of CD4 + lymphocytes in male than female rat dLN cell cultures. In neuroantigen-stimulated dLN cells of both sexes propranolol increased IL-1 beta and IL-23/p19 expression and IL-17 + CD4 + cell frequency, but enhanced IL-17 production only in male rat CD4 + lymphocytes, thereby abrogating sexual dimorphism in IL-17 concentration observed in propranolol-free cultures. Thus, beta-adrenoceptor-mediated signalling may contribute to sex bias in rat IL-17-producing cell secretory capacity.",
publisher = "Academic Press Inc Elsevier Science, San Diego",
journal = "Cellular Immunology",
title = "Noradrenaline through beta-adrenoceptor contributes to sexual dimorphism in primary CD4+T-cell response in DA rat EAE model?",
pages = "57-48",
volume = "336",
doi = "10.1016/j.cellimm.2018.12.009"
}
Vujnović, I., Pilipović, I., Jasnić, N., Petrović, R., Blagojević, V., Arsenović-Ranin, N., Stojić-Vukanić, Z., Đorđević, J.,& Leposavić, G.. (2019). Noradrenaline through beta-adrenoceptor contributes to sexual dimorphism in primary CD4+T-cell response in DA rat EAE model?. in Cellular Immunology
Academic Press Inc Elsevier Science, San Diego., 336, 48-57.
https://doi.org/10.1016/j.cellimm.2018.12.009
Vujnović I, Pilipović I, Jasnić N, Petrović R, Blagojević V, Arsenović-Ranin N, Stojić-Vukanić Z, Đorđević J, Leposavić G. Noradrenaline through beta-adrenoceptor contributes to sexual dimorphism in primary CD4+T-cell response in DA rat EAE model?. in Cellular Immunology. 2019;336:48-57.
doi:10.1016/j.cellimm.2018.12.009 .
Vujnović, Ivana, Pilipović, Ivan, Jasnić, Nebojša, Petrović, Raisa, Blagojević, Veljko, Arsenović-Ranin, Nevena, Stojić-Vukanić, Zorica, Đorđević, Jelena, Leposavić, Gordana, "Noradrenaline through beta-adrenoceptor contributes to sexual dimorphism in primary CD4+T-cell response in DA rat EAE model?" in Cellular Immunology, 336 (2019):48-57,
https://doi.org/10.1016/j.cellimm.2018.12.009 . .
1
14
9
13

Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor

Pilipović, Ivan; Vujnović, Ivana; Stojić-Vukanić, Zorica; Petrović, Raisa; Kosec, Duško; Nacka-Aleksić, Mirjana; Jasnić, Nebojša; Leposavić, Gordana

(Humana Press Inc, Totowa, 2019)

