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  - 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  - 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/123456789/3295
AB  - Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25 + Foxp3 + CD4 + T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-gamma/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-beta concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-gamma/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1 beta- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.
PB  - Academic Press Inc Elsevier Science, San Diego
T2  - Brain Behavior and Immunity
T1  - Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis
VL  - 76
SP  - 198
EP  - 214
DO  - 10.1016/j.bbi.2018.11.311
ER  - 

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

Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2019). Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis. in Brain Behavior and Immunity
Academic Press Inc Elsevier Science, San Diego., 76, 198-214.
https://doi.org/10.1016/j.bbi.2018.11.311

Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis. in Brain Behavior and Immunity. 2019;76:198-214.
doi:10.1016/j.bbi.2018.11.311 .

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis" in Brain Behavior and Immunity, 76 (2019):198-214,
https://doi.org/10.1016/j.bbi.2018.11.311 . .

TY  - JOUR
AU  - Nacka-Aleksić, Mirjana
AU  - Stojanović, Marija
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Kosec, Duško
AU  - Leposavić, Gordana
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3221
AB  - An accumulating body of evidence suggests that development of autoimmune pathologies leads to thymic dysfunction and changes in peripheral T-cell compartment, which, in turn, perpetuate their pathogenesis. To test this hypothesis, thymocyte differentiation/maturation in rats susceptible (Dark Agouti, DA) and relatively resistant (Albino Oxford, AO) to experimental autoimmune encephalomyelitis (EAE) induction was examined. Irrespective of strain, immunization for EAE (i) increased the circulating levels of IL-6, a cytokine causally linked with thymic atrophy, and (ii) led to thymic atrophy reflecting partly enhanced thymocyte apoptosis associated with downregulated thymic IL-7 expression. Additionally, immunization diminished the expression of Thy-1, a negative regulator of TCR alpha beta-mediated signaling and activation thresholds, on CD4+CD8+ TCR alpha beta(lo/hi) thymocytes undergoing selection and thereby impaired thymocyte selection/survival. This diminished the generation of mature CD4+ and CD8+ single positive TCR alpha beta(hi) thymocytes and, consequently, CD4+ and CD8+ recent thymic emigrants. In immunized rats, thymic differentiation of natural regulatory CD4+Foxp3+CD25+ T cells (nTregs) was particularly affected reflecting a diminished expression of IL-7, IL-2 and IL-15. The decline in the overall thymic T-cell output and nTreg generation was more pronounced in DA than AO rats. Additionally, differently from immunized AO rats, in DA ones the frequency of CD28- cells secreting cytolytic enzymes within peripheral blood CD4+ T lymphocytes increased, as a consequence of thymic atrophy-related replicative stress (mirrored in CD4+ cell memory pool expansion and p16(INK4a) accumulation). The higher circulating level of TNF-alpha in DA compared with AO rats could also contribute to this difference. Consistently, higher frequency of cytolytic CD4+ granzyme B+ cells (associated with greater tissue damage) was found in spinal cord of immunized DA rats compared with their AO counterparts. In conclusion, the study indicated that strain differences in immunization-induced changes in thymopoiesis and peripheral CD4+CD28- T-cell generation could contribute to rat strain-specific clinical outcomes of immunization for EAE.
PB  - Public Library Science, San Francisco
T2  - PLoS One
T1  - Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization
VL  - 13
IS  - 8
DO  - 10.1371/journal.pone.0201848
ER  - 

@article{
author = "Nacka-Aleksić, Mirjana and Stojanović, Marija and Pilipović, Ivan and Stojić-Vukanić, Zorica and Kosec, Duško and Leposavić, Gordana",
year = "2018",
abstract = "An accumulating body of evidence suggests that development of autoimmune pathologies leads to thymic dysfunction and changes in peripheral T-cell compartment, which, in turn, perpetuate their pathogenesis. To test this hypothesis, thymocyte differentiation/maturation in rats susceptible (Dark Agouti, DA) and relatively resistant (Albino Oxford, AO) to experimental autoimmune encephalomyelitis (EAE) induction was examined. Irrespective of strain, immunization for EAE (i) increased the circulating levels of IL-6, a cytokine causally linked with thymic atrophy, and (ii) led to thymic atrophy reflecting partly enhanced thymocyte apoptosis associated with downregulated thymic IL-7 expression. Additionally, immunization diminished the expression of Thy-1, a negative regulator of TCR alpha beta-mediated signaling and activation thresholds, on CD4+CD8+ TCR alpha beta(lo/hi) thymocytes undergoing selection and thereby impaired thymocyte selection/survival. This diminished the generation of mature CD4+ and CD8+ single positive TCR alpha beta(hi) thymocytes and, consequently, CD4+ and CD8+ recent thymic emigrants. In immunized rats, thymic differentiation of natural regulatory CD4+Foxp3+CD25+ T cells (nTregs) was particularly affected reflecting a diminished expression of IL-7, IL-2 and IL-15. The decline in the overall thymic T-cell output and nTreg generation was more pronounced in DA than AO rats. Additionally, differently from immunized AO rats, in DA ones the frequency of CD28- cells secreting cytolytic enzymes within peripheral blood CD4+ T lymphocytes increased, as a consequence of thymic atrophy-related replicative stress (mirrored in CD4+ cell memory pool expansion and p16(INK4a) accumulation). The higher circulating level of TNF-alpha in DA compared with AO rats could also contribute to this difference. Consistently, higher frequency of cytolytic CD4+ granzyme B+ cells (associated with greater tissue damage) was found in spinal cord of immunized DA rats compared with their AO counterparts. In conclusion, the study indicated that strain differences in immunization-induced changes in thymopoiesis and peripheral CD4+CD28- T-cell generation could contribute to rat strain-specific clinical outcomes of immunization for EAE.",
publisher = "Public Library Science, San Francisco",
journal = "PLoS One",
title = "Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization",
volume = "13",
number = "8",
doi = "10.1371/journal.pone.0201848"
}

Nacka-Aleksić, M., Stojanović, M., Pilipović, I., Stojić-Vukanić, Z., Kosec, D.,& Leposavić, G.. (2018). Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization. in PLoS One
Public Library Science, San Francisco., 13(8).
https://doi.org/10.1371/journal.pone.0201848

Nacka-Aleksić M, Stojanović M, Pilipović I, Stojić-Vukanić Z, Kosec D, Leposavić G. Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization. in PLoS One. 2018;13(8).
doi:10.1371/journal.pone.0201848 .

Nacka-Aleksić, Mirjana, Stojanović, Marija, Pilipović, Ivan, Stojić-Vukanić, Zorica, Kosec, Duško, Leposavić, Gordana, "Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization" in PLoS One, 13, no. 8 (2018),
https://doi.org/10.1371/journal.pone.0201848 . .

