TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Petrušić, Marija
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5411
AB  - INTRODUCTION: Considering significance of mechanisms of central tolerance for development of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), and suppressive influence of circulating proinflammatory cytokines and alterations in brain-thymus communication, characteristic for the central nervous system (CNS) autoimmune diseases, on thymopoiesis, the study interogated putative strain-based thymus-related specificities relevant for the opposite effects of ageing on susceptibility of Dark Agouti (DA) and Albino Oxford (AO) rats to EAE. METHODS: Quantitative and qualitative changes in thymopoiesis including underlying mechanisms were examined using flow cytometry and RT-qPCR quantification of mRNAs for molecules relevant for integrity of stroma and T-cell development, respectively. RESULTS: With ageing, differently from DA rats, in AO rats the surface density of CD90, a negative regulator of selection threshold, on thymocytes undergoing lineage commitment was upregulated (consistent with TGF-β expression downregulation), whereas the generation of natural CD4+CD25+Foxp3+ regulatory T cells (nTregs) was impaired reflecting differences in thymic expression of cytokines supporting their development. Additionally, specifically in old AO rats, in whom EAE development depends on IL-17-producing CD8+ T cells, their thymic differentiation was augmented, reflecting augmented thymic IL-4 expression. In turn, differently from old DA rats developing self-limiting EAE, in age-matched AO rats developing EAE of prolonged duration, EAE development led to impaired generation of nTregs and accumulation of proinflammatory, cytotoxic CD28-CD4+ T cells in the periphery. DISCUSSION: The study indicates that strain differences in age-related changes in the efficacy of central tolerance, in addition to enhanced thymic generation of CD8+ T cells prone to differentiate into IL-17-producing cells, could partly explain the opposite effect of ageing on DA and AO rat susceptibility to EAE induction. Additionally, it suggested that EAE development leading to a less efficient thymic output of CD4+ cells and nTregs in old AO rats than their DA counterparts could contribute to prolonged EAE duration in AO compared with DA rats. CONCLUSION: The study warns to caution when designing therapeutic interventions to enhance thymic activity in genetically diverse populations, e.g., humans, and interpreting their outcomes. Furthermore, it indicates that CNS autoimmune pathology may additionally worsen thymic involution and age-related immune changes.
PB  - S. Karger AG, Basel.
T2  - Neuroimmunomodulation
T1  - Ageing Affects Thymopoiesis and Experimental Autoimmune Encephalomyelitis Development in a Strain-Dependent Manner
VL  - 30
IS  - 1
SP  - 346
EP  - 373
DO  - 10.1159/000535150
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Petrušić, Marija and Pilipović, Ivan and Leposavić, Gordana",
year = "2023",
abstract = "INTRODUCTION: Considering significance of mechanisms of central tolerance for development of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), and suppressive influence of circulating proinflammatory cytokines and alterations in brain-thymus communication, characteristic for the central nervous system (CNS) autoimmune diseases, on thymopoiesis, the study interogated putative strain-based thymus-related specificities relevant for the opposite effects of ageing on susceptibility of Dark Agouti (DA) and Albino Oxford (AO) rats to EAE. METHODS: Quantitative and qualitative changes in thymopoiesis including underlying mechanisms were examined using flow cytometry and RT-qPCR quantification of mRNAs for molecules relevant for integrity of stroma and T-cell development, respectively. RESULTS: With ageing, differently from DA rats, in AO rats the surface density of CD90, a negative regulator of selection threshold, on thymocytes undergoing lineage commitment was upregulated (consistent with TGF-β expression downregulation), whereas the generation of natural CD4+CD25+Foxp3+ regulatory T cells (nTregs) was impaired reflecting differences in thymic expression of cytokines supporting their development. Additionally, specifically in old AO rats, in whom EAE development depends on IL-17-producing CD8+ T cells, their thymic differentiation was augmented, reflecting augmented thymic IL-4 expression. In turn, differently from old DA rats developing self-limiting EAE, in age-matched AO rats developing EAE of prolonged duration, EAE development led to impaired generation of nTregs and accumulation of proinflammatory, cytotoxic CD28-CD4+ T cells in the periphery. DISCUSSION: The study indicates that strain differences in age-related changes in the efficacy of central tolerance, in addition to enhanced thymic generation of CD8+ T cells prone to differentiate into IL-17-producing cells, could partly explain the opposite effect of ageing on DA and AO rat susceptibility to EAE induction. Additionally, it suggested that EAE development leading to a less efficient thymic output of CD4+ cells and nTregs in old AO rats than their DA counterparts could contribute to prolonged EAE duration in AO compared with DA rats. CONCLUSION: The study warns to caution when designing therapeutic interventions to enhance thymic activity in genetically diverse populations, e.g., humans, and interpreting their outcomes. Furthermore, it indicates that CNS autoimmune pathology may additionally worsen thymic involution and age-related immune changes.",
publisher = "S. Karger AG, Basel.",
journal = "Neuroimmunomodulation",
title = "Ageing Affects Thymopoiesis and Experimental Autoimmune Encephalomyelitis Development in a Strain-Dependent Manner",
volume = "30",
number = "1",
pages = "346-373",
doi = "10.1159/000535150"
}

Stojić-Vukanić, Z., Petrušić, M., Pilipović, I.,& Leposavić, G.. (2023). Ageing Affects Thymopoiesis and Experimental Autoimmune Encephalomyelitis Development in a Strain-Dependent Manner. in Neuroimmunomodulation
S. Karger AG, Basel.., 30(1), 346-373.
https://doi.org/10.1159/000535150

Stojić-Vukanić Z, Petrušić M, Pilipović I, Leposavić G. Ageing Affects Thymopoiesis and Experimental Autoimmune Encephalomyelitis Development in a Strain-Dependent Manner. in Neuroimmunomodulation. 2023;30(1):346-373.
doi:10.1159/000535150 .

Stojić-Vukanić, Zorica, Petrušić, Marija, Pilipović, Ivan, Leposavić, Gordana, "Ageing Affects Thymopoiesis and Experimental Autoimmune Encephalomyelitis Development in a Strain-Dependent Manner" in Neuroimmunomodulation, 30, no. 1 (2023):346-373,
https://doi.org/10.1159/000535150 . .

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4470
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 Inc.
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 Inc.",
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 Inc.., 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 . .

TY  - JOUR
AU  - Petrušić, Marija
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Prijić, Ivana
AU  - Leposavić, Gordana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4316
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 Inc.
T2  - Experimental Gerontology
T1  - Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development
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 Inc.",
journal = "Experimental Gerontology",
title = "Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development",
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 Inc.., 171.
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.
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),
https://doi.org/10.1016/j.exger.2022.112009 . .

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
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 . .