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Vujnović, Ivana
AU  - Stojić-Vukanić, Zorica
AU  - Petrović, Raisa
AU  - Kosec, Duško
AU  - Nacka-Aleksić, Mirjana
AU  - Jasnić, Nebojša
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/531
AB  - Pharmacological blockade of alpha(1)-adrenoceptor is shown to influence development of experimental autoimmune encephalomyelitis (EAE), an IL-17-producing CD4+TCR+ (Th17) cell-mediated disease mimicking multiple sclerosis. Considering significance of CD4+ cell priming for the clinical outcome of EAE, the study examined alpha(1)-adrenoceptor-mediated influence of catecholamines, particularly those derived from draining lymph node (dLN) cells (as catecholamine supply from nerve fibers decreases with the initiation of autoimmune diseases) for CD4+ cell priming. The results confirmed diminishing effect of immunization on nerve fiber-derived noradrenaline supply and showed that antigen presenting and CD4+ cells synthesize catecholamines, while antigen presenting cells and only CD4+CD25+Foxp3+ regulatory T cells (Tregs) express alpha(1)-adrenoceptor. The analysis of influence of alpha(1)-adrenoceptor antagonist prazosin on the myelin basic protein (MBP)-stimulated CD4+ lymphocytes in dLN cell culture showed their diminished proliferation in the presence of prazosin. This was consistent with prazosin enhancing effect on Treg frequency and their Foxp3 expression in these cultures. The latter was associated with upregulation of TGF-beta expression. Additionally, prazosin decreased antigen presenting cell activation and affected their cytokine profile by diminishing the frequency of cells that produce Th17 polarizing cytokines (IL-1 beta and IL-23) and increasing that of IL-10-producing cells. Consistently, the frequency of all IL-17A+ cells and those co-expressing GM-CSF within CD4+ lymphocytes was decreased in prazosin-supplemented MBP-stimulated dLN cell cultures. Collectively, the results indicated that dLN cell-derived catecholamines may influence EAE development by modulating interactions between distinct subtypes of CD4+ T cells and antigen presenting cells through alpha(1)-adrenoceptor and consequently CD4+ T cell priming.
PB  - Humana Press Inc, Totowa
T2  - Immunologic Research
T1  - Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor
EP  - 240
IS  - 2-3
SP  - 223
VL  - 67
DO  - 10.1007/s12026-019-09082-y
ER  - 
@article{
author = "Pilipović, Ivan and Vujnović, Ivana and Stojić-Vukanić, Zorica and Petrović, Raisa and Kosec, Duško and Nacka-Aleksić, Mirjana and Jasnić, Nebojša and Leposavić, Gordana",
year = "2019",
abstract = "Pharmacological blockade of alpha(1)-adrenoceptor is shown to influence development of experimental autoimmune encephalomyelitis (EAE), an IL-17-producing CD4+TCR+ (Th17) cell-mediated disease mimicking multiple sclerosis. Considering significance of CD4+ cell priming for the clinical outcome of EAE, the study examined alpha(1)-adrenoceptor-mediated influence of catecholamines, particularly those derived from draining lymph node (dLN) cells (as catecholamine supply from nerve fibers decreases with the initiation of autoimmune diseases) for CD4+ cell priming. The results confirmed diminishing effect of immunization on nerve fiber-derived noradrenaline supply and showed that antigen presenting and CD4+ cells synthesize catecholamines, while antigen presenting cells and only CD4+CD25+Foxp3+ regulatory T cells (Tregs) express alpha(1)-adrenoceptor. The analysis of influence of alpha(1)-adrenoceptor antagonist prazosin on the myelin basic protein (MBP)-stimulated CD4+ lymphocytes in dLN cell culture showed their diminished proliferation in the presence of prazosin. This was consistent with prazosin enhancing effect on Treg frequency and their Foxp3 expression in these cultures. The latter was associated with upregulation of TGF-beta expression. Additionally, prazosin decreased antigen presenting cell activation and affected