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Đikić, Jasmina
AU  - Vujnović, Ivana
AU  - Nacka-Aleksić, Mirjana
AU  - Bufan, Biljana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Leposavić, Gordana
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3188
AB  - The study investigated strain specificities in age-related differences in CD8+ T cell-and microglial cell-mediated mechanisms implicated in induction/perpetuation and/or control of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in Albino Oxford (AO) and Dark Agouti (DA) rats exhibiting age-related changes in the susceptibility to EAE in the opposite direction (increase in relatively resistant AO rats vs decrease in DA rats). In the inductive phase of EAE, the greater number of fully differentiated effector CD8+ T lymphocytes was found in draining lymph nodes (dLNs) from aged rats of both strains than in strain-matched young rats, but this was particularly prominent in AO rats, which exhibited milder EAE of prolonged duration compared with their DA counterparts. Consistently, dLN IFN-gamma+ and IL-17+ CD8+ T cell counts were greater in aged AO than in DA rats. Additionally, the magnitudes of myelin basic protein (MBP)-induced rise in the frequency of IFN-gamma+ and IL-17+ CD8+ T cells (providing important help to neuroantigen-specific CD4+ T cells in EAE models characterized by clinically mild disease) were greater in dLN cell cultures from aged AO rats. Consistently, the magnitudes of MBP-induced rise in the frequency of both IFN-gamma+ and IL-17+ CD8+ T cells were greater in spinal cord mononuclear cell cultures from aged AO rats compared with their DA counterparts. Besides, with aging CD4+ CD25+ Foxp3+/CD8+ CD25+ Foxp3+ regulatory T cell ratio changed in spinal cord in the opposite direction. Consequently, in aged AO rats it was shifted towards CD8+ CD25+ Foxp3+ regulatory T cells (exhibiting lower suppressive capacity) when compared with DA rats. Moreover, the frequency of CX3CR1+ cells among microglia changed with aging and the disease development. In aged rats, in the effector phase of EAE it was lower in AO than in DA rats. This was accompanied by higher frequency of cells expressing IL-1 beta (whose down-regulation is central for CX3CR1-mediated neuroprotection), but lower that of phagocyting cells among microglia from aged AO compared their DA counterparts. The study indicates the control points linked with strain differences in age-related changes in EAE pathogenesis.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Experimental Gerontology
T1  - Strain specificities in age-related changes in mechanisms promoting and controlling rat spinal cord damage in experimental autoimmune encephalomyelitis
VL  - 101
SP  - 37
EP  - 53
DO  - 10.1016/j.exger.2017.11.002
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Pilipović, Ivan and Đikić, Jasmina and Vujnović, Ivana and Nacka-Aleksić, Mirjana and Bufan, Biljana and Arsenović-Ranin, Nevena and Kosec, Duško and Leposavić, Gordana",
year = "2018",
abstract = "The study investigated strain specificities in age-related differences in CD8+ T cell-and microglial cell-mediated mechanisms implicated in induction/perpetuation and/or control of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in Albino Oxford (AO) and Dark Agouti (DA) rats exhibiting age-related changes in the susceptibility to EAE in the opposite direction (increase in relatively resistant AO rats vs decrease in DA rats). In the inductive phase of EAE, the greater number of fully differentiated effector CD8+ T lymphocytes was found in draining lymph nodes (dLNs) from aged rats of both strains than in strain-matched young rats, but this was particularly prominent in AO rats, which exhibited milder EAE of prolonged duration compared with their DA counterparts. Consistently, dLN IFN-gamma+ and IL-17+ CD8+ T cell counts were greater in aged AO than in DA rats. Additionally, the magnitudes of myelin basic protein (MBP)-induced rise in the frequency of IFN-gamma+ and IL-17+ CD8+ T cells (providing important help to neuroantigen-specific CD4+ T cells in EAE models characterized by clinically mild disease) were greater in dLN cell cultures from aged AO rats. Consistently, the magnitudes of MBP-induced rise in the frequency of both IFN-gamma+ and IL-17+ CD8+ T cells were greater in spinal cord mononuclear cell cultures from aged AO rats compared with their DA counterparts. Besides, with aging CD4+ CD25+ Foxp3+/CD8+ CD25+ Foxp3+ regulatory T cell ratio changed in spinal cord in the opposite direction. Consequently, in aged AO rats it was shifted towards CD8+ CD25+ Foxp3+ regulatory T cells (exhibiting lower suppressive capacity) when compared with DA rats. Moreover, the frequency of CX3CR1+ cells among microglia changed with aging and the disease development. In aged rats, in the effector phase of EAE it was lower in AO than in DA rats. This was accompanied by higher frequency of cells expressing IL-1 beta (whose down-regulation is central for CX3CR1-mediated neuroprotection), but lower that of phagocyting cells among microglia from aged AO compared their DA counterparts. The study indicates the control points linked with strain differences in age-related changes in EAE pathogenesis.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Experimental Gerontology",
title = "Strain specificities in age-related changes in mechanisms promoting and controlling rat spinal cord damage in experimental autoimmune encephalomyelitis",
volume = "101",
pages = "37-53",
doi = "10.1016/j.exger.2017.11.002"
}

Stojić-Vukanić, Z., Pilipović, I., Đikić, J., Vujnović, I., Nacka-Aleksić, M., Bufan, B., Arsenović-Ranin, N., Kosec, D.,& Leposavić, G.. (2018). Strain specificities in age-related changes in mechanisms promoting and controlling rat spinal cord damage in experimental autoimmune encephalomyelitis. in Experimental Gerontology
Pergamon-Elsevier Science Ltd, Oxford., 101, 37-53.
https://doi.org/10.1016/j.exger.2017.11.002

Stojić-Vukanić Z, Pilipović I, Đikić J, Vujnović I, Nacka-Aleksić M, Bufan B, Arsenović-Ranin N, Kosec D, Leposavić G. Strain specificities in age-related changes in mechanisms promoting and controlling rat spinal cord damage in experimental autoimmune encephalomyelitis. in Experimental Gerontology. 2018;101:37-53.
doi:10.1016/j.exger.2017.11.002 .

Stojić-Vukanić, Zorica, Pilipović, Ivan, Đikić, Jasmina, Vujnović, Ivana, Nacka-Aleksić, Mirjana, Bufan, Biljana, Arsenović-Ranin, Nevena, Kosec, Duško, Leposavić, Gordana, "Strain specificities in age-related changes in mechanisms promoting and controlling rat spinal cord damage in experimental autoimmune encephalomyelitis" in Experimental Gerontology, 101 (2018):37-53,
https://doi.org/10.1016/j.exger.2017.11.002 . .

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Kotur-Stevuljević, Jelena
AU  - Nacka-Aleksić, Mirjana
AU  - Kosec, Duško
AU  - Vujnović, Ivana
AU  - Pilipović, Ivan
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3183
AB  - In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-gamma+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCR alpha beta- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCR alpha beta- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage.
PB  - Springer, New York
T2  - Molecular Neurobiology
T1  - Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action
VL  - 55
IS  - 5
SP  - 3755
EP  - 3774
DO  - 10.1007/s12035-017-0595-2
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Kotur-Stevuljević, Jelena and Nacka-Aleksić, Mirjana and Kosec, Duško and Vujnović, Ivana and Pilipović, Ivan and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2018",
abstract = "In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-gamma+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCR alpha beta- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCR alpha beta- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage.",
publisher = "Springer, New York",
journal = "Molecular Neurobiology",
title = "Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action",
volume = "55",
number = "5",
pages = "3755-3774",
doi = "10.1007/s12035-017-0595-2"
}

Stojić-Vukanić, Z., Kotur-Stevuljević, J., Nacka-Aleksić, M., Kosec, D., Vujnović, I., Pilipović, I., Dimitrijević, M.,& Leposavić, G.. (2018). Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action. in Molecular Neurobiology
Springer, New York., 55(5), 3755-3774.
https://doi.org/10.1007/s12035-017-0595-2

Stojić-Vukanić Z, Kotur-Stevuljević J, Nacka-Aleksić M, Kosec D, Vujnović I, Pilipović I, Dimitrijević M, Leposavić G. Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action. in Molecular Neurobiology. 2018;55(5):3755-3774.
doi:10.1007/s12035-017-0595-2 .