TY  - JOUR
AU  - Bufan, Biljana
AU  - Arsenović-Ranin, Nevena
AU  - Živković, Irena
AU  - Petrović, Raisa
AU  - Leposavić, Gordana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4109
AB  - Aims: Given that deprivation of noradrenaline acting on lymphocytes through β-adrenoceptor influences anti- body response, the effects of propranolol treatment beginning two days before immunization with quadrivalent inactivated influenza vaccine (QIV) on IgG response and underlying cellular molecular mechanism in mice were investigated. Main methods: Twenty-one days post-immunization the total QIV antigen-specific IgG titer and IgG subclass titers in sera were determined using ELISA. Additionally, the total counts of germinal centre (GC) B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in draining lymph nodes (dLNs) and spleens, in vitro prolif- eration of interacting B cells and Th cells and IL-21 synthesis in Th cells in response to QIV antigens and/or mitogen were attested using flow cytometry analysis. In QIV antigen-stimulated dLN cell and splenocyte cultures were also measured concentrations of INF-γ and IL-4, cytokines upregulating IgG2a and IgG1 synthesis, respectively. Key findings: Propranolol decreased the total QIV antigen-specific IgG titer. This correlated with lower GC B cell count and the shift in Tfr/Tfh cell and Tfr/GC B cell ratio towards Tfr in propranolol-treated mice compared with controls. Consistently, QIV antigen-stimulated proliferation of B cells and Th cells from propranolol-treated mice in vitro was impaired. This correlated with the lower frequency of QIV antigen-specific IL-21-producing cells among Th cells. Additionally, in propranolol-treated mice, in accordance with the changes in INF-γ/IL-4 ratio in dLN cell/splenocyte cultures, serum IgG2a/IgG1 ratio was shifted towards IgG1 reflecting decreased IgG2a response. Significance: The study indicates that chronic propranolol treatment may impair response to QIV.
PB  - Elsevier Inc.
T2  - Life Sciences
T1  - B-cell response to seasonal influenza vaccine in mice is amenable to pharmacological modulation through β-adrenoceptor
VL  - 301
DO  - 10.1016/j.lfs.2022.120617
ER  - 

@article{
author = "Bufan, Biljana and Arsenović-Ranin, Nevena and Živković, Irena and Petrović, Raisa and Leposavić, Gordana",
year = "2022",
abstract = "Aims: Given that deprivation of noradrenaline acting on lymphocytes through β-adrenoceptor influences anti- body response, the effects of propranolol treatment beginning two days before immunization with quadrivalent inactivated influenza vaccine (QIV) on IgG response and underlying cellular molecular mechanism in mice were investigated. Main methods: Twenty-one days post-immunization the total QIV antigen-specific IgG titer and IgG subclass titers in sera were determined using ELISA. Additionally, the total counts of germinal centre (GC) B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in draining lymph nodes (dLNs) and spleens, in vitro prolif- eration of interacting B cells and Th cells and IL-21 synthesis in Th cells in response to QIV antigens and/or mitogen were attested using flow cytometry analysis. In QIV antigen-stimulated dLN cell and splenocyte cultures were also measured concentrations of INF-γ and IL-4, cytokines upregulating IgG2a and IgG1 synthesis, respectively. Key findings: Propranolol decreased the total QIV antigen-specific IgG titer. This correlated with lower GC B cell count and the shift in Tfr/Tfh cell and Tfr/GC B cell ratio towards Tfr in propranolol-treated mice compared with controls. Consistently, QIV antigen-stimulated proliferation of B cells and Th cells from propranolol-treated mice in vitro was impaired. This correlated with the lower frequency of QIV antigen-specific IL-21-producing cells among Th cells. Additionally, in propranolol-treated mice, in accordance with the changes in INF-γ/IL-4 ratio in dLN cell/splenocyte cultures, serum IgG2a/IgG1 ratio was shifted towards IgG1 reflecting decreased IgG2a response. Significance: The study indicates that chronic propranolol treatment may impair response to QIV.",
publisher = "Elsevier Inc.",
journal = "Life Sciences",
title = "B-cell response to seasonal influenza vaccine in mice is amenable to pharmacological modulation through β-adrenoceptor",
volume = "301",
doi = "10.1016/j.lfs.2022.120617"
}

Bufan, B., Arsenović-Ranin, N., Živković, I., Petrović, R.,& Leposavić, G.. (2022). B-cell response to seasonal influenza vaccine in mice is amenable to pharmacological modulation through β-adrenoceptor. in Life Sciences
Elsevier Inc.., 301.
https://doi.org/10.1016/j.lfs.2022.120617

Bufan B, Arsenović-Ranin N, Živković I, Petrović R, Leposavić G. B-cell response to seasonal influenza vaccine in mice is amenable to pharmacological modulation through β-adrenoceptor. in Life Sciences. 2022;301.
doi:10.1016/j.lfs.2022.120617 .

Bufan, Biljana, Arsenović-Ranin, Nevena, Živković, Irena, Petrović, Raisa, Leposavić, Gordana, "B-cell response to seasonal influenza vaccine in mice is amenable to pharmacological modulation through β-adrenoceptor" in Life Sciences, 301 (2022),
https://doi.org/10.1016/j.lfs.2022.120617 . .

TY  - CONF
AU  - Petrušić, Marija
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5088
AB  - Multiple studies reveal differences in the phenotype and function of tolerogenic dendritic cells (tolDCs) depending on a tolerizing compound used during DC induction towards tolDCs. ...
PB  - Wiley-VCH GmbH
C3  - European Journal of Immunology
T1  - Alterations in hemopoiesis in old albino oxford rats contribute  to their increased susceptibility to EAE
VL  - 52
IS  - Suppl. 2
SP  - 103
EP  - 103
DO  - 10.1002/eji.202270200
ER  - 

@conference{
author = "Petrušić, Marija and Stojić-Vukanić, Zorica and Pilipović, Ivan and Leposavić, Gordana",
year = "2022",
abstract = "Multiple studies reveal differences in the phenotype and function of tolerogenic dendritic cells (tolDCs) depending on a tolerizing compound used during DC induction towards tolDCs. ...",
publisher = "Wiley-VCH GmbH",
journal = "European Journal of Immunology",
title = "Alterations in hemopoiesis in old albino oxford rats contribute  to their increased susceptibility to EAE",
volume = "52",
number = "Suppl. 2",
pages = "103-103",
doi = "10.1002/eji.202270200"
}

Petrušić, M., Stojić-Vukanić, Z., Pilipović, I.,& Leposavić, G.. (2022). Alterations in hemopoiesis in old albino oxford rats contribute  to their increased susceptibility to EAE. in European Journal of Immunology
Wiley-VCH GmbH., 52(Suppl. 2), 103-103.
https://doi.org/10.1002/eji.202270200

Petrušić M, Stojić-Vukanić Z, Pilipović I, Leposavić G. Alterations in hemopoiesis in old albino oxford rats contribute  to their increased susceptibility to EAE. in European Journal of Immunology. 2022;52(Suppl. 2):103-103.
doi:10.1002/eji.202270200 .

Petrušić, Marija, Stojić-Vukanić, Zorica, Pilipović, Ivan, Leposavić, Gordana, "Alterations in hemopoiesis in old albino oxford rats contribute  to their increased susceptibility to EAE" in European Journal of Immunology, 52, no. Suppl. 2 (2022):103-103,
https://doi.org/10.1002/eji.202270200 . .

