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  - Nikodijević, Slavomir
AU  - Blagojević, Veljko
AU  - Ćuruvija, Ivana
AU  - Kosanović, Dejana
AU  - Đukić, Tamara
AU  - Đorđević, Brižita
AU  - Ilić, Vesna
AU  - Minić, Rajna
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4294
AB  - Increased interest in microbiota calls for the thorough analysis of antibody reactivity to different microorganisms. As salivary IgA represents the first line of defence against microorganisms contacting mucosal surfaces, we explored the binding and specificity of salivary IgA by testing the binding of purified, FITC-labelled salivary IgA to different microorganisms in flow cytometry and conclude that this kind of analysis enables the differentiation of species/strains with high IgA binding capacity, which should be corroborated on a larger sample size. Further we compare, with in-house ELISA, the binding of polyclonal salivary IgA with the binding of polyclonal serum IgA from the same individuals to whole microbial cells and to purified microbial components. High correlations were obtained in total salivary IgA binding to Lactobacillus rhamnosus and Escherichia coli, very distant bacterial species, as well as to isolated bacterial components (r =.70–.97). The binding of total salivary IgA resembled the binding of both salivary IgA1 and IgA2, with IgA2 predominating. For serum polyclonal IgA repertoire, substantially higher specificity was obtained. Serum IgA binding to E. coli correlated best with serum IgA binding to lipopolysaccharide (r =.86), and serum IgA against L. rhamnosus correlated best with the anti-peptidoglycan IgA levels (r =.88). We have also detected that total serum IgA response is governed by either IgA1 or IgA2 response, depending on the nature of the antigen/s. We conclude that steady state salivary IgA repertoire, unlike serum IgA repertoire, consists of polyreactive antibodies with innate specificity, questioning its capacity to select resident microbiota.
PB  - John Wiley and Sons Inc
T2  - Scandinavian Journal of Immunology
T1  - Selectivity of polyclonal repertoire of anti-microbial IgA and its subclasses in saliva and serum in humans
VL  - 96
IS  - 6
DO  - 10.1111/sji.13223
ER  - 

@article{
author = "Nikodijević, Slavomir and Blagojević, Veljko and Ćuruvija, Ivana and Kosanović, Dejana and Đukić, Tamara and Đorđević, Brižita and Ilić, Vesna and Minić, Rajna",
year = "2022",
abstract = "Increased interest in microbiota calls for the thorough analysis of antibody reactivity to different microorganisms. As salivary IgA represents the first line of defence against microorganisms contacting mucosal surfaces, we explored the binding and specificity of salivary IgA by testing the binding of purified, FITC-labelled salivary IgA to different microorganisms in flow cytometry and conclude that this kind of analysis enables the differentiation of species/strains with high IgA binding capacity, which should be corroborated on a larger sample size. Further we compare, with in-house ELISA, the binding of polyclonal salivary IgA with the binding of polyclonal serum IgA from the same individuals to whole microbial cells and to purified microbial components. High correlations were obtained in total salivary IgA binding to Lactobacillus rhamnosus and Escherichia coli, very distant bacterial species, as well as to isolated bacterial components (r =.70–.97). The binding of total salivary IgA resembled the binding of both salivary IgA1 and IgA2, with IgA2 predominating. For serum polyclonal IgA repertoire, substantially higher specificity was obtained. Serum IgA binding to E. coli correlated best with serum IgA binding to lipopolysaccharide (r =.86), and serum IgA against L. rhamnosus correlated best with the anti-peptidoglycan IgA levels (r =.88). We have also detected that total serum IgA response is governed by either IgA1 or IgA2 response, depending on the nature of the antigen/s. We conclude that steady state salivary IgA repertoire, unlike serum IgA repertoire, consists of polyreactive antibodies with innate specificity, questioning its capacity to select resident microbiota.",
publisher = "John Wiley and Sons Inc",
journal = "Scandinavian Journal of Immunology",
title = "Selectivity of polyclonal repertoire of anti-microbial IgA and its subclasses in saliva and serum in humans",
volume = "96",
number = "6",
doi = "10.1111/sji.13223"
}

Nikodijević, S., Blagojević, V., Ćuruvija, I., Kosanović, D., Đukić, T., Đorđević, B., Ilić, V.,& Minić, R.. (2022). Selectivity of polyclonal repertoire of anti-microbial IgA and its subclasses in saliva and serum in humans. in Scandinavian Journal of Immunology
John Wiley and Sons Inc., 96(6).
https://doi.org/10.1111/sji.13223

Nikodijević S, Blagojević V, Ćuruvija I, Kosanović D, Đukić T, Đorđević B, Ilić V, Minić R. Selectivity of polyclonal repertoire of anti-microbial IgA and its subclasses in saliva and serum in humans. in Scandinavian Journal of Immunology. 2022;96(6).
doi:10.1111/sji.13223 .

Nikodijević, Slavomir, Blagojević, Veljko, Ćuruvija, Ivana, Kosanović, Dejana, Đukić, Tamara, Đorđević, Brižita, Ilić, Vesna, Minić, Rajna, "Selectivity of polyclonal repertoire of anti-microbial IgA and its subclasses in saliva and serum in humans" in Scandinavian Journal of Immunology, 96, no. 6 (2022),
https://doi.org/10.1111/sji.13223 . .

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  - 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 . .