Stojić-Vukanić, Zorica, Kotur-Stevuljević, Jelena, Nacka-Aleksić, Mirjana, Kosec, Duško, Vujnović, Ivana, Pilipović, Ivan, Dimitrijević, Mirjana, Leposavić, Gordana, "Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action" in Molecular Neurobiology, 55, no. 5 (2018):3755-3774,
https://doi.org/10.1007/s12035-017-0595-2 . .

TY  - JOUR
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Nacka-Aleksić, Mirjana
AU  - Bufan, Biljana
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2898
AB  - The study examined the influence of age, sex and peripubertal gonadectomy on a set of T-cell phenotypic parameters. Rats of both sexes were gonadectomised at the age of 1 month and peripheral blood and spleen T lymphocytes from non-gonadectomised and gonadectomised 3- and 11-month-old rats were examined for the expression of differentiation/activation (CD90/CD45RC) and immunoregulatory markers. Peripheral blood T lymphocytes from non-gonadectomised rats showed age-dependent sexual dimorphisms in (1) total count (lower in female than male 11-month-old rats); (2) CD4+:CD8 + cell ratio (higher in female than male rats of both ages); (3) the proportion of recent thymic emigrants in CD8 + T cells (lower in female than male 3-month-old rats) and (4) the proportions of mature na  lt  ve and memory/activated cells (irrespective of age, the proportion of na  lt  ve cells was higher, whereas that of memory/activated cells was lower in females). Gonadectomy influenced magnitudes or direction of these sex differences. Additionally, sex differences in peripheral blood T-lymphocyte parameters did not fully correspond to those observed in T-splenocyte parameters, suggesting the compartment-specific regulation of the major T-cell subpopulations' and their subsets' composition. Furthermore, there was no sexual dimorphism in the proportion of either CD25 + Foxp3 + cells among CD4 + or CD161+ (NKT) cells within CD8 + T lymphocytes. However, there was gonadal hormone-independent age-associated sexual dimorphism in the proportion of CD161 + cells (NKT cells) in CD8 + T splenocytes. Overall, the study revealed age-dependent variations in sexual dimorphisms in T-cell parameters relevant for immune response efficacy and showed that they are T-cell compartment-specific and partly gonadal hormone-related.
PB  - Springer, Dordrecht
T2  - Molecular and Cellular Biochemistry
T1  - Sex and age as determinants of rat T-cell phenotypic characteristics: influence of peripubertal gonadectomy
VL  - 431
IS  - 1-2
SP  - 169
EP  - 185
DO  - 10.1007/s11010-017-2989-x
ER  - 

@article{
author = "Arsenović-Ranin, Nevena and Kosec, Duško and Pilipović, Ivan and Nacka-Aleksić, Mirjana and Bufan, Biljana and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2017",
abstract = "The study examined the influence of age, sex and peripubertal gonadectomy on a set of T-cell phenotypic parameters. Rats of both sexes were gonadectomised at the age of 1 month and peripheral blood and spleen T lymphocytes from non-gonadectomised and gonadectomised 3- and 11-month-old rats were examined for the expression of differentiation/activation (CD90/CD45RC) and immunoregulatory markers. Peripheral blood T lymphocytes from non-gonadectomised rats showed age-dependent sexual dimorphisms in (1) total count (lower in female than male 11-month-old rats); (2) CD4+:CD8 + cell ratio (higher in female than male rats of both ages); (3) the proportion of recent thymic emigrants in CD8 + T cells (lower in female than male 3-month-old rats) and (4) the proportions of mature na  lt  ve and memory/activated cells (irrespective of age, the proportion of na  lt  ve cells was higher, whereas that of memory/activated cells was lower in females). Gonadectomy influenced magnitudes or direction of these sex differences. Additionally, sex differences in peripheral blood T-lymphocyte parameters did not fully correspond to those observed in T-splenocyte parameters, suggesting the compartment-specific regulation of the major T-cell subpopulations' and their subsets' composition. Furthermore, there was no sexual dimorphism in the proportion of either CD25 + Foxp3 + cells among CD4 + or CD161+ (NKT) cells within CD8 + T lymphocytes. However, there was gonadal hormone-independent age-associated sexual dimorphism in the proportion of CD161 + cells (NKT cells) in CD8 + T splenocytes. Overall, the study revealed age-dependent variations in sexual dimorphisms in T-cell parameters relevant for immune response efficacy and showed that they are T-cell compartment-specific and partly gonadal hormone-related.",
publisher = "Springer, Dordrecht",
journal = "Molecular and Cellular Biochemistry",
title = "Sex and age as determinants of rat T-cell phenotypic characteristics: influence of peripubertal gonadectomy",
volume = "431",
number = "1-2",
pages = "169-185",
doi = "10.1007/s11010-017-2989-x"
}

Arsenović-Ranin, N., Kosec, D., Pilipović, I., Nacka-Aleksić, M., Bufan, B., Stojić-Vukanić, Z.,& Leposavić, G.. (2017). Sex and age as determinants of rat T-cell phenotypic characteristics: influence of peripubertal gonadectomy. in Molecular and Cellular Biochemistry
Springer, Dordrecht., 431(1-2), 169-185.
https://doi.org/10.1007/s11010-017-2989-x

Arsenović-Ranin N, Kosec D, Pilipović I, Nacka-Aleksić M, Bufan B, Stojić-Vukanić Z, Leposavić G. Sex and age as determinants of rat T-cell phenotypic characteristics: influence of peripubertal gonadectomy. in Molecular and Cellular Biochemistry. 2017;431(1-2):169-185.
doi:10.1007/s11010-017-2989-x .

Arsenović-Ranin, Nevena, Kosec, Duško, Pilipović, Ivan, Nacka-Aleksić, Mirjana, Bufan, Biljana, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Sex and age as determinants of rat T-cell phenotypic characteristics: influence of peripubertal gonadectomy" in Molecular and Cellular Biochemistry, 431, no. 1-2 (2017):169-185,
https://doi.org/10.1007/s11010-017-2989-x . .

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Vujnović, Ivana
AU  - Arsenović-Ranin, Nevena
AU  - Dimitrijević, Mirjana
AU  - Kosec, Duško
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2664
AB  - The study investigated the influence of peripubertal ovariectomy on the thymic noradrenaline (NA) concentration, and the thymocyte NA content and beta(2)- and alpha(1)-adrenoceptor (AR) expression in adult 2- and 11-month-old rats. In control rats, the thymic NA concentration increased with age. This increase reflected rise in the density of catecholamine (CA)-containing fluorescent nerve fibers and cells and their CA content. Additionally, the average beta(2)- and alpha(1)-AR thymocyte surface density changed in the opposite direction with age; the density of beta(2)-AR decreased, whereas that of alpha(1)-AR increased. Ovariectomy diminished the thymic NA concentration in 2-month-old rats. This reflected the decrease in the density of fluorescent nerve fibers, and CA content in fluorescent nerve fibers and non-lymphoid cells, since the thymocyte NA content was increased in ovariectomized (Ox) rats. Estrogen supplementation prevented the ovariectomy-induced changes. In Ox rats, the density of CA-synthesizing nerve fibers and non-lymphoid cells diminished with age. To the contrary, NA content in thymocytes increased with age, but it did not exceed that in 11-month-old controls. Additionally, ovariectomy diminished the average thymocyte surface density of beta(2)-ARs, but it increased that of alpha(1)-ARs in 2-month-old-rats (due to estrogen, and estrogen and progesterone deficiency, respectively). These changes, despite of the rise in circulating estrogen level post-ovariectomy, remained stable with age. This most likely reflected a decreased sensitivity to estrogen action, as a consequence of the hormone misprinting in peripubertal age. The analysis of thymocyte proliferation in culture suggested that age-and ovariectomy-induced alterations in thymocyte NA synthesis and AR expression altered NA autocrine/paracrine action on thymocytes. In conclusion, the study indicates that the ovarian hormone deficiency in peripubertal age affects ovarian steroid-dependent remodeling of thymic adrenergic regulatory network in adult rats.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Neuroimmunology
T1  - Peripubertal ovariectomy influences thymic adrenergic network plasticity in adult rats
VL  - 297
SP  - 103
EP  - 116
DO  - 10.1016/j.jneuroim.2016.05.017
ER  - 