TY  - JOUR
AU  - Leposavić, Gordana
AU  - Stojić-Vukanić, Zorica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4184
AB  - It has been well-established that age-associated low-grade chronic inflammation
contributes to the development of a spectrum of chronic diseases, including diabetes mellitus,
ischemic heart disease, stroke, cancer, chronic kidney disease, non-alcoholic fatty liver disease
and neurodegenerative diseases, which affect the quality of life of the elderly and influence their
life span. This phenomenon is suggested to arise due to the weakening of the regulatory
mechanisms of the immune response, and the persistence of exogenous and endogenous
(reflecting oxidative cell injury) antigenic challenges, so it is referred to as oxi-inflamm-aging.
Considering that the development of age-associated chronic inflammation is “silent”, i.e., without
clinical signs until the aforementioned complications become apparent, it is important to identify
the biomarker(s) or pattern/cluster of biomarkers for this inflammation. It is also important to
define new strategies to combat the “silent” damage induced by chronic inflammation. Given that
at present there are no reliable biomarkers for chronic inflammation, this review points out the
problems in defining biomarker(s) or patterns/clusters of biomarkers for chronic inflammation in
order to stimulate further research and points to some possible routes of investigation.
AB  - Činjenično je dobro argumentovano da hronična inflamacija niskog stepena koja se javlja u toku starenja ima važnu ulogu u razvoju čitavog spektra hroničnih bolesti, uključujući šećernu bolest, ishemijsku bolest srca, moždani udar, malignu bolest, hronično oštećenje bubrega, nealkoholnu masnu bolest jetre, neurodegenerativne i autoimunske bolesti, koje utiču na kvalitet i dužinu života starih osoba. Smatra se da ovaj fenomen nastaje kao rezultat slabljenja regulatornih mehanizama imunskog sistema i perzistentnog izlaganja organizma delovanju egzogenih i endogenih (generisanih oštećenjem ćelija oksidativnim stresom) antigenskih izazova, što se u literaturi opisuje terminom oksidativno-inflamatorno starenje. Imajući u vidu da se hronična inflamacija razvija klinički "nemo", odnosno da postaje manifestna tek kada se razviju prethodno pomenute komplikacije, jasno je koliko je važno identifikovati biomarker(e) ili obrasce/klastere biomarkera te inflamacije. S obzirom na to da u ovom trenutku nema pouzdanih markera hronične inflamacije, ovaj pregledni rad je tako koncipiran da ukaže na probleme u identifikaciji biomarkera ili obrazaca/klastera biomarkera hronične inflamacije, s ciljem da stimuliše dalja istraživanja, ali i da da smernice za buduća istraživanja.
PB  - Beograd : Savez farmaceutskih udruženja Srbije
T2  - Arhiv za farmaciju
T1  - Biomarkers of aging-associated chronic inflammation as a prognostic factor for human longevity
T1  - Biomarkeri hronične inflamacije povezane sa starenjem kao prediktora dužine života
VL  - 72
IS  - 2
SP  - 91
EP  - 104
DO  - 10.5937/arhfarm72-36135
ER  - 

@article{
author = "Leposavić, Gordana and Stojić-Vukanić, Zorica",
year = "2022",
abstract = "It has been well-established that age-associated low-grade chronic inflammation
contributes to the development of a spectrum of chronic diseases, including diabetes mellitus,
ischemic heart disease, stroke, cancer, chronic kidney disease, non-alcoholic fatty liver disease
and neurodegenerative diseases, which affect the quality of life of the elderly and influence their
life span. This phenomenon is suggested to arise due to the weakening of the regulatory
mechanisms of the immune response, and the persistence of exogenous and endogenous
(reflecting oxidative cell injury) antigenic challenges, so it is referred to as oxi-inflamm-aging.
Considering that the development of age-associated chronic inflammation is “silent”, i.e., without
clinical signs until the aforementioned complications become apparent, it is important to identify
the biomarker(s) or pattern/cluster of biomarkers for this inflammation. It is also important to
define new strategies to combat the “silent” damage induced by chronic inflammation. Given that
at present there are no reliable biomarkers for chronic inflammation, this review points out the
problems in defining biomarker(s) or patterns/clusters of biomarkers for chronic inflammation in
order to stimulate further research and points to some possible routes of investigation., Činjenično je dobro argumentovano da hronična inflamacija niskog stepena koja se javlja u toku starenja ima važnu ulogu u razvoju čitavog spektra hroničnih bolesti, uključujući šećernu bolest, ishemijsku bolest srca, moždani udar, malignu bolest, hronično oštećenje bubrega, nealkoholnu masnu bolest jetre, neurodegenerativne i autoimunske bolesti, koje utiču na kvalitet i dužinu života starih osoba. Smatra se da ovaj fenomen nastaje kao rezultat slabljenja regulatornih mehanizama imunskog sistema i perzistentnog izlaganja organizma delovanju egzogenih i endogenih (generisanih oštećenjem ćelija oksidativnim stresom) antigenskih izazova, što se u literaturi opisuje terminom oksidativno-inflamatorno starenje. Imajući u vidu da se hronična inflamacija razvija klinički "nemo", odnosno da postaje manifestna tek kada se razviju prethodno pomenute komplikacije, jasno je koliko je važno identifikovati biomarker(e) ili obrasce/klastere biomarkera te inflamacije. S obzirom na to da u ovom trenutku nema pouzdanih markera hronične inflamacije, ovaj pregledni rad je tako koncipiran da ukaže na probleme u identifikaciji biomarkera ili obrazaca/klastera biomarkera hronične inflamacije, s ciljem da stimuliše dalja istraživanja, ali i da da smernice za buduća istraživanja.",
publisher = "Beograd : Savez farmaceutskih udruženja Srbije",
journal = "Arhiv za farmaciju",
title = "Biomarkers of aging-associated chronic inflammation as a prognostic factor for human longevity, Biomarkeri hronične inflamacije povezane sa starenjem kao prediktora dužine života",
volume = "72",
number = "2",
pages = "91-104",
doi = "10.5937/arhfarm72-36135"
}

Leposavić, G.,& Stojić-Vukanić, Z.. (2022). Biomarkers of aging-associated chronic inflammation as a prognostic factor for human longevity. in Arhiv za farmaciju
Beograd : Savez farmaceutskih udruženja Srbije., 72(2), 91-104.
https://doi.org/10.5937/arhfarm72-36135

Leposavić G, Stojić-Vukanić Z. Biomarkers of aging-associated chronic inflammation as a prognostic factor for human longevity. in Arhiv za farmaciju. 2022;72(2):91-104.
doi:10.5937/arhfarm72-36135 .

Leposavić, Gordana, Stojić-Vukanić, Zorica, "Biomarkers of aging-associated chronic inflammation as a prognostic factor for human longevity" in Arhiv za farmaciju, 72, no. 2 (2022):91-104,
https://doi.org/10.5937/arhfarm72-36135 . .