their cytokine profile by diminishing the frequency of cells that produce Th17 polarizing cytokines (IL-1 beta and IL-23) and increasing that of IL-10-producing cells. Consistently, the frequency of all IL-17A+ cells and those co-expressing GM-CSF within CD4+ lymphocytes was decreased in prazosin-supplemented MBP-stimulated dLN cell cultures. Collectively, the results indicated that dLN cell-derived catecholamines may influence EAE development by modulating interactions between distinct subtypes of CD4+ T cells and antigen presenting cells through alpha(1)-adrenoceptor and consequently CD4+ T cell priming.",
publisher = "Humana Press Inc, Totowa",
journal = "Immunologic Research",
title = "Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor",
pages = "240-223",
number = "2-3",
volume = "67",
doi = "10.1007/s12026-019-09082-y"
}
Pilipović, I., Vujnović, I., Stojić-Vukanić, Z., Petrović, R., Kosec, D., Nacka-Aleksić, M., Jasnić, N.,& Leposavić, G.. (2019). Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor. in Immunologic Research
Humana Press Inc, Totowa., 67(2-3), 223-240.
https://doi.org/10.1007/s12026-019-09082-y
Pilipović I, Vujnović I, Stojić-Vukanić Z, Petrović R, Kosec D, Nacka-Aleksić M, Jasnić N, Leposavić G. Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor. in Immunologic Research. 2019;67(2-3):223-240.
doi:10.1007/s12026-019-09082-y .
Pilipović, Ivan, Vujnović, Ivana, Stojić-Vukanić, Zorica, Petrović, Raisa, Kosec, Duško, Nacka-Aleksić, Mirjana, Jasnić, Nebojša, Leposavić, Gordana, "Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor" in Immunologic Research, 67, no. 2-3 (2019):223-240,
https://doi.org/10.1007/s12026-019-09082-y . .
1
13
6
13

Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis

Dimitrijević, Mirjana; Arsenović-Ranin, Nevena; Kosec, Duško; Bufan, Biljana; Nacka-Aleksić, Mirjana; Pilipović, Ivan; Leposavić, Gordana

(Academic Press Inc Elsevier Science, San Diego, 2019)

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/538
AB  - Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25 + Foxp3 + CD4 + T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-gamma/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-beta concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-gamma/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1 beta- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.
PB  - Academic Press Inc Elsevier Science, San Diego
T2  - Brain Behavior and Immunity
T1  - Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis
EP  - 214
SP  - 198
VL  - 76
DO  - 10.1016/j.bbi.2018.11.311
ER  - 
@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Kosec, Duško and Bufan, Biljana and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Leposavić, Gordana",
year = "2019",
abstract = "Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25 + Foxp3 + CD4 + T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-gamma/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-beta concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-gamma/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1 beta- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.",
publisher = "Academic Press Inc Elsevier Science, San Diego",
journal = "Brain Behavior and Immunity",
title = "Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis",
pages = "214-198",
volume = "76",
doi = "10.1016/j.bbi.2018.11.311"
}
Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2019). Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis. in Brain Behavior and Immunity
Academic Press Inc Elsevier Science, San Diego., 76, 198-214.
https://doi.org/10.1016/j.bbi.2018.11.311
Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis. in Brain Behavior and Immunity. 2019;76:198-214.
doi:10.1016/j.bbi.2018.11.311 .
Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis" in Brain Behavior and Immunity, 76 (2019):198-214,
https://doi.org/10.1016/j.bbi.2018.11.311 . .
4
18
12
19

Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation

Nacka-Aleksić, Mirjana; Pilipović, Ivan; Kotur-Stevuljević, Jelena; Petrović, Raisa; Sopta, Jelena; Leposavić, Gordana

(Springer, New York, 2019)

TY  - JOUR
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Kotur-Stevuljević, Jelena
AU  - Petrović, Raisa
AU  - Sopta, Jelena
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/540
AB  - The study investigated mechanisms underlying sex differences in thymic involution in Dark Agouti rats. Adverse effects of aging on thymus were more pronounced in males than in females. Thymi from old males exhibited more prominent: (i) fibro-adipose degeneration which correlated with greater intensity of thymic oxidative stress and enhanced thymic TGF- and IL-6 expression and (ii) decline in thymopoiesis, as suggested by the number of the most mature CD4+CD8-/CD4-CD8+ single positive (SP) TCRhigh thymocytes. The greater accumulation of adipose tissue in old male thymus was linked with greater age-related increase in thymic expression of PPAR and STAT3, a transcription factor regulating the expression of PPAR downstream genes, in male than in female rats. In aged thymi of both sexes the early CD4-CD8- double negative (DN) stage of thymocyte development was affected, so relative accumulation of the least mature CD45RC+CD2- cells followed by decreased frequency of their DN and CD4+CD8+ double positive (DP) TCR- descendants was observed. Additionally, in old males, because of the increased thymic expression of Nur77, a nuclear receptor involved in negative selection, and decreased CD90 (a negative regulator of thymocyte selection threshold) MFI on DP TCRint thymocytes, less efficient positive/more efficient negative selection was found. Moreover, in male rats, thymocyte post-selection differentiation/maturation was skewed towards CD4-CD8+ SP TCRhigh cells compared with age-matched females, reflecting, at least partly, greater IL-15 expression in their thymi. The study indicated mechanisms underlying sex-based differences in age-related thymic changes and consequently necessity of sex-specific approaches in designing strategies to rejuvenate thymus.
PB  - Springer, New York
T2  - Biogerontology
T1  - Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation
EP  - 569
IS  - 4
SP  - 545
VL  - 20
DO  - 10.1007/s10522-019-09816-3
ER  - 
@article{
author = "Nacka-Aleksić, Mirjana and Pilipović, Ivan and Kotur-Stevuljević, Jelena and Petrović, Raisa and Sopta, Jelena and Leposavić, Gordana",
year = "2019",
abstract = "The study investigated mechanisms underlying sex differences in thymic involution in Dark Agouti rats. Adverse effects of aging on thymus were more pronounced in males than in females. Thymi from old males exhibited more prominent: (i) fibro-adipose degeneration which correlated with greater intensity of thymic oxidative stress and enhanced thymic TGF- and IL-6 expression and (ii) decline in thymopoiesis, as suggested by the number of the most mature CD4+CD8-/CD4-CD8+ single positive (SP) TCRhigh thymocytes. The greater accumulation of adipose tissue in old male thymus was linked with greater age-related increase in thymic expression of PPAR and STAT3, a transcription factor regulating the expression of PPAR downstream genes, in male than in female rats. In aged thymi of both sexes the early CD4-CD8- double negative (DN) stage of thymocyte development was affected, so relative accumulation of the least mature CD45RC+CD2- cells followed by decreased frequency of their DN and CD4+CD8+ double positive (DP) TCR- descendants was observed. Additionally, in old males, because of the increased thymic expression of Nur77, a nuclear receptor involved in negative selection, and decreased CD90 (a negative regulator of thymocyte selection threshold) MFI on DP TCRint thymocytes, less efficient positive/more efficient negative selection was found. Moreover, in male rats, thymocyte post-selection differentiation/maturation was skewed towards CD4-CD8+ SP TCRhigh cells compared with age-matched females, reflecting, at least partly, greater IL-15 expression in their thymi. The study indicated mechanisms underlying sex-based differences in age-related thymic changes and consequently necessity of sex-specific approaches in designing strategies to rejuvenate thymus.",
publisher = "Springer, New York",
journal = "Biogerontology",
title = "Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation",
pages = "569-545",
number = "4",
volume = "20",
doi = "10.1007/s10522-019-09816-3"
}
Nacka-Aleksić, M., Pilipović, I., Kotur-Stevuljević, J., Petrović, R., Sopta, J.,& Leposavić, G.. (2019). Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation. in Biogerontology
Springer, New York., 20(4), 545-569.
https://doi.org/10.1007/s10522-019-09816-3
Nacka-Aleksić M, Pilipović I, Kotur-Stevuljević J, Petrović R, Sopta J, Leposavić G. Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation. in Biogerontology. 2019;20(4):545-569.
doi:10.1007/s10522-019-09816-3 .
Nacka-Aleksić, Mirjana, Pilipović, Ivan, Kotur-Stevuljević, Jelena, Petrović, Raisa, Sopta, Jelena, Leposavić, Gordana, "Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation" in Biogerontology, 20, no. 4 (2019):545-569,
https://doi.org/10.1007/s10522-019-09816-3 . .
1
13
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13