@article{
author = "Pilipović, Ivan and Vujnović, Ivana and Arsenović-Ranin, Nevena and Dimitrijević, Mirjana and Kosec, Duško and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2016",
abstract = "The study investigated the influence of peripubertal ovariectomy on the thymic noradrenaline (NA) concentration, and the thymocyte NA content and beta(2)- and alpha(1)-adrenoceptor (AR) expression in adult 2- and 11-month-old rats. In control rats, the thymic NA concentration increased with age. This increase reflected rise in the density of catecholamine (CA)-containing fluorescent nerve fibers and cells and their CA content. Additionally, the average beta(2)- and alpha(1)-AR thymocyte surface density changed in the opposite direction with age; the density of beta(2)-AR decreased, whereas that of alpha(1)-AR increased. Ovariectomy diminished the thymic NA concentration in 2-month-old rats. This reflected the decrease in the density of fluorescent nerve fibers, and CA content in fluorescent nerve fibers and non-lymphoid cells, since the thymocyte NA content was increased in ovariectomized (Ox) rats. Estrogen supplementation prevented the ovariectomy-induced changes. In Ox rats, the density of CA-synthesizing nerve fibers and non-lymphoid cells diminished with age. To the contrary, NA content in thymocytes increased with age, but it did not exceed that in 11-month-old controls. Additionally, ovariectomy diminished the average thymocyte surface density of beta(2)-ARs, but it increased that of alpha(1)-ARs in 2-month-old-rats (due to estrogen, and estrogen and progesterone deficiency, respectively). These changes, despite of the rise in circulating estrogen level post-ovariectomy, remained stable with age. This most likely reflected a decreased sensitivity to estrogen action, as a consequence of the hormone misprinting in peripubertal age. The analysis of thymocyte proliferation in culture suggested that age-and ovariectomy-induced alterations in thymocyte NA synthesis and AR expression altered NA autocrine/paracrine action on thymocytes. In conclusion, the study indicates that the ovarian hormone deficiency in peripubertal age affects ovarian steroid-dependent remodeling of thymic adrenergic regulatory network in adult rats.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Neuroimmunology",
title = "Peripubertal ovariectomy influences thymic adrenergic network plasticity in adult rats",
volume = "297",
pages = "103-116",
doi = "10.1016/j.jneuroim.2016.05.017"
}

Pilipović, I., Vujnović, I., Arsenović-Ranin, N., Dimitrijević, M., Kosec, D., Stojić-Vukanić, Z.,& Leposavić, G.. (2016). Peripubertal ovariectomy influences thymic adrenergic network plasticity in adult rats. in Journal of Neuroimmunology
Elsevier Science BV, Amsterdam., 297, 103-116.
https://doi.org/10.1016/j.jneuroim.2016.05.017

Pilipović I, Vujnović I, Arsenović-Ranin N, Dimitrijević M, Kosec D, Stojić-Vukanić Z, Leposavić G. Peripubertal ovariectomy influences thymic adrenergic network plasticity in adult rats. in Journal of Neuroimmunology. 2016;297:103-116.
doi:10.1016/j.jneuroim.2016.05.017 .

Pilipović, Ivan, Vujnović, Ivana, Arsenović-Ranin, Nevena, Dimitrijević, Mirjana, Kosec, Duško, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Peripubertal ovariectomy influences thymic adrenergic network plasticity in adult rats" in Journal of Neuroimmunology, 297 (2016):103-116,
https://doi.org/10.1016/j.jneuroim.2016.05.017 . .

TY  - JOUR
AU  - Bufan, Biljana
AU  - Stojić-Vukanić, Zorica
AU  - Đikić, Jasmina
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Nacka-Aleksić, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Leposavić, Gordana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2416
AB  - The study was undertaken considering: i) that relative proportion of distinct subsets of splenic dendritic cells (DCs) is strain-specific and predictive for the susceptibility to autoimmune diseases; ii) age-related changes in endocytic, allostimulatory and polarizing capacity of splenic OX62+ DCs from Albino Oxford rats (relatively resistant to Th1/Th17-mediated diseases) and iii) strain specificities in age-related changes of mouse DCs. To ascertain whether there are strain specificities in age-related rat DC changes, we examined the influence of aging on OX62+ DCs from Dark Agouti (DA) rats prone to Th1/Th17-mediated autoimmune diseases. The study provided additional evidence that the predominance of CD4-cells within OX62+ DCs from young adult rats correlates with their susceptibility to Th1/Th17-mediated diseases. Consistently, lipopolysaccharide (LPS)-matured DCs from 3-month-old (young) rats exhibited Th1 driving force when co-cultured with allogeneic CD4+ T cells. This most likely reflected enhanced TNF-alpha and iNOS expression. Comparing with young rats, OX62+ DCs from 26-month-old (aged) rats showed: i) diminished endocytic capacity; ii) impaired ability to mature in vitro upon LPS stimulation (as indicated by lower MHC II, CD86 and CD40 surface expression), which is consistent with the increase in their IL-10 production, and iii) diminished allostimulatory capacity and loss of Th1-driving capacity in the mixed lymphocyte reaction. The latter, probably, reflected greater IL-10 production by LPS-stimulated DC from aged rats, as well as lower CD40 density on their surface. Overall, our findings suggest that aging might affect DA rat capability to mount an efficient Th1 immune response, and consequently susceptibility to Th1/Th17-mediated pathology.
PB  - Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd
T2  - Acta veterinaria
T1  - Aging impairs endocytic capacity of splenic dendritic cells from Dark Agouti rats and alters their response to TLR4 stimulation
VL  - 65
IS  - 1
SP  - 30
EP  - 55
DO  - 10.1515/acve-2015-0003
ER  - 

@article{
author = "Bufan, Biljana and Stojić-Vukanić, Zorica and Đikić, Jasmina and Kosec, Duško and Pilipović, Ivan and Nacka-Aleksić, Mirjana and Arsenović-Ranin, Nevena and Leposavić, Gordana",
year = "2015",
abstract = "The study was undertaken considering: i) that relative proportion of distinct subsets of splenic dendritic cells (DCs) is strain-specific and predictive for the susceptibility to autoimmune diseases; ii) age-related changes in endocytic, allostimulatory and polarizing capacity of splenic OX62+ DCs from Albino Oxford rats (relatively resistant to Th1/Th17-mediated diseases) and iii) strain specificities in age-related changes of mouse DCs. To ascertain whether there are strain specificities in age-related rat DC changes, we examined the influence of aging on OX62+ DCs from Dark Agouti (DA) rats prone to Th1/Th17-mediated autoimmune diseases. The study provided additional evidence that the predominance of CD4-cells within OX62+ DCs from young adult rats correlates with their susceptibility to Th1/Th17-mediated diseases. Consistently, lipopolysaccharide (LPS)-matured DCs from 3-month-old (young) rats exhibited Th1 driving force when co-cultured with allogeneic CD4+ T cells. This most likely reflected enhanced TNF-alpha and iNOS expression. Comparing with young rats, OX62+ DCs from 26-month-old (aged) rats showed: i) diminished endocytic capacity; ii) impaired ability to mature in vitro upon LPS stimulation (as indicated by lower MHC II, CD86 and CD40 surface expression), which is consistent with the increase in their IL-10 production, and iii) diminished allostimulatory capacity and loss of Th1-driving capacity in the mixed lymphocyte reaction. The latter, probably, reflected greater IL-10 production by LPS-stimulated DC from aged rats, as well as lower CD40 density on their surface. Overall, our findings suggest that aging might affect DA rat capability to mount an efficient Th1 immune response, and consequently susceptibility to Th1/Th17-mediated pathology.",
publisher = "Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd",
journal = "Acta veterinaria",
title = "Aging impairs endocytic capacity of splenic dendritic cells from Dark Agouti rats and alters their response to TLR4 stimulation",
volume = "65",
number = "1",
pages = "30-55",
doi = "10.1515/acve-2015-0003"
}