TY  - CONF
AU  - Pilipović, Ivan
AU  - Prijić, Ivana
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4724
AB  - Our previous studies showed more severe EAE in male compared with female adult rats, and moderating effect of propranolol‐induced β‐adrenoceptor blockade on EAE in female rats through stimulation of Nrf2/HO‐1 signalling pathway in spinal cord microglia. This study was designed to examine putative sexual dimorphism in Nrf2/HO‐1 signalling pathway and CX3CL1, as one of its activators. Propranolol treatment beginning from the appearance of the first clinical signs of EAE mitigated the disease severity in rats of both sexes, but its effect was more prominent in males. This correlated with more prominent effect of propranolol on the expression of CX3CL1 in spinal cord tissue, CX3CR1 on microglial surface, and Nrf2/HO‐1 in spinal cord microglia in males. Consistently, the proportion of CX3CR1‐expressing microglia and CX3CR1 density on their surface increased more prominently in males. 
Consistently, propranolol increased the proportion of IL‐10/TGF‐β‐producing microglia and microglia expressing CD163, molecule highlighting ramified microglia with neuroprotective 
properties in damaged tissue, to a greater extent in males. Additionally, propranolol increased phagocyting capacity of microglia to a greater extent in males. Moreover, propranolol more prominently decreased the frequency of blood‐borne myeloid cells and highly pathogenic IL‐17+ T‐cells, coexpressing GM‐CSF/IFN‐γ, in male rat spinal cord. This correlated with greater reducing effect of propranolol on the spinal cord tissue expression of CCL2/CCL19/CCL21 chemokines in males. The study as a whole indicates that sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis could contribute to greater severity of EAE in male rats, and sexually dimorphic action of substances affecting its signalling capacity.
C3  - European Journal of Immunology
T1  - Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats
VL  - 51
IS  - Suppl.1
SP  - 246
EP  - 246
DO  - 10.1002/eji.202170200
ER  - 

@conference{
author = "Pilipović, Ivan and Prijić, Ivana and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2021",
abstract = "Our previous studies showed more severe EAE in male compared with female adult rats, and moderating effect of propranolol‐induced β‐adrenoceptor blockade on EAE in female rats through stimulation of Nrf2/HO‐1 signalling pathway in spinal cord microglia. This study was designed to examine putative sexual dimorphism in Nrf2/HO‐1 signalling pathway and CX3CL1, as one of its activators. Propranolol treatment beginning from the appearance of the first clinical signs of EAE mitigated the disease severity in rats of both sexes, but its effect was more prominent in males. This correlated with more prominent effect of propranolol on the expression of CX3CL1 in spinal cord tissue, CX3CR1 on microglial surface, and Nrf2/HO‐1 in spinal cord microglia in males. Consistently, the proportion of CX3CR1‐expressing microglia and CX3CR1 density on their surface increased more prominently in males. 
Consistently, propranolol increased the proportion of IL‐10/TGF‐β‐producing microglia and microglia expressing CD163, molecule highlighting ramified microglia with neuroprotective 
properties in damaged tissue, to a greater extent in males. Additionally, propranolol increased phagocyting capacity of microglia to a greater extent in males. Moreover, propranolol more prominently decreased the frequency of blood‐borne myeloid cells and highly pathogenic IL‐17+ T‐cells, coexpressing GM‐CSF/IFN‐γ, in male rat spinal cord. This correlated with greater reducing effect of propranolol on the spinal cord tissue expression of CCL2/CCL19/CCL21 chemokines in males. The study as a whole indicates that sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis could contribute to greater severity of EAE in male rats, and sexually dimorphic action of substances affecting its signalling capacity.",
journal = "European Journal of Immunology",
title = "Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats",
volume = "51",
number = "Suppl.1",
pages = "246-246",
doi = "10.1002/eji.202170200"
}

Pilipović, I., Prijić, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2021). Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats. in European Journal of Immunology, 51(Suppl.1), 246-246.
https://doi.org/10.1002/eji.202170200

Pilipović I, Prijić I, Stojić-Vukanić Z, Leposavić G. Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats. in European Journal of Immunology. 2021;51(Suppl.1):246-246.
doi:10.1002/eji.202170200 .

Pilipović, Ivan, Prijić, Ivana, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats" in European Journal of Immunology, 51, no. Suppl.1 (2021):246-246,
https://doi.org/10.1002/eji.202170200 . .

TY  - JOUR
AU  - Đuretić, Jasmina
AU  - Dimitrijević, Mirjana
AU  - Stojanović, Marija
AU  - Kotur-Stevuljević, Jelena
AU  - Hamblin, Michael R.
AU  - Micov, Ana
AU  - Stepanović-Petrović, Radica
AU  - Leposavić, Gordana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3781
AB  - The development of collagen type II (CII)-induced arthritis (CIA), a model of rheumatoid arthritis, in rats housed in cages with bedding composed of Celliant fibres containing ceramic particles, which absorb body heat and re-emit the energy back to the body in the form of infrared radiation (+IRF rats), and those housed in cages with standard wooden shaving bedding (−IRF control rats) was examined. The appearance of the first signs of CIA was postponed, while the disease was milder (judging by the arthritic score, paw volume, and burrowing behaviour) in +IRF compared with −IRF rats. This correlated with a lower magnitude of serum anti-CII IgG antibody levels in +IRF rats, and lower production level of IL-17, the Th17 signature cytokine, in cultures of their paws. This could be partly ascribed to impaired migration of antigen-loaded CD11b + dendritic cells and their positioning within lymph nodes in +IRF rats reflecting diminished lymph node expression of CCL19 /CCL21. Additionally, as confirmed in rats with carrageenan-induced paw inflammation (CIPI), the infrared radiation from Celliant fibres, independently from immunomodulatory effects, exerted anti-inflammatory effects (judging by a shift in pro-inflammatory mediator to anti-inflammatory/immunoregulatory mediator ratio towards the latter in paw cultures) and ameliorated burrowing behaviour in CIA rats.
PB  - Nature Research
T2  - Scientific Reports
T1  - Infrared radiation from cage bedding moderates rat inflammatory and autoimmune responses in collagen-induced arthritis
VL  - 11
IS  - 1
DO  - 10.1038/s41598-021-81999-7
ER  - 

@article{
author = "Đuretić, Jasmina and Dimitrijević, Mirjana and Stojanović, Marija and Kotur-Stevuljević, Jelena and Hamblin, Michael R. and Micov, Ana and Stepanović-Petrović, Radica and Leposavić, Gordana",
year = "2021",
abstract = "The development of collagen type II (CII)-induced arthritis (CIA), a model of rheumatoid arthritis, in rats housed in cages with bedding composed of Celliant fibres containing ceramic particles, which absorb body heat and re-emit the energy back to the body in the form of infrared radiation (+IRF rats), and those housed in cages with standard wooden shaving bedding (−IRF control rats) was examined. The appearance of the first signs of CIA was postponed, while the disease was milder (judging by the arthritic score, paw volume, and burrowing behaviour) in +IRF compared with −IRF rats. This correlated with a lower magnitude of serum anti-CII IgG antibody levels in +IRF rats, and lower production level of IL-17, the Th17 signature cytokine, in cultures of their paws. This could be partly ascribed to impaired migration of antigen-loaded CD11b + dendritic cells and their positioning within lymph nodes in +IRF rats reflecting diminished lymph node expression of CCL19 /CCL21. Additionally, as confirmed in rats with carrageenan-induced paw inflammation (CIPI), the infrared radiation from Celliant fibres, independently from immunomodulatory effects, exerted anti-inflammatory effects (judging by a shift in pro-inflammatory mediator to anti-inflammatory/immunoregulatory mediator ratio towards the latter in paw cultures) and ameliorated burrowing behaviour in CIA rats.",
publisher = "Nature Research",
journal = "Scientific Reports",
title = "Infrared radiation from cage bedding moderates rat inflammatory and autoimmune responses in collagen-induced arthritis",
volume = "11",
number = "1",
doi = "10.1038/s41598-021-81999-7"
}

Đuretić, J., Dimitrijević, M., Stojanović, M., Kotur-Stevuljević, J., Hamblin, M. R., Micov, A., Stepanović-Petrović, R.,& Leposavić, G.. (2021). Infrared radiation from cage bedding moderates rat inflammatory and autoimmune responses in collagen-induced arthritis. in Scientific Reports
Nature Research., 11(1).
https://doi.org/10.1038/s41598-021-81999-7

Đuretić J, Dimitrijević M, Stojanović M, Kotur-Stevuljević J, Hamblin MR, Micov A, Stepanović-Petrović R, Leposavić G. Infrared radiation from cage bedding moderates rat inflammatory and autoimmune responses in collagen-induced arthritis. in Scientific Reports. 2021;11(1).
doi:10.1038/s41598-021-81999-7 .