Natural killer cells as participants in pathogenesis of rat experimental autoimmune encephalomyelitis (EAE): lessons from research on rats with distinct age and strain

Đuretić, Jasmina; Pilipović, Ivan; Stojić-Vukanić, Zorica; Leposavić, Gordana

(Termedia Publishing House Ltd, Poznan, 2019)

TY  - JOUR
AU  - Đuretić, Jasmina
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/525
AB  - Natural killer (NK) cells, influencing dendritic cell (DC)-mediated CD4+ lymphocyte priming in draining lymph nodes (dLNs) and controlling spinal cord (SC) infiltration with encephalitogenic CD4+T lymphocytes, modulate EAE (multiple sclerosis model). This study examined their putative contribution to age-related differences in EAE development in Dark Agouti (DA) (exhibiting age-related decrease in EAE susceptibility) and Albino Oxford (AO) (becoming susceptible to EAE with aging) rats. Aging increased NK cell number in dLNs from rats of both strains. In AO rats, but not in DA ones, it also increased the numbers of IFN-gamma-producing NK cells (important for DC activation) and activated/matured DCs, thereby increasing activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated CD25+Foxp3-CD4+ cell number. Aging in DA rats diminished activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated Foxp3-CD4+ cell number. However, MBP-stimulated CD4+ cell proliferation did not differ in dLN cell cultures from young and aged AO rats (as more favorable activated/matured DC/Foxp3-CD4+ cell ratio was abrogated by lower intrinsic CD4+ cell proliferative capacity and a greater regulatory CD25+Foxp3+CD4+ lymphocyte frequency), but was lower in those from aged compared with young DA rats. At SC level, aging shifted Foxp3-CD4+/cytotoxic CX3CR1+ NK cell ratio towards the former in AO rats, so it was less favorable in aged AO rats exhibiting prolonged neurological deficit compared with their DA counterparts. The study showed strain and age differences in number of IFN-gamma-producing NK cells in EAE rat dLNs, and suggested that their pathogenetic relevance depends on frequency and/or activity of other cells involved in CD4+ T cell (auto)immune response.
PB  - Termedia Publishing House Ltd, Poznan
T2  - Central European Journal of Immunology
T1  - Natural killer cells as participants in pathogenesis of rat experimental autoimmune encephalomyelitis (EAE): lessons from research on rats with distinct age and strain
EP  - 356
IS  - 4
SP  - 337
VL  - 44
DO  - 10.5114/ceji.2019.92777
ER  - 
@article{
author = "Đuretić, Jasmina and Pilipović, Ivan and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2019",
abstract = "Natural killer (NK) cells, influencing dendritic cell (DC)-mediated CD4+ lymphocyte priming in draining lymph nodes (dLNs) and controlling spinal cord (SC) infiltration with encephalitogenic CD4+T lymphocytes, modulate EAE (multiple sclerosis model). This study examined their putative contribution to age-related differences in EAE development in Dark Agouti (DA) (exhibiting age-related decrease in EAE susceptibility) and Albino Oxford (AO) (becoming susceptible to EAE with aging) rats. Aging increased NK cell number in dLNs from rats of both strains. In AO rats, but not in DA ones, it also increased the numbers of IFN-gamma-producing NK cells (important for DC activation) and activated/matured DCs, thereby increasing activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated CD25+Foxp3-CD4+ cell number. Aging in DA rats diminished activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated Foxp3-CD4+ cell number. However, MBP-stimulated CD4+ cell proliferation did not differ in dLN cell cultures from young and aged AO rats (as more favorable activated/matured DC/Foxp3-CD4+ cell ratio was abrogated by lower intrinsic CD4+ cell proliferative capacity and a greater regulatory CD25+Foxp3+CD4+ lymphocyte frequency), but was lower in those from aged compared with young DA rats. At SC level, aging shifted Foxp3-CD4+/cytotoxic CX3CR1+ NK cell ratio towards the former in AO rats, so it was less favorable in aged AO rats exhibiting prolonged neurological deficit compared with their DA counterparts. The study showed strain and age differences in number of IFN-gamma-producing NK cells in EAE rat dLNs, and suggested that their pathogenetic relevance depends on frequency and/or activity of other cells involved in CD4+ T cell (auto)immune response.",
publisher = "Termedia Publishing House Ltd, Poznan",
journal = "Central European Journal of Immunology",
title = "Natural killer cells as participants in pathogenesis of rat experimental autoimmune encephalomyelitis (EAE): lessons from research on rats with distinct age and strain",
pages = "356-337",
number = "4",
volume = "44",
doi = "10.5114/ceji.2019.92777"
}
Đuretić, J., Pilipović, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2019). Natural killer cells as participants in pathogenesis of rat experimental autoimmune encephalomyelitis (EAE): lessons from research on rats with distinct age and strain. in Central European Journal of Immunology
Termedia Publishing House Ltd, Poznan., 44(4), 337-356.
https://doi.org/10.5114/ceji.2019.92777
Đuretić J, Pilipović I, Stojić-Vukanić Z, Leposavić G. Natural killer cells as participants in pathogenesis of rat experimental autoimmune encephalomyelitis (EAE): lessons from research on rats with distinct age and strain. in Central European Journal of Immunology. 2019;44(4):337-356.
doi:10.5114/ceji.2019.92777 .
Đuretić, Jasmina, Pilipović, Ivan, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Natural killer cells as participants in pathogenesis of rat experimental autoimmune encephalomyelitis (EAE): lessons from research on rats with distinct age and strain" in Central European Journal of Immunology, 44, no. 4 (2019):337-356,
https://doi.org/10.5114/ceji.2019.92777 . .
3
2
3