Bufan, B., Stojić-Vukanić, Z., Đikić, J., Kosec, D., Pilipović, I., Nacka-Aleksić, M., Arsenović-Ranin, N.,& Leposavić, G.. (2015). Aging impairs endocytic capacity of splenic dendritic cells from Dark Agouti rats and alters their response to TLR4 stimulation. in Acta veterinaria
Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd., 65(1), 30-55.
https://doi.org/10.1515/acve-2015-0003

Bufan B, Stojić-Vukanić Z, Đikić J, Kosec D, Pilipović I, Nacka-Aleksić M, Arsenović-Ranin N, Leposavić G. Aging impairs endocytic capacity of splenic dendritic cells from Dark Agouti rats and alters their response to TLR4 stimulation. in Acta veterinaria. 2015;65(1):30-55.
doi:10.1515/acve-2015-0003 .

Bufan, Biljana, Stojić-Vukanić, Zorica, Đikić, Jasmina, Kosec, Duško, Pilipović, Ivan, Nacka-Aleksić, Mirjana, Arsenović-Ranin, Nevena, Leposavić, Gordana, "Aging impairs endocytic capacity of splenic dendritic cells from Dark Agouti rats and alters their response to TLR4 stimulation" in Acta veterinaria, 65, no. 1 (2015):30-55,
https://doi.org/10.1515/acve-2015-0003 . .

TY  - JOUR
AU  - Đikić, Jasmina
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Arsenović-Ranin, Nevena
AU  - Stojić-Vukanić, Zorica
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2413
AB  - The study was undertaken considering age-related changes in susceptibility to experimental autoimmune encephalomyelitis (EAE) and a putative role of spleen in pathogenesis of this disease. The phenotypic and functional characteristics of T splenocytes were examined in young (3-month-old), middle-aged (8-month-old) and aged (26-month-old) Dark Agouti rats immunized for EAE with rat spinal cord in complete Freund's adjuvant The rat susceptibility to EAE induction, as well as the number of activated CD4+CD134+ lymphocytes retrieved from their spinal cords progressively decreased with aging. To the contrary, in rats immunized for EAE the number of activated CD4+ splenocytes, i.e., CD4+CD134+, CD4+CD25+FoxP3 and CD4+CD40L+ cells, progressively increased with aging. This was associated with age-related increase in (i) CD4+ splenocyte surface expression of CD44, the molecule suggested to be involved in limiting emigration of encephalitogenic CD4+ cells from spleen into blood and (ii) frequency of regulatory T cells, including CD4+CD25+FoxP3 + cells, which are also shown to control encephalitogenic cell migration from spleen into the central nervous system. In favor of expansion of T-regulatory cell pool in aged rats was the greater concentration of IL-10 in unstimulated, Concanavalin A (ConA)- and myelin basic protein (MBP)-stimulated splenocyte cultures from aged rats compared with the corresponding cultures from young ones. Consistent with the age-related increase in the expression of CD44, which is shown to favor Th1 effector cell survival by interfering with CD95-mediated signaling, the frequency of apoptotic cells among CD4+ splenocytes, despite the greater frequency of CD95+ cells, was diminished in splenocyte cultures from aged compared with young rats. In addition, in control, as well as in ConA-and MBP-stimulated splenocyte cultures from aged rats, despite of impaired CD4+ cell proliferation, IFN-gamma concentrations were greater than in corresponding cultures from young rats. This most likely reflected increased abundance of IFN-gamma-producing cells in splenocyte cultures from aged compared with young rats. The diminished CD4+ cell proliferation in response to ConA and MBP in splenocyte cultures from aged compared with young rats could be, at least partly, associated with an enhanced splenic expression of iNOS mRNA in aged rats. Thus, the study suggests that age-associated changes leading to entrapping of activated CD4+ cells in the spleen could contribute to the restriction in development of EAE in aged rats.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Neuroimmunology
T1  - Age-related changes in spleen of Dark Agouti rats immunized for experimental autoimmune encephalomyelitis
VL  - 278
SP  - 123
EP  - 135
DO  - 10.1016/j.jneuroim.2014.12.014
ER  - 

@article{
author = "Đikić, Jasmina and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Kosec, Duško and Arsenović-Ranin, Nevena and Stojić-Vukanić, Zorica and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2015",
abstract = "The study was undertaken considering age-related changes in susceptibility to experimental autoimmune encephalomyelitis (EAE) and a putative role of spleen in pathogenesis of this disease. The phenotypic and functional characteristics of T splenocytes were examined in young (3-month-old), middle-aged (8-month-old) and aged (26-month-old) Dark Agouti rats immunized for EAE with rat spinal cord in complete Freund's adjuvant The rat susceptibility to EAE induction, as well as the number of activated CD4+CD134+ lymphocytes retrieved from their spinal cords progressively decreased with aging. To the contrary, in rats immunized for EAE the number of activated CD4+ splenocytes, i.e., CD4+CD134+, CD4+CD25+FoxP3 and CD4+CD40L+ cells, progressively increased with aging. This was associated with age-related increase in (i) CD4+ splenocyte surface expression of CD44, the molecule suggested to be involved in limiting emigration of encephalitogenic CD4+ cells from spleen into blood and (ii) frequency of regulatory T cells, including CD4+CD25+FoxP3 + cells, which are also shown to control encephalitogenic cell migration from spleen into the central nervous system. In favor of expansion of T-regulatory cell pool in aged rats was the greater concentration of IL-10 in unstimulated, Concanavalin A (ConA)- and myelin basic protein (MBP)-stimulated splenocyte cultures from aged rats compared with the corresponding cultures from young ones. Consistent with the age-related increase in the expression of CD44, which is shown to favor Th1 effector cell survival by interfering with CD95-mediated signaling, the frequency of apoptotic cells among CD4+ splenocytes, despite the greater frequency of CD95+ cells, was diminished in splenocyte cultures from aged compared with young rats. In addition, in control, as well as in ConA-and MBP-stimulated splenocyte cultures from aged rats, despite of impaired CD4+ cell proliferation, IFN-gamma concentrations were greater than in corresponding cultures from young rats. This most likely reflected increased abundance of IFN-gamma-producing cells in splenocyte cultures from aged compared with young rats. The diminished CD4+ cell proliferation in response to ConA and MBP in splenocyte cultures from aged compared with young rats could be, at least partly, associated with an enhanced splenic expression of iNOS mRNA in aged rats. Thus, the study suggests that age-associated changes leading to entrapping of activated CD4+ cells in the spleen could contribute to the restriction in development of EAE in aged rats.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Neuroimmunology",
title = "Age-related changes in spleen of Dark Agouti rats immunized for experimental autoimmune encephalomyelitis",
volume = "278",
pages = "123-135",
doi = "10.1016/j.jneuroim.2014.12.014"
}

Đikić, J., Nacka-Aleksić, M., Pilipović, I., Kosec, D., Arsenović-Ranin, N., Stojić-Vukanić, Z., Dimitrijević, M.,& Leposavić, G.. (2015). Age-related changes in spleen of Dark Agouti rats immunized for experimental autoimmune encephalomyelitis. in Journal of Neuroimmunology
Elsevier Science BV, Amsterdam., 278, 123-135.
https://doi.org/10.1016/j.jneuroim.2014.12.014

Đikić J, Nacka-Aleksić M, Pilipović I, Kosec D, Arsenović-Ranin N, Stojić-Vukanić Z, Dimitrijević M, Leposavić G. Age-related changes in spleen of Dark Agouti rats immunized for experimental autoimmune encephalomyelitis. in Journal of Neuroimmunology. 2015;278:123-135.
doi:10.1016/j.jneuroim.2014.12.014 .