Đuretić, Jasmina, Dimitrijević, Mirjana, Stojanović, Marija, Kotur-Stevuljević, Jelena, Hamblin, Michael R., Micov, Ana, Stepanović-Petrović, Radica, Leposavić, Gordana, "Infrared radiation from cage bedding moderates rat inflammatory and autoimmune responses in collagen-induced arthritis" in Scientific Reports, 11, no. 1 (2021),
https://doi.org/10.1038/s41598-021-81999-7 . .

TY  - CONF
AU  - Bufan, Biljana
AU  - Arsenović-Ranin, Nevena
AU  - Petrović, Raisa
AU  - Živković, Irena
AU  - Leposavić, Gordana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4725
AB  - The study was undertaken considering importance of antibody response for influenza vaccine efficacy and data indicating that β2‐adrenoceptor stimulation may affect antibody generation. To elucidate influence of β‐adrenoceptor‐mediated signaling on antibody response to QIV, serum titers of QIV‐specific IgG and draining lymph node and splenic germinal center (GC) reaction to QIV were examined in BALB/c mice treated with propranolol, non‐selective β‐adrenoceptor blocker, or vehicle (controls) daily, beginning two days before immunization. Four weeks after immunization IgG antibody titer was decreased in propranolol‐treated mice. This correlated with lower frequency of GC B cells in lymphoid organs of propranolol‐treated mice, and their diminished proliferation upon restimulation with QIV antigens in culture. Consistently, Tfh/Tfr cell ratio was shifted towards the latter in propranolol‐treated mice. This correlated with lower frequency of QIV‐specific CD4+ cells that produce IL‐21, the key regulator of GC reaction, in lymphoid organs of propranolol‐ 
treated mice, as suggested by in vitro recall test. Additionally, propranolol treatment shifted IgG1/IgG2a antibody ratio towards IgG1 antibody (contributing mainly to the virus clearance). This was consistent with the shift in IFN‐γ/IL‐4 ratio to the site of IL‐4 in QIV‐stimulated splenocyte cultures from propranolol‐treated mice compared with controls. Thus, the study suggests that chronic administration of propranolol, drug widely used for cardiovascular pathology, and recently repurposed for several other pathologies, including cancer, rheumatoid arthritis, and anxiety may impair efficacy of QIV by affecting CD4+ T‐cell cytokine secretory profile and thereby overall efficacy of Tfh help to B cells, and its influence on IgG subclass switching pattern.
C3  - European Journal of Immunology
T1  - β‐adrenoceptor blockade affects the germinal center B cell response to seasonal quadrivalent inactivated influenza vaccine (QIV) in mice
VL  - 51
IS  - Suppl.1
SP  - 305
EP  - 305
DO  - 10.1002/eji.202170200
ER  - 

@conference{
author = "Bufan, Biljana and Arsenović-Ranin, Nevena and Petrović, Raisa and Živković, Irena and Leposavić, Gordana",
year = "2021",
abstract = "The study was undertaken considering importance of antibody response for influenza vaccine efficacy and data indicating that β2‐adrenoceptor stimulation may affect antibody generation. To elucidate influence of β‐adrenoceptor‐mediated signaling on antibody response to QIV, serum titers of QIV‐specific IgG and draining lymph node and splenic germinal center (GC) reaction to QIV were examined in BALB/c mice treated with propranolol, non‐selective β‐adrenoceptor blocker, or vehicle (controls) daily, beginning two days before immunization. Four weeks after immunization IgG antibody titer was decreased in propranolol‐treated mice. This correlated with lower frequency of GC B cells in lymphoid organs of propranolol‐treated mice, and their diminished proliferation upon restimulation with QIV antigens in culture. Consistently, Tfh/Tfr cell ratio was shifted towards the latter in propranolol‐treated mice. This correlated with lower frequency of QIV‐specific CD4+ cells that produce IL‐21, the key regulator of GC reaction, in lymphoid organs of propranolol‐ 
treated mice, as suggested by in vitro recall test. Additionally, propranolol treatment shifted IgG1/IgG2a antibody ratio towards IgG1 antibody (contributing mainly to the virus clearance). This was consistent with the shift in IFN‐γ/IL‐4 ratio to the site of IL‐4 in QIV‐stimulated splenocyte cultures from propranolol‐treated mice compared with controls. Thus, the study suggests that chronic administration of propranolol, drug widely used for cardiovascular pathology, and recently repurposed for several other pathologies, including cancer, rheumatoid arthritis, and anxiety may impair efficacy of QIV by affecting CD4+ T‐cell cytokine secretory profile and thereby overall efficacy of Tfh help to B cells, and its influence on IgG subclass switching pattern.",
journal = "European Journal of Immunology",
title = "β‐adrenoceptor blockade affects the germinal center B cell response to seasonal quadrivalent inactivated influenza vaccine (QIV) in mice",
volume = "51",
number = "Suppl.1",
pages = "305-305",
doi = "10.1002/eji.202170200"
}

Bufan, B., Arsenović-Ranin, N., Petrović, R., Živković, I.,& Leposavić, G.. (2021). β‐adrenoceptor blockade affects the germinal center B cell response to seasonal quadrivalent inactivated influenza vaccine (QIV) in mice. in European Journal of Immunology, 51(Suppl.1), 305-305.
https://doi.org/10.1002/eji.202170200

Bufan B, Arsenović-Ranin N, Petrović R, Živković I, Leposavić G. β‐adrenoceptor blockade affects the germinal center B cell response to seasonal quadrivalent inactivated influenza vaccine (QIV) in mice. in European Journal of Immunology. 2021;51(Suppl.1):305-305.
doi:10.1002/eji.202170200 .

Bufan, Biljana, Arsenović-Ranin, Nevena, Petrović, Raisa, Živković, Irena, Leposavić, Gordana, "β‐adrenoceptor blockade affects the germinal center B cell response to seasonal quadrivalent inactivated influenza vaccine (QIV) in mice" in European Journal of Immunology, 51, no. Suppl.1 (2021):305-305,
https://doi.org/10.1002/eji.202170200 . .