Noradrenaline synthesized locally in draining lymph node cells modulates CD4+ T-cell development in rat EAE model: a role for a1-adrenoceptor

Pilipović, Ivan; Vujnović, I.; Petrović, Raisa; Kosec, Duško; Stojić-Vukanić, Z.; Leposavić, Gordana

(2018)

TY  - CONF
AU  - Pilipović, Ivan
AU  - Vujnović, I.
AU  - Petrović, Raisa
AU  - Kosec, Duško
AU  - Stojić-Vukanić, Z.
AU  - Leposavić, Gordana
PY  - 2018
UR  - http://intor.torlakinstitut.com/handle/123456789/853
AB  - Introduction: It has been suggested that: i) noradrenaline synthesis in ,,adrenergic“ immune cells changes during development of EAE and multiple sclerosis and ii) noradrenaline influences EAE development through a1−adrenoceptor. To elucidate mechanisms standing behind this phenomenon, a1−adrenoceptor−mediated influence of draining lymph node (dLN) cell−derived noradrenaline on CD4+ T−cell response in dLNs from Dark Agouti rats of both sexes immunized for EAE was examined. Methods: Cells recovered from dLNs on 7th day post−immunization were examined for noradrenaline synthesis/content and a1B−adrenoceptor expression using HPLC and/or flow cytometry. Additionally, effects of prazosin (a1- AR blocker) on CD4+ T−cell proliferation, the frequency of IL−17+ CD4+ T−cells and regulatory (Foxp3+CD25+) CD4+ T−cells (Tregs), activational/maturational molecule expression on antigen presenting cells (APCs) and their cytokine profile in dLN cell culture were examined using flow cytometry and/or qRT−PCR/ELISA. Results: Irrespective of sex, conventional CD4+ T−cells and Tregs, and APCs from rat dLNs synthesized noradrenaline, while only Tregs and APCs expressed a1B-adrenoceptor.
In myelin basic protein−stimulated dLN cell cultures from rats of both sexes prazosin increased Treg frequency and Foxp3 expression, but diminished co−stimulatory CD80 and CD86
molecule expression on APCs, thereby reducing CD4+ cell proliferation.
C3  - Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands
T1  - Noradrenaline synthesized locally in draining lymph node cells modulates CD4+ T-cell development in rat EAE model: a role for a1-adrenoceptor
SP  - P.A5.06.15
UR  - https://hdl.handle.net/21.15107/rcub_intor_853
ER  - 
@conference{
author = "Pilipović, Ivan and Vujnović, I. and Petrović, Raisa and Kosec, Duško and Stojić-Vukanić, Z. and Leposavić, Gordana",
year = "2018",
abstract = "Introduction: It has been suggested that: i) noradrenaline synthesis in ,,adrenergic“ immune cells changes during development of EAE and multiple sclerosis and ii) noradrenaline influences EAE development through a1−adrenoceptor. To elucidate mechanisms standing behind this phenomenon, a1−adrenoceptor−mediated influence of draining lymph node (dLN) cell−derived noradrenaline on CD4+ T−cell response in dLNs from Dark Agouti rats of both sexes immunized for EAE was examined. Methods: Cells recovered from dLNs on 7th day post−immunization were examined for noradrenaline synthesis/content and a1B−adrenoceptor expression using HPLC and/or flow cytometry. Additionally, effects of prazosin (a1- AR blocker) on CD4+ T−cell proliferation, the frequency of IL−17+ CD4+ T−cells and regulatory (Foxp3+CD25+) CD4+ T−cells (Tregs), activational/maturational molecule expression on antigen presenting cells (APCs) and their cytokine profile in dLN cell culture were examined using flow cytometry and/or qRT−PCR/ELISA. Results: Irrespective of sex, conventional CD4+ T−cells and Tregs, and APCs from rat dLNs synthesized noradrenaline, while only Tregs and APCs expressed a1B-adrenoceptor.
In myelin basic protein−stimulated dLN cell cultures from rats of both sexes prazosin increased Treg frequency and Foxp3 expression, but diminished co−stimulatory CD80 and CD86
molecule expression on APCs, thereby reducing CD4+ cell proliferation.",
journal = "Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands",
title = "Noradrenaline synthesized locally in draining lymph node cells modulates CD4+ T-cell development in rat EAE model: a role for a1-adrenoceptor",
pages = "P.A5.06.15",
url = "https://hdl.handle.net/21.15107/rcub_intor_853"
}
Pilipović, I., Vujnović, I., Petrović, R., Kosec, D., Stojić-Vukanić, Z.,& Leposavić, G.. (2018). Noradrenaline synthesized locally in draining lymph node cells modulates CD4+ T-cell development in rat EAE model: a role for a1-adrenoceptor. in Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands, P.A5.06.15.
https://hdl.handle.net/21.15107/rcub_intor_853
Pilipović I, Vujnović I, Petrović R, Kosec D, Stojić-Vukanić Z, Leposavić G. Noradrenaline synthesized locally in draining lymph node cells modulates CD4+ T-cell development in rat EAE model: a role for a1-adrenoceptor. in Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands. 2018;:P.A5.06.15.
https://hdl.handle.net/21.15107/rcub_intor_853 .
Pilipović, Ivan, Vujnović, I., Petrović, Raisa, Kosec, Duško, Stojić-Vukanić, Z., Leposavić, Gordana, "Noradrenaline synthesized locally in draining lymph node cells modulates CD4+ T-cell development in rat EAE model: a role for a1-adrenoceptor" in Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands (2018):P.A5.06.15,
https://hdl.handle.net/21.15107/rcub_intor_853 .