Đikić, Jasmina, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Kosec, Duško, Arsenović-Ranin, Nevena, Stojić-Vukanić, Zorica, Dimitrijević, Mirjana, Leposavić, Gordana, "Age-related changes in spleen of Dark Agouti rats immunized for experimental autoimmune encephalomyelitis" in Journal of Neuroimmunology, 278 (2015):123-135,
https://doi.org/10.1016/j.jneuroim.2014.12.014 . .

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Nacka-Aleksić, Mirjana
AU  - Bufan, Biljana
AU  - Pilipović, Ivan
AU  - Arsenović-Ranin, Nevena
AU  - Đikić, Jasmina
AU  - Kosec, Duško
AU  - Leposavić, Gordana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2401
AB  - This study was undertaken considering that, despite the broad use of the unopposed estrogen replacement therapy in elderly women, data on estrogen influence on the functional capacity of dendritic cells (DCs), and consequently immune response are limited. We examined the influence of 17 beta-estradiol on phenotype, cytokine secretory profile, and allostimulatory and polarizing capacity of splenic (OX62+) conventional DCs from 26-month-old (aged) Albino Oxford rats matured in vitro in the presence of LPS, a TLR4 agonist, and R848, a TLR7/8 agonist In the presence of 17 beta-estradiol, DCs from aged rats exhibited an impaired ability to mature upon stimulation with LPS, as shown by the lower surface density of MHC II and costimulatory CD80 and CD86 molecules. 17 beta-Estradiol alone enhanced CD40 expression in OX62+ DCs without affecting the expression of other costimulatory molecules, thereby confirming that the expression of this molecule is regulated independently from the regulation of other costimulatory molecules. However, although R848 upregulated the expression of MHC II and CD80 and CD40 costimulatory molecules on DCs, 17 beta-estradiol diminished the effect of this TLR agonist only on MHC II expression. In conjunction, the previous findings suggest that LPS and R848 elicit changes in the expression of costimulatory molecules via triggering differential intracellular signaling pathways. Furthermore, 17 beta-estradiol diminished the stimulatory influence of both LPS- and R848-matured OX62+ DCs on allogeneic CD4+ T lymphocyte proliferation in a mixed lymphocyte reaction (MLR). Moreover, as shown in MLR, the exposure to 17 beta-estradiol during LPS- and R848-induced maturation diminished Th1- and enhanced Th17-driving capacity and reduced Th1-driving capacity of OX62+ DCs, respectively. This suggests that LPS and R848 affect not only the surface phenotype, but also functional characteristics of OX62+ DCs triggering distinct intracellular signaling pathways. Collectively, the findings indicate that estrogen directly acting on OX62+ DCs, may affect CD4+ lymphocyte-dependent immune response in aged female rats.
PB  - Elsevier Science BV, Amsterdam
T2  - International Immunopharmacology
T1  - 17 beta-Estradiol influences in vitro response of aged rat splenic conventional dendritic cells to TLR4 and TLR7/8 agonists in an agonist specific manner
VL  - 24
IS  - 1
SP  - 24
EP  - 35
DO  - 10.1016/j.intimp.2014.11.008
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Nacka-Aleksić, Mirjana and Bufan, Biljana and Pilipović, Ivan and Arsenović-Ranin, Nevena and Đikić, Jasmina and Kosec, Duško and Leposavić, Gordana",
year = "2015",
abstract = "This study was undertaken considering that, despite the broad use of the unopposed estrogen replacement therapy in elderly women, data on estrogen influence on the functional capacity of dendritic cells (DCs), and consequently immune response are limited. We examined the influence of 17 beta-estradiol on phenotype, cytokine secretory profile, and allostimulatory and polarizing capacity of splenic (OX62+) conventional DCs from 26-month-old (aged) Albino Oxford rats matured in vitro in the presence of LPS, a TLR4 agonist, and R848, a TLR7/8 agonist In the presence of 17 beta-estradiol, DCs from aged rats exhibited an impaired ability to mature upon stimulation with LPS, as shown by the lower surface density of MHC II and costimulatory CD80 and CD86 molecules. 17 beta-Estradiol alone enhanced CD40 expression in OX62+ DCs without affecting the expression of other costimulatory molecules, thereby confirming that the expression of this molecule is regulated independently from the regulation of other costimulatory molecules. However, although R848 upregulated the expression of MHC II and CD80 and CD40 costimulatory molecules on DCs, 17 beta-estradiol diminished the effect of this TLR agonist only on MHC II expression. In conjunction, the previous findings suggest that LPS and R848 elicit changes in the expression of costimulatory molecules via triggering differential intracellular signaling pathways. Furthermore, 17 beta-estradiol diminished the stimulatory influence of both LPS- and R848-matured OX62+ DCs on allogeneic CD4+ T lymphocyte proliferation in a mixed lymphocyte reaction (MLR). Moreover, as shown in MLR, the exposure to 17 beta-estradiol during LPS- and R848-induced maturation diminished Th1- and enhanced Th17-driving capacity and reduced Th1-driving capacity of OX62+ DCs, respectively. This suggests that LPS and R848 affect not only the surface phenotype, but also functional characteristics of OX62+ DCs triggering distinct intracellular signaling pathways. Collectively, the findings indicate that estrogen directly acting on OX62+ DCs, may affect CD4+ lymphocyte-dependent immune response in aged female rats.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "International Immunopharmacology",
title = "17 beta-Estradiol influences in vitro response of aged rat splenic conventional dendritic cells to TLR4 and TLR7/8 agonists in an agonist specific manner",
volume = "24",
number = "1",
pages = "24-35",
doi = "10.1016/j.intimp.2014.11.008"
}

Stojić-Vukanić, Z., Nacka-Aleksić, M., Bufan, B., Pilipović, I., Arsenović-Ranin, N., Đikić, J., Kosec, D.,& Leposavić, G.. (2015). 17 beta-Estradiol influences in vitro response of aged rat splenic conventional dendritic cells to TLR4 and TLR7/8 agonists in an agonist specific manner. in International Immunopharmacology
Elsevier Science BV, Amsterdam., 24(1), 24-35.
https://doi.org/10.1016/j.intimp.2014.11.008

Stojić-Vukanić Z, Nacka-Aleksić M, Bufan B, Pilipović I, Arsenović-Ranin N, Đikić J, Kosec D, Leposavić G. 17 beta-Estradiol influences in vitro response of aged rat splenic conventional dendritic cells to TLR4 and TLR7/8 agonists in an agonist specific manner. in International Immunopharmacology. 2015;24(1):24-35.
doi:10.1016/j.intimp.2014.11.008 .