TY  - CONF
AU  - Prijić, Ivana
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5089
AB  - Претпоставља се да дисфункција симпатичког нервног система 
доприноси развоју мултипле склерозе и експерименталног аутоимунског 
енцефаломијелитиса (ЕАЕ). Имајући у виду важност микроглије за 
развој/резолуцију неуроинфламације, испитиван је имуномодулаторни 
потенцијал главног симпатичког медијатора норадреналина коришћењем 
пацовског модела ЕАЕ-а. Резултати су показали да третман пропранололом, 
неселективним блокатором β-адренергичких рецептора, у ефекторској 
фази ЕАЕ-а смањује тежину болести. Ово је корелирало са повећаном 
заступљеношћу микроглије која експримира CX3CR1, кључан молекул за 
њену имуномодулаторну/неуропротективну активност, и њеном појачаном 
експресијом Nrf2 гена, као и гена за хем оксигеназу-1, која се сматра 
ефекторским молекулом анти-инфламаторног CX3CR1/Nrf2 сигналног 
пута. Истраживања in vitro показала су да активација β-адренергичких 
рецептора доводи до нисходне регулације експресије Nrf2 и путем 
независним од CX3CR1. Сходно претходним резултатима, пропранолол 
је повећао фагоцитну способност микроглије, што је корелирало са 
повећањем површинске експресије анти-инфламаторних маркера CD163 
и CD83. Повећање експресије хем оксигеназе-1 праћено је порастом 
заступљености микроглије која синтетише IL-10, а смањењем удела оне 
која експримира проинфламаторне цитокине IL-1β и IL-23. Пропранолол 
је смањио и експресију MCP-1/CCL2 у кичменој мождини. Консекутивно, 
инфилтрација кичмене мождине мијелоидним ћелијама и CD4+ Т-ћелијама 
била је смањена код пацова третираних пропранололом. У складу са свим 
претходним, пропранолол је лимитирао и реактивацију/пролиферацију 
CD4+ Т-лимфоцита и њихову диференцијацију у изузетно патогене IL 17+IFN-γ+GM-CSF+ ћелије. Студија указује да норадреналин, делујући 
посредством β-адренергичких рецептора, подстиче неуроинфламацију 
у ЕАЕ-у тако што модулише експресију Nrf2 у ћелијама микроглије. 
Такође, она представља могућу полазну основу за будућа транслациона 
фармаколошка истраживања у циљу дизајнирања нових приступа у лечењу 
мултипле склерозе.
PB  - Српска академија наука и уметности
PB  - Друштво имунолога Србије
C3  - Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд
T1  - Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5089
ER  - 

@conference{
author = "Prijić, Ivana and Pilipović, Ivan and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2021",
abstract = "Претпоставља се да дисфункција симпатичког нервног система 
доприноси развоју мултипле склерозе и експерименталног аутоимунског 
енцефаломијелитиса (ЕАЕ). Имајући у виду важност микроглије за 
развој/резолуцију неуроинфламације, испитиван је имуномодулаторни 
потенцијал главног симпатичког медијатора норадреналина коришћењем 
пацовског модела ЕАЕ-а. Резултати су показали да третман пропранололом, 
неселективним блокатором β-адренергичких рецептора, у ефекторској 
фази ЕАЕ-а смањује тежину болести. Ово је корелирало са повећаном 
заступљеношћу микроглије која експримира CX3CR1, кључан молекул за 
њену имуномодулаторну/неуропротективну активност, и њеном појачаном 
експресијом Nrf2 гена, као и гена за хем оксигеназу-1, која се сматра 
ефекторским молекулом анти-инфламаторног CX3CR1/Nrf2 сигналног 
пута. Истраживања in vitro показала су да активација β-адренергичких 
рецептора доводи до нисходне регулације експресије Nrf2 и путем 
независним од CX3CR1. Сходно претходним резултатима, пропранолол 
је повећао фагоцитну способност микроглије, што је корелирало са 
повећањем површинске експресије анти-инфламаторних маркера CD163 
и CD83. Повећање експресије хем оксигеназе-1 праћено је порастом 
заступљености микроглије која синтетише IL-10, а смањењем удела оне 
која експримира проинфламаторне цитокине IL-1β и IL-23. Пропранолол 
је смањио и експресију MCP-1/CCL2 у кичменој мождини. Консекутивно, 
инфилтрација кичмене мождине мијелоидним ћелијама и CD4+ Т-ћелијама 
била је смањена код пацова третираних пропранололом. У складу са свим 
претходним, пропранолол је лимитирао и реактивацију/пролиферацију 
CD4+ Т-лимфоцита и њихову диференцијацију у изузетно патогене IL 17+IFN-γ+GM-CSF+ ћелије. Студија указује да норадреналин, делујући 
посредством β-адренергичких рецептора, подстиче неуроинфламацију 
у ЕАЕ-у тако што модулише експресију Nrf2 у ћелијама микроглије. 
Такође, она представља могућу полазну основу за будућа транслациона 
фармаколошка истраживања у циљу дизајнирања нових приступа у лечењу 
мултипле склерозе.",
publisher = "Српска академија наука и уметности, Друштво имунолога Србије",
journal = "Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд",
title = "Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5089"
}

Prijić, I., Pilipović, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2021). Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса. in Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд
Српска академија наука и уметности..
https://hdl.handle.net/21.15107/rcub_farfar_5089

Prijić I, Pilipović I, Stojić-Vukanić Z, Leposavić G. Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса. in Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд. 2021;.
https://hdl.handle.net/21.15107/rcub_farfar_5089 .

Prijić, Ivana, Pilipović, Ivan, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса" in Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд (2021),
https://hdl.handle.net/21.15107/rcub_farfar_5089 .

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
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
VL  - 239
SP  - 42
EP  - 59
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",
volume = "239",
pages = "42-59",
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 . .

TY  - JOUR
AU  - Gentile, Antonietta
AU  - D’Acquisto, Fulvio
AU  - Leposavić, Gordana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3987
PB  - Frontiers Media S.A.
T2  - Frontiers in Immunology
T1  - Editorial: The Bidirectional Communication Between Neurons and Immune Cells in the Development of Psychiatric, Neurological and Immune-Mediated Disorders
VL  - 12
DO  - 10.3389/fimmu.2021.781151
ER  - 

@article{
author = "Gentile, Antonietta and D’Acquisto, Fulvio and Leposavić, Gordana",
year = "2021",
publisher = "Frontiers Media S.A.",
journal = "Frontiers in Immunology",
title = "Editorial: The Bidirectional Communication Between Neurons and Immune Cells in the Development of Psychiatric, Neurological and Immune-Mediated Disorders",
volume = "12",
doi = "10.3389/fimmu.2021.781151"
}

Gentile, A., D’Acquisto, F.,& Leposavić, G.. (2021). Editorial: The Bidirectional Communication Between Neurons and Immune Cells in the Development of Psychiatric, Neurological and Immune-Mediated Disorders. in Frontiers in Immunology
Frontiers Media S.A.., 12.
https://doi.org/10.3389/fimmu.2021.781151

Gentile A, D’Acquisto F, Leposavić G. Editorial: The Bidirectional Communication Between Neurons and Immune Cells in the Development of Psychiatric, Neurological and Immune-Mediated Disorders. in Frontiers in Immunology. 2021;12.
doi:10.3389/fimmu.2021.781151 .

Gentile, Antonietta, D’Acquisto, Fulvio, Leposavić, Gordana, "Editorial: The Bidirectional Communication Between Neurons and Immune Cells in the Development of Psychiatric, Neurological and Immune-Mediated Disorders" in Frontiers in Immunology, 12 (2021),
https://doi.org/10.3389/fimmu.2021.781151 . .