Immunization-induced thymic atrophy as a contributing factor in strain differences in rat susceptibility to EAE

Nacka-Aleksić, M.; Stojanović, M.; Pilipović, Ivan; Kosec, Duško; Leposavić, Gordana

(2018)

TY  - CONF
AU  - Nacka-Aleksić, M.
AU  - Stojanović, M.
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Leposavić, Gordana
PY  - 2018
UR  - http://intor.torlakinstitut.com/handle/123456789/851
AB  - Introduction: It is suggested that impaired thymopoiesis in autoimmune diseases contributes to their perpetuation. To prove this hypothesis, influence of immunization for EAE on thymopoiesis and the putative thymic−dependent changes in the periphery were examined in susceptible (Dark Agouti, DA) and resistant (Albino Oxford, AO) rats. Methods: On the 13th day post−immunization, expression of differentiation/maturation markers of conventional T cells and regulatory CD4+Foxp3+CD25+ cells (nTregs) on thymocytes, their apoptosis and proliferation, frequency of recent thymic emigrants (RTEs) and CD28null cells in CD4+ and CD8+ peripheral blood lymphocytes (PBLs), and thymic expression and circulating levels of cytokines influencing thymus/thymopoiesis were investigated. Results: In rats of both strains increase in proinflammatory−cytokine circulating levels followed by thymic atrophy and changes at multiple thymocyte developmental points, leading to decreased number of the most mature CD4+ and CD8+ TCRaβhi thymocytes and frequency of RTEs among PBLs (as in chronobiological aging), was found. This was more prominent in DA rats. Consistently, compared with AO rats, in DA rats were found higher frequencies
of cytolitic CD28null cells (contributing to target tissue damage) among CD4+ PBLs and cytolitic granzyme B+ CD4+ T cells in spinal cord. Additionally, compared with non−immunized controls, DA rats exhibited greater decline in thymic nTreg generation (reflecting diminished thymic IL−7, IL−2 and IL−15 expression) than AO ones. Conclusions: The study suggests that differences in thymopoiesis, and consequently nTreg generation and CD4+CD28null cell frequency in the periphery, contribute to strain differences in EAE clinical presentation.
C3  - Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands
T1  - Immunization-induced thymic atrophy as a contributing factor in strain differences in rat susceptibility to EAE
SP  - P.A2.03.06
UR  - https://hdl.handle.net/21.15107/rcub_intor_851
ER  - 
@conference{
author = "Nacka-Aleksić, M. and Stojanović, M. and Pilipović, Ivan and Kosec, Duško and Leposavić, Gordana",
year = "2018",
abstract = "Introduction: It is suggested that impaired thymopoiesis in autoimmune diseases contributes to their perpetuation. To prove this hypothesis, influence of immunization for EAE on thymopoiesis and the putative thymic−dependent changes in the periphery were examined in susceptible (Dark Agouti, DA) and resistant (Albino Oxford, AO) rats. Methods: On the 13th day post−immunization, expression of differentiation/maturation markers of conventional T cells and regulatory CD4+Foxp3+CD25+ cells (nTregs) on thymocytes, their apoptosis and proliferation, frequency of recent thymic emigrants (RTEs) and CD28null cells in CD4+ and CD8+ peripheral blood lymphocytes (PBLs), and thymic expression and circulating levels of cytokines influencing thymus/thymopoiesis were investigated. Results: In rats of both strains increase in proinflammatory−cytokine circulating levels followed by thymic atrophy and changes at multiple thymocyte developmental points, leading to decreased number of the most mature CD4+ and CD8+ TCRaβhi thymocytes and frequency of RTEs among PBLs (as in chronobiological aging), was found. This was more prominent in DA rats. Consistently, compared with AO rats, in DA rats were found higher frequencies
of cytolitic CD28null cells (contributing to target tissue damage) among CD4+ PBLs and cytolitic granzyme B+ CD4+ T cells in spinal cord. Additionally, compared with non−immunized controls, DA rats exhibited greater decline in thymic nTreg generation (reflecting diminished thymic IL−7, IL−2 and IL−15 expression) than AO ones. Conclusions: The study suggests that differences in thymopoiesis, and consequently nTreg generation and CD4+CD28null cell frequency in the periphery, contribute to strain differences in EAE clinical presentation.",
journal = "Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands",
title = "Immunization-induced thymic atrophy as a contributing factor in strain differences in rat susceptibility to EAE",
pages = "P.A2.03.06",
url = "https://hdl.handle.net/21.15107/rcub_intor_851"
}
Nacka-Aleksić, M., Stojanović, M., Pilipović, I., Kosec, D.,& Leposavić, G.. (2018). Immunization-induced thymic atrophy as a contributing factor in strain differences in rat susceptibility to EAE. in Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands, P.A2.03.06.
https://hdl.handle.net/21.15107/rcub_intor_851
Nacka-Aleksić M, Stojanović M, Pilipović I, Kosec D, Leposavić G. Immunization-induced thymic atrophy as a contributing factor in strain differences in rat susceptibility to EAE. in Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands. 2018;:P.A2.03.06.
https://hdl.handle.net/21.15107/rcub_intor_851 .
Nacka-Aleksić, M., Stojanović, M., Pilipović, Ivan, Kosec, Duško, Leposavić, Gordana, "Immunization-induced thymic atrophy as a contributing factor in strain differences in rat susceptibility to EAE" in Abstracts of the 5th European Congress of Immunology - ECI 2018 - Amsterdam, The Netherlands (2018):P.A2.03.06,
https://hdl.handle.net/21.15107/rcub_intor_851 .

Sexual dimorphism in mechanisms controlling development of CD4+ T cell response in collagen-induced arthritis

Bufan, B.; Arsenović-Ranin, N.; Dimitrijević, M.; Nacka-Aleksić, M.; Kosec, Duško; Pilipović, Ivan; Stojanović, M.; Leposavić, Gordana

(2018)