Stojić-Vukanić, Zorica, Nacka-Aleksić, Mirjana, Bufan, Biljana, Pilipović, Ivan, Arsenović-Ranin, Nevena, Đikić, Jasmina, Kosec, Duško, Leposavić, Gordana, "17 beta-Estradiol influences in vitro response of aged rat splenic conventional dendritic cells to TLR4 and TLR7/8 agonists in an agonist specific manner" in International Immunopharmacology, 24, no. 1 (2015):24-35,
https://doi.org/10.1016/j.intimp.2014.11.008 . .

TY  - JOUR
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Vujnović, Ivana
AU  - Arsenović-Ranin, Nevena
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2355
AB  - Considering the crucial pathogenic role of CD4+ T cells in experimental autoimmune encephalomyelitis (EAE) and the opposite direction of the sexual dimorphism in the severity of the disease in 22-24-and 3-month-old dark agouti rats, sex differences in CD4+ T-cell-mediated immune response in aged rats immunized for EAE were examined and compared with those in young animals. In the inductive phase of EAE, fewer activated CD4+ lymphocytes were-retrieved from draining lymph nodes of male (developing less severe disease) compared with female rats, due, at least partly, to their lesser expansion. The former reflected a greater suppressive capacity of CD4+CD25+Foxp3+ cells. Consequently, CD4+ lymphocyte infiltration into the spinal cord of aged male rats was diminished. At the peak of EAE, the frequency of reactivated cells was lower, whereas that of the regulatory CD4+ cells was higher in male rat spinal cord. Consistently, microglial activation and the expression of proinflammatory/damaging cytokines in male rat spinal cord mononuclear cells were diminished. Additionally, the frequency of the highly pathogenic IL-17+IFN-gamma+ T lymphocytes infiltrating their spinal cord was lower. Together, these results point to (i) an age-specificity in CD4+ cell-mediated immune response and (ii) mechanisms underlying the sex differences in this response in aged rats.
PB  - Elsevier Ireland Ltd, Clare
T2  - Mechanisms of Ageing and Development
T1  - Sexual dimorphism in the aged rat CD4+T lymphocyte-mediated immune response elicited by inoculation with spinal cord homogenate
VL  - 152
SP  - 15
EP  - 31
DO  - 10.1016/j.mad.2015.09.004
ER  - 

@article{
author = "Nacka-Aleksić, Mirjana and Pilipović, Ivan and Stojić-Vukanić, Zorica and Kosec, Duško and Bufan, Biljana and Vujnović, Ivana and Arsenović-Ranin, Nevena and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2015",
abstract = "Considering the crucial pathogenic role of CD4+ T cells in experimental autoimmune encephalomyelitis (EAE) and the opposite direction of the sexual dimorphism in the severity of the disease in 22-24-and 3-month-old dark agouti rats, sex differences in CD4+ T-cell-mediated immune response in aged rats immunized for EAE were examined and compared with those in young animals. In the inductive phase of EAE, fewer activated CD4+ lymphocytes were-retrieved from draining lymph nodes of male (developing less severe disease) compared with female rats, due, at least partly, to their lesser expansion. The former reflected a greater suppressive capacity of CD4+CD25+Foxp3+ cells. Consequently, CD4+ lymphocyte infiltration into the spinal cord of aged male rats was diminished. At the peak of EAE, the frequency of reactivated cells was lower, whereas that of the regulatory CD4+ cells was higher in male rat spinal cord. Consistently, microglial activation and the expression of proinflammatory/damaging cytokines in male rat spinal cord mononuclear cells were diminished. Additionally, the frequency of the highly pathogenic IL-17+IFN-gamma+ T lymphocytes infiltrating their spinal cord was lower. Together, these results point to (i) an age-specificity in CD4+ cell-mediated immune response and (ii) mechanisms underlying the sex differences in this response in aged rats.",
publisher = "Elsevier Ireland Ltd, Clare",
journal = "Mechanisms of Ageing and Development",
title = "Sexual dimorphism in the aged rat CD4+T lymphocyte-mediated immune response elicited by inoculation with spinal cord homogenate",
volume = "152",
pages = "15-31",
doi = "10.1016/j.mad.2015.09.004"
}

Nacka-Aleksić, M., Pilipović, I., Stojić-Vukanić, Z., Kosec, D., Bufan, B., Vujnović, I., Arsenović-Ranin, N., Dimitrijević, M.,& Leposavić, G.. (2015). Sexual dimorphism in the aged rat CD4+T lymphocyte-mediated immune response elicited by inoculation with spinal cord homogenate. in Mechanisms of Ageing and Development
Elsevier Ireland Ltd, Clare., 152, 15-31.
https://doi.org/10.1016/j.mad.2015.09.004

Nacka-Aleksić M, Pilipović I, Stojić-Vukanić Z, Kosec D, Bufan B, Vujnović I, Arsenović-Ranin N, Dimitrijević M, Leposavić G. Sexual dimorphism in the aged rat CD4+T lymphocyte-mediated immune response elicited by inoculation with spinal cord homogenate. in Mechanisms of Ageing and Development. 2015;152:15-31.
doi:10.1016/j.mad.2015.09.004 .

Nacka-Aleksić, Mirjana, Pilipović, Ivan, Stojić-Vukanić, Zorica, Kosec, Duško, Bufan, Biljana, Vujnović, Ivana, Arsenović-Ranin, Nevena, Dimitrijević, Mirjana, Leposavić, Gordana, "Sexual dimorphism in the aged rat CD4+T lymphocyte-mediated immune response elicited by inoculation with spinal cord homogenate" in Mechanisms of Ageing and Development, 152 (2015):15-31,
https://doi.org/10.1016/j.mad.2015.09.004 . .

TY  - JOUR
AU  - Nacka-Aleksić, Mirjana
AU  - Đikić, Jasmina
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Arsenović-Ranin, Nevena
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2348
AB  - Compared with females, male Dark Agouti (DA) rats immunized for experimental autoimmune encephalomyelitis (EAE) with rat spinal cord homogenate in complete Freund's adjuvant (CFA) exhibited lower incidence of the disease, but the maximal neurological deficit was greater in the animals that developed the disease. Consistently, at the peak of the disease greater number of reactivated CD4+CD134+CD45RC- T lymphocytes was retrieved from male rat spinal cord. Their microglia/-macrophages were more activated and produced greater amount of prototypic proinflammatory cytokines in vitro. Additionally, oppositely to the expression of mRNAs for IL-12/p35, IL-10 and IL-27/p28, the expression of mRNA for IL-23/p19 was upregulated in male rat spinal cord mononuclear cells. Consequently, the IL-17+:IFN-gamma+ cell ratio within T lymphocytes from their spinal cord was skewed towards IL-17+ cells. Within this subpopulation, the IL-17+IFN-gamma+:IL-1 7+IL-10+ cell ratio was shifted towards IL-17+IFN-gamma+ cells, which have prominent tissue damaging capacity. This was associated with an upregulated expression of mRNAs for IL-1 beta and IL-6, but downregulated TGF-beta mRNA expression in male rat spinal cord mononuclear cells. The enhanced GM-CSF mRNA expression in these cells supported the greater pathogenicity of IL-17+ T lymphocytes infiltrating male spinal cord. In the inductive phase of the disease, contrary to the draining lymph node, in the spinal cord the frequency of CD 134+ cells among CD4+ T lymphocytes and the frequency of IL-17+ cells among T lymphocytes were greater in male than in female rats. This most likely reflected an enhanced transmigration of mononuclear cells into the spinal cord (judging by the lesser spinal cord CXCL12 mRNA expression), the greater frequency of activated microglia/macrophages and the increased expression of mRNAs for Th17 polarizing cytokines in male rat spinal cord mononuclear cells. Collectively, the results showed cellular and molecular mechanisms underlying the target organ specific sexual dimorphism in the T lymphocyte-dependent immune/inflammatory response, and suggested a substantial role for the target organ in shaping the sexually dimorphic clinical outcome of EAE.
PB  - Academic Press Inc Elsevier Science, San Diego
T2  - Brain Behavior and Immunity
T1  - Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: Sexual dimorphism and diergism at the spinal cord level
VL  - 49
SP  - 101
EP  - 118
DO  - 10.1016/j.bbi.2015.04.017
ER  - 