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Kosec, Dušan
AU  - Pilipović, Ivan
AU  - Kotur-Stevuljević, Jelena
AU  - Simić, Ljubica
AU  - Sopta, Jelena
AU  - Leposavić, Gordana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3714
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-CD43lowCD11b+ and CCR2-CX3CR1+CD43hiCD11b+ 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-α and IL-6, IL-1β (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 Nature
T2  - Inflammation
T1  - Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats
VL  - 43
IS  - 6
SP  - 2312
EP  - 2331
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, Dušan 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-CD43lowCD11b+ and CCR2-CX3CR1+CD43hiCD11b+ 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-α and IL-6, IL-1β (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 Nature",
journal = "Inflammation",
title = "Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats",
volume = "43",
number = "6",
pages = "2312-2331",
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 Nature., 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, Dušan, 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 . .

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Hadžibegović, Senka
AU  - Nicole, Olivier
AU  - Nacka-Aleksić, Mirjana
AU  - Leštarević, Sanja
AU  - Leposavić, Gordana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3750
AB  - Neurocognitive impairment (NCI) is one of the most relevant clinical manifestations of multiple sclerosis (MS). The profile of NCI and the structural and functional changes in the brain structures relevant for cognition in MS share some similarities to those in Alzheimer's disease (AD), the most common cause of neurocognitive disorders. Additionally, despite clear etiopathological differences between MS and AD, an accumulation of effector/memory CD8+ T cells and CD8+ tissue-resident memory T (Trm) cells in cognitively relevant brain structures of MS/AD patients, and higher frequency of effector/memory CD8+ T cells re-expressing CD45RA (TEMRA) with high capacity to secrete cytotoxic molecules and proinflammatory cytokines in their blood, were found. Thus, an active pathogenetic role of CD8+ T cells in the progression of MS and AD may be assumed. In this mini-review, findings supporting the putative role of CD8+ T cells in the pathogenesis of MS and AD are displayed, and putative mechanisms underlying their pathogenetic action are discussed. A special effort was made to identify the gaps in the current knowledge about the role of CD8+ T cells in the development of NCI to “catalyze” translational research leading to new feasible therapeutic interventions.
PB  - Frontiers Media S.A.
T2  - Frontiers in Immunology
T1  - CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease?
VL  - 11
DO  - 10.3389/fimmu.2020.566225
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Hadžibegović, Senka and Nicole, Olivier and Nacka-Aleksić, Mirjana and Leštarević, Sanja and Leposavić, Gordana",
year = "2020",
abstract = "Neurocognitive impairment (NCI) is one of the most relevant clinical manifestations of multiple sclerosis (MS). The profile of NCI and the structural and functional changes in the brain structures relevant for cognition in MS share some similarities to those in Alzheimer's disease (AD), the most common cause of neurocognitive disorders. Additionally, despite clear etiopathological differences between MS and AD, an accumulation of effector/memory CD8+ T cells and CD8+ tissue-resident memory T (Trm) cells in cognitively relevant brain structures of MS/AD patients, and higher frequency of effector/memory CD8+ T cells re-expressing CD45RA (TEMRA) with high capacity to secrete cytotoxic molecules and proinflammatory cytokines in their blood, were found. Thus, an active pathogenetic role of CD8+ T cells in the progression of MS and AD may be assumed. In this mini-review, findings supporting the putative role of CD8+ T cells in the pathogenesis of MS and AD are displayed, and putative mechanisms underlying their pathogenetic action are discussed. A special effort was made to identify the gaps in the current knowledge about the role of CD8+ T cells in the development of NCI to “catalyze” translational research leading to new feasible therapeutic interventions.",
publisher = "Frontiers Media S.A.",
journal = "Frontiers in Immunology",
title = "CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease?",
volume = "11",
doi = "10.3389/fimmu.2020.566225"
}

Stojić-Vukanić, Z., Hadžibegović, S., Nicole, O., Nacka-Aleksić, M., Leštarević, S.,& Leposavić, G.. (2020). CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease?. in Frontiers in Immunology
Frontiers Media S.A.., 11.
https://doi.org/10.3389/fimmu.2020.566225

Stojić-Vukanić Z, Hadžibegović S, Nicole O, Nacka-Aleksić M, Leštarević S, Leposavić G. CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease?. in Frontiers in Immunology. 2020;11.
doi:10.3389/fimmu.2020.566225 .

Stojić-Vukanić, Zorica, Hadžibegović, Senka, Nicole, Olivier, Nacka-Aleksić, Mirjana, Leštarević, Sanja, Leposavić, Gordana, "CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease?" in Frontiers in Immunology, 11 (2020),
https://doi.org/10.3389/fimmu.2020.566225 . .

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  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3734
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 naïve (recent thymic emigrants and mature naïve 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-1high 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  - Elsevier Inc.
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 naïve (recent thymic emigrants and mature naïve 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-1high 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 = "Elsevier Inc.",
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
Elsevier Inc.., 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 . .

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Bufan, Biljana
AU  - Stojanović, Marija
AU  - Leposavić, Gordana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3529
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-β 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-β production level ratio in LPS-stimulated DC cultures towards TGF-β, 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-γ 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 Nature
T2  - Biogerontology
T1  - Age and sex determine CD4+ T cell stimulatory and polarizing capacity of rat splenic dendritic cells
VL  - 21
IS  - 1
SP  - 83
EP  - 107
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-β 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-β production level ratio in LPS-stimulated DC cultures towards TGF-β, 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-γ 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 Nature",
journal = "Biogerontology",
title = "Age and sex determine CD4+ T cell stimulatory and polarizing capacity of rat splenic dendritic cells",
volume = "21",
number = "1",
pages = "83-107",
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 Nature., 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 . .

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Jasnić, Nebojša
AU  - Leposavić, Gordana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3509
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 upregulation 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-1β 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-γ 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 β-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests β-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  - Elsevier
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 upregulation 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-1β 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-γ 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 β-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests β-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 = "Elsevier",
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
Elsevier., 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 . .

TY  - JOUR
AU  - Pilipović, Iivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Leposavić, Gordana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3503
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 β2-adrenoceptor, a role for α-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 S.A.
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, Iivan 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 β2-adrenoceptor, a role for α-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 S.A.",
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 S.A.., 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, Iivan, 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 . .

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  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3504
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-γ/IL-4 production ratio was shifted towards IFN-γ. 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  - Springer Nature
T2  - Scientific Reports
T1  - Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis
VL  - 10
IS  - 1
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-γ/IL-4 production ratio was shifted towards IFN-γ. 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 = "Springer Nature",
journal = "Scientific Reports",
title = "Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis",
volume = "10",
number = "1",
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
Springer Nature., 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 . .