TY  - CONF
AU  - Bufan, B.
AU  - Arsenović-Ranin, N.
AU  - Dimitrijević, M.
AU  - Nacka-Aleksić, M.
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Stojanović, M.
AU  - Leposavić, Gordana
PY  - 2018
UR  - http://intor.torlakinstitut.com/handle/123456789/850
AB  - Introduction: Considering sex bias in rheumatoid arthritis prevalence, influence of biological sex on the disease development in Dark Agouti rat collagen II (CII)−induced arthritis (CIA) model of the human disease was examined. Methods: Sex bias in CD4+ T cell responses in inguinal (draining the site of immunization in preclinical CIA) and popliteal (draining inflamed joints at the peak of CIA) lymph nodes (LNs) and mechanisms controlling their development were examined using flow cytometry and/or ELISA/qRT−PCR. Results: In both inguinal and popliteal LNs greater number of CD4+CD25+Foxp3− cells, presumably activated effector T cells, was found in females compared with males, and they exhibited greater CII−specific proliferation. Consistently, more IL−17+, IFN−γ+ and IL−17+IFN−γ+ T cells were retrieved from both inguinal and popliteal female rat LNs. Moreover, more GM−CSF+ and IL−17+IFN−γ+GM−CSF+ T cells were retrieved from female compared with male rat popliteal LNs. On the other hand, lower frequency of PD−1+ cells among CD4+CD25+Foxp3+ regulatory T cells (Tregs) from female popliteal and inguinal LNs suggested lower suppressive capacity of their Tregs. Additionally, from female rat popliteal LNs fewer Tregs were recovered. Furthermore, the number of regulatory LN B10 cells was lower in females. Moreover, compared with males, in females was shifted LN INF−γ+/IL−4+ T−cell ratio towards the former, and accordingly serum CII−specific IgG2a/IgG1 antibody ratio was shifted towards pathogenic IgG2a antibodies. Conclusion: The study suggests that a less efficient control of (auto)immune Th1/Th17 cell responses during CIA development contributes to sex bias in the susceptibility to CIA.
C3  - 5th European Congress of Immunology, Septembar 2-5, Abstract Book
T1  - Sexual dimorphism in mechanisms controlling development of CD4+ T cell response in collagen-induced arthritis
SP  - P.C1.01.02
UR  - https://hdl.handle.net/21.15107/rcub_intor_850
ER  - 
@conference{
author = "Bufan, B. and Arsenović-Ranin, N. and Dimitrijević, M. and Nacka-Aleksić, M. and Kosec, Duško and Pilipović, Ivan and Stojanović, M. and Leposavić, Gordana",
year = "2018",
abstract = "Introduction: Considering sex bias in rheumatoid arthritis prevalence, influence of biological sex on the disease development in Dark Agouti rat collagen II (CII)−induced arthritis (CIA) model of the human disease was examined. Methods: Sex bias in CD4+ T cell responses in inguinal (draining the site of immunization in preclinical CIA) and popliteal (draining inflamed joints at the peak of CIA) lymph nodes (LNs) and mechanisms controlling their development were examined using flow cytometry and/or ELISA/qRT−PCR. Results: In both inguinal and popliteal LNs greater number of CD4+CD25+Foxp3− cells, presumably activated effector T cells, was found in females compared with males, and they exhibited greater CII−specific proliferation. Consistently, more IL−17+, IFN−γ+ and IL−17+IFN−γ+ T cells were retrieved from both inguinal and popliteal female rat LNs. Moreover, more GM−CSF+ and IL−17+IFN−γ+GM−CSF+ T cells were retrieved from female compared with male rat popliteal LNs. On the other hand, lower frequency of PD−1+ cells among CD4+CD25+Foxp3+ regulatory T cells (Tregs) from female popliteal and inguinal LNs suggested lower suppressive capacity of their Tregs. Additionally, from female rat popliteal LNs fewer Tregs were recovered. Furthermore, the number of regulatory LN B10 cells was lower in females. Moreover, compared with males, in females was shifted LN INF−γ+/IL−4+ T−cell ratio towards the former, and accordingly serum CII−specific IgG2a/IgG1 antibody ratio was shifted towards pathogenic IgG2a antibodies. Conclusion: The study suggests that a less efficient control of (auto)immune Th1/Th17 cell responses during CIA development contributes to sex bias in the susceptibility to CIA.",
journal = "5th European Congress of Immunology, Septembar 2-5, Abstract Book",
title = "Sexual dimorphism in mechanisms controlling development of CD4+ T cell response in collagen-induced arthritis",
pages = "P.C1.01.02",
url = "https://hdl.handle.net/21.15107/rcub_intor_850"
}
Bufan, B., Arsenović-Ranin, N., Dimitrijević, M., Nacka-Aleksić, M., Kosec, D., Pilipović, I., Stojanović, M.,& Leposavić, G.. (2018). Sexual dimorphism in mechanisms controlling development of CD4+ T cell response in collagen-induced arthritis. in 5th European Congress of Immunology, Septembar 2-5, Abstract Book, P.C1.01.02.
https://hdl.handle.net/21.15107/rcub_intor_850
Bufan B, Arsenović-Ranin N, Dimitrijević M, Nacka-Aleksić M, Kosec D, Pilipović I, Stojanović M, Leposavić G. Sexual dimorphism in mechanisms controlling development of CD4+ T cell response in collagen-induced arthritis. in 5th European Congress of Immunology, Septembar 2-5, Abstract Book. 2018;:P.C1.01.02.
https://hdl.handle.net/21.15107/rcub_intor_850 .
Bufan, B., Arsenović-Ranin, N., Dimitrijević, M., Nacka-Aleksić, M., Kosec, Duško, Pilipović, Ivan, Stojanović, M., Leposavić, Gordana, "Sexual dimorphism in mechanisms controlling development of CD4+ T cell response in collagen-induced arthritis" in 5th European Congress of Immunology, Septembar 2-5, Abstract Book (2018):P.C1.01.02,
https://hdl.handle.net/21.15107/rcub_intor_850 .