TY  - JOUR
AU  - Bufan, Biljana
AU  - Arsenović-Ranin, Nevena
AU  - Petrović, Raisa
AU  - Živković, Irena
AU  - Stoiljković, Vera
AU  - Leposavić, Gordana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3521
AB  - Considering variability in vaccine responsiveness across human populations, in respect to magnitude and quality, and importance of vaccines in the elderly, the influence of recipient genetic background on the kinetics of age-related changes in the serum IgG antibody responses to seasonal trivalent inactivated split-virus influenza bulk (TIV) was studied in BALB/c and C57BL/6 mice showing quantitative and qualitative differences in this responses in young adult ages. With ageing the total serum IgG response to influenza viruses declined, in a strain-specific manner, so the strain disparity observed in young adult mice (the greater magnitude of IgG response in BALB/c mice) disappeared in aged mice. However, the sexual dimorphisms in this response (more prominent in females of both strains) remained in aged ones. The strain-specific differences in age-related decline in the magnitude of IgG response to TIV correlated with the number of germinal centre (GC) B splenocytes. The age-related decline in GC B cell number was consistent with the decrease in the proliferation of B cells and CD4+ cells in splenocyte cultures upon restimulation with TIV. Additionally, the age-related decrease in the magnitude of IgG response correlated with the increase in follicular T regulatory (fTreg)/follicular T helper (fTh) and fTreg/GC B splenocyte ratios (reflecting decrease in fTh and GC B numbers without changes in fTreg number), and the frequency of CD4+ splenocytes producing IL-21, a key factor in balancing the B cell and fTreg cell activity. With ageing the avidity of virus influenza-specific antibody increased in females of both strains. Moreover, ageing affected IgG2a/IgG1 and IgG2c/IgG1 ratios (reflecting Th1/Th2 balance) in male BALB/c mice and female C57BL/6 mice, respectively. Consequently, differently from young mice exhibiting the similar ratios in male and female mice, in aged female mice of both strains IgG2a(c)/IgG1 ratios were shifted towards a less effective IgG1 response (stimulated by IL-4 cytokines) compared with males. The age-related alterations in IgG subclass profiles in both strains correlated with those in IFN-γ/IL-4 production level ratio in splenocyte cultures restimulated with TIV. These findings stimulate further research to formulate sex-specific strategies to improve efficacy of influenza vaccine in the elderly.
PB  - Elsevier
T2  - Experimental Gerontology
T1  - Strain specificities in influence of ageing on germinal centre reaction to inactivated influenza virus antigens in mice: Sex-based differences
VL  - 133
DO  - 10.1016/j.exger.2020.110857
ER  - 

@article{
author = "Bufan, Biljana and Arsenović-Ranin, Nevena and Petrović, Raisa and Živković, Irena and Stoiljković, Vera and Leposavić, Gordana",
year = "2020",
abstract = "Considering variability in vaccine responsiveness across human populations, in respect to magnitude and quality, and importance of vaccines in the elderly, the influence of recipient genetic background on the kinetics of age-related changes in the serum IgG antibody responses to seasonal trivalent inactivated split-virus influenza bulk (TIV) was studied in BALB/c and C57BL/6 mice showing quantitative and qualitative differences in this responses in young adult ages. With ageing the total serum IgG response to influenza viruses declined, in a strain-specific manner, so the strain disparity observed in young adult mice (the greater magnitude of IgG response in BALB/c mice) disappeared in aged mice. However, the sexual dimorphisms in this response (more prominent in females of both strains) remained in aged ones. The strain-specific differences in age-related decline in the magnitude of IgG response to TIV correlated with the number of germinal centre (GC) B splenocytes. The age-related decline in GC B cell number was consistent with the decrease in the proliferation of B cells and CD4+ cells in splenocyte cultures upon restimulation with TIV. Additionally, the age-related decrease in the magnitude of IgG response correlated with the increase in follicular T regulatory (fTreg)/follicular T helper (fTh) and fTreg/GC B splenocyte ratios (reflecting decrease in fTh and GC B numbers without changes in fTreg number), and the frequency of CD4+ splenocytes producing IL-21, a key factor in balancing the B cell and fTreg cell activity. With ageing the avidity of virus influenza-specific antibody increased in females of both strains. Moreover, ageing affected IgG2a/IgG1 and IgG2c/IgG1 ratios (reflecting Th1/Th2 balance) in male BALB/c mice and female C57BL/6 mice, respectively. Consequently, differently from young mice exhibiting the similar ratios in male and female mice, in aged female mice of both strains IgG2a(c)/IgG1 ratios were shifted towards a less effective IgG1 response (stimulated by IL-4 cytokines) compared with males. The age-related alterations in IgG subclass profiles in both strains correlated with those in IFN-γ/IL-4 production level ratio in splenocyte cultures restimulated with TIV. These findings stimulate further research to formulate sex-specific strategies to improve efficacy of influenza vaccine in the elderly.",
publisher = "Elsevier",
journal = "Experimental Gerontology",
title = "Strain specificities in influence of ageing on germinal centre reaction to inactivated influenza virus antigens in mice: Sex-based differences",
volume = "133",
doi = "10.1016/j.exger.2020.110857"
}

Bufan, B., Arsenović-Ranin, N., Petrović, R., Živković, I., Stoiljković, V.,& Leposavić, G.. (2020). Strain specificities in influence of ageing on germinal centre reaction to inactivated influenza virus antigens in mice: Sex-based differences. in Experimental Gerontology
Elsevier., 133.
https://doi.org/10.1016/j.exger.2020.110857

Bufan B, Arsenović-Ranin N, Petrović R, Živković I, Stoiljković V, Leposavić G. Strain specificities in influence of ageing on germinal centre reaction to inactivated influenza virus antigens in mice: Sex-based differences. in Experimental Gerontology. 2020;133.
doi:10.1016/j.exger.2020.110857 .

Bufan, Biljana, Arsenović-Ranin, Nevena, Petrović, Raisa, Živković, Irena, Stoiljković, Vera, Leposavić, Gordana, "Strain specificities in influence of ageing on germinal centre reaction to inactivated influenza virus antigens in mice: Sex-based differences" in Experimental Gerontology, 133 (2020),
https://doi.org/10.1016/j.exger.2020.110857 . .

TY  - JOUR
AU  - Đuretić, Jasmina
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3571
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-γ-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-γ-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.
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
VL  - 44
IS  - 4
SP  - 337
EP  - 356
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-γ-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-γ-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.",
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",
volume = "44",
number = "4",
pages = "337-356",
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.., 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 . .

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  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5087
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
PB  - Immunological Society of Serbia
C3  - Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8. 2019, Abstract book
T1  - Sexual dimorphism in the severity of rat collagen-induced arthritis: The relevance of T follicular cell help to B cells
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5087
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, Immunological Society of Serbia",
journal = "Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8. 2019, Abstract book",
title = "Sexual dimorphism in the severity of rat collagen-induced arthritis: The relevance of T follicular cell help to B cells",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5087"
}

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 approaces, Belgrade December 6.-8. 2019, Abstract book
Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia..
https://hdl.handle.net/21.15107/rcub_farfar_5087

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 approaces, Belgrade December 6.-8. 2019, Abstract book. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_5087 .

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 approaces, Belgrade December 6.-8. 2019, Abstract book (2019),
https://hdl.handle.net/21.15107/rcub_farfar_5087 .

TY  - CONF
AU  - Pilipović, Ivan
AU  - Prijić, Ivana
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5085
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-γ 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. Funding: 
MPNTR RS (grant number 175050)
PB  - Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia
PB  - Immunological Society of Serbia
C3  - Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book
T1  - Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5085
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-γ 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. Funding: 
MPNTR RS (grant number 175050)",
publisher = "Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia, Immunological Society of Serbia",
journal = "Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book",
title = "Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5085"
}

Pilipović, I., Prijić, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2019). Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia. in Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book
Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia..
https://hdl.handle.net/21.15107/rcub_farfar_5085

Pilipović I, Prijić I, Stojić-Vukanić Z, Leposavić G. Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia. in Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_5085 .

Pilipović, Ivan, Prijić, Ivana, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia" in Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book (2019),
https://hdl.handle.net/21.15107/rcub_farfar_5085 .

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  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3323
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?
VL  - 336
SP  - 48
EP  - 57
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?",
volume = "336",
pages = "48-57",
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 . .