@article{
author = "Nacka-Aleksić, Mirjana and Đikić, Jasmina and Pilipović, Ivan and Stojić-Vukanić, Zorica and Kosec, Duško and Bufan, Biljana and Arsenović-Ranin, Nevena and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2015",
abstract = "Compared with females, male Dark Agouti (DA) rats immunized for experimental autoimmune encephalomyelitis (EAE) with rat spinal cord homogenate in complete Freund's adjuvant (CFA) exhibited lower incidence of the disease, but the maximal neurological deficit was greater in the animals that developed the disease. Consistently, at the peak of the disease greater number of reactivated CD4+CD134+CD45RC- T lymphocytes was retrieved from male rat spinal cord. Their microglia/-macrophages were more activated and produced greater amount of prototypic proinflammatory cytokines in vitro. Additionally, oppositely to the expression of mRNAs for IL-12/p35, IL-10 and IL-27/p28, the expression of mRNA for IL-23/p19 was upregulated in male rat spinal cord mononuclear cells. Consequently, the IL-17+:IFN-gamma+ cell ratio within T lymphocytes from their spinal cord was skewed towards IL-17+ cells. Within this subpopulation, the IL-17+IFN-gamma+:IL-1 7+IL-10+ cell ratio was shifted towards IL-17+IFN-gamma+ cells, which have prominent tissue damaging capacity. This was associated with an upregulated expression of mRNAs for IL-1 beta and IL-6, but downregulated TGF-beta mRNA expression in male rat spinal cord mononuclear cells. The enhanced GM-CSF mRNA expression in these cells supported the greater pathogenicity of IL-17+ T lymphocytes infiltrating male spinal cord. In the inductive phase of the disease, contrary to the draining lymph node, in the spinal cord the frequency of CD 134+ cells among CD4+ T lymphocytes and the frequency of IL-17+ cells among T lymphocytes were greater in male than in female rats. This most likely reflected an enhanced transmigration of mononuclear cells into the spinal cord (judging by the lesser spinal cord CXCL12 mRNA expression), the greater frequency of activated microglia/macrophages and the increased expression of mRNAs for Th17 polarizing cytokines in male rat spinal cord mononuclear cells. Collectively, the results showed cellular and molecular mechanisms underlying the target organ specific sexual dimorphism in the T lymphocyte-dependent immune/inflammatory response, and suggested a substantial role for the target organ in shaping the sexually dimorphic clinical outcome of EAE.",
publisher = "Academic Press Inc Elsevier Science, San Diego",
journal = "Brain Behavior and Immunity",
title = "Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: Sexual dimorphism and diergism at the spinal cord level",
volume = "49",
pages = "101-118",
doi = "10.1016/j.bbi.2015.04.017"
}

Nacka-Aleksić, M., Đikić, J., Pilipović, I., Stojić-Vukanić, Z., Kosec, D., Bufan, B., Arsenović-Ranin, N., Dimitrijević, M.,& Leposavić, G.. (2015). Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: Sexual dimorphism and diergism at the spinal cord level. in Brain Behavior and Immunity
Academic Press Inc Elsevier Science, San Diego., 49, 101-118.
https://doi.org/10.1016/j.bbi.2015.04.017

Nacka-Aleksić M, Đikić J, Pilipović I, Stojić-Vukanić Z, Kosec D, Bufan B, Arsenović-Ranin N, Dimitrijević M, Leposavić G. Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: Sexual dimorphism and diergism at the spinal cord level. in Brain Behavior and Immunity. 2015;49:101-118.
doi:10.1016/j.bbi.2015.04.017 .

Nacka-Aleksić, Mirjana, Đikić, Jasmina, Pilipović, Ivan, Stojić-Vukanić, Zorica, Kosec, Duško, Bufan, Biljana, Arsenović-Ranin, Nevena, Dimitrijević, Mirjana, Leposavić, Gordana, "Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: Sexual dimorphism and diergism at the spinal cord level" in Brain Behavior and Immunity, 49 (2015):101-118,
https://doi.org/10.1016/j.bbi.2015.04.017 . .

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Vujnović, Ivana
AU  - Blagojević, Veljko
AU  - Kosec, Duško
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2326
AB  - Background: Aging influences immune response and susceptibility to EAE in a strain specific manner. The study was designed to examine influence of aging on EAE induction in Albino Oxford (AO) rats. Results: Differently from 3-month-old (young) rats, which were resistant to EAE induction, the majority of aged (24-26-month-old) rats developed mild chronic form of EAE. On 16th day post-immunization, when in aged rats the neurological deficit reached plateau, more mononuclear cells, including CD4+ T lymphocytes was retrieved from spinal cord of aged than young rats. The frequencies of IL-17+ and GM-CSF+ cells within spinal cord infiltrating CD4+ lymphocytes were greater in aged rats. To their increased frequency contributed the expansion of GM-CSF + IL-17 + IFN-gamma+ cells, which are highly pathogenic in mice. The expression of the cytokines (IL-1 beta and IL-23/p19) driving GM-CSF + IL-17 + IFN-gamma + cell differentiation in mice was also augmented in aged rat spinal cord mononuclear cells. Additionally, in aged rat spinal cord the expansion of GM-CSF + IL-17-IFN-gamma- CD4+ T lymphocytes was found. Consistently, the expression of mRNAs for IL-3, the cytokine exhibiting the same expression pattern as GM-CSF, and IL-7, the cytokine driving differentiation of GM-CSF + IL-17-IFN-gamma- CD4 + lymphocytes in mice, was upregulated in aged rat spinal cord mononuclear cells, and the tissue, respectively. This was in accordance with the enhanced generation of the brain antigen-specific GM-CSF+ CD4+ lymphocytes in aged rat draining lymph nodes, as suggested by (i) the higher frequency of GM-CSF+ cells (reflecting the expansion of IL-17-IFN-gamma- cells) within their CD4+ lymphocytes and (ii) the upregulated GM-CSF and IL-3 mRNA expression in fresh CD4+ lymphocytes and MBP-stimulated draining lymph node cells and IL-7 mRNA in lymph node tissue from aged rats. In agreement with the upregulated GM-CSF expression in aged rats, strikingly more CD11b + CD45(int) (activated microglia) and CD45(hi) (mainly proinflammatory dendritic cells and macrophages) cells was retrieved from aged than young rat spinal cord. Besides, expression of mRNA for SOCS1, a negative regulator of proinflammatory cytokine expression in innate immunity cells, was downregulated in aged rat spinal cord mononuclear cells. Conclusions: The study revealed that aging may overcome genetic resistance to EAE, and indicated the cellular and molecular mechanisms contributing to this phenomenon in AO rats.
PB  - BMC, LONDON
T2  - Immunity & Ageing
T1  - Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+T cells in aged rats
VL  - 12
DO  - 10.1186/s12979-015-0044-x
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Vujnović, Ivana and Blagojević, Veljko and Kosec, Duško and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2015",
abstract = "Background: Aging influences immune response and susceptibility to EAE in a strain specific manner. The study was designed to examine influence of aging on EAE induction in Albino Oxford (AO) rats. Results: Differently from 3-month-old (young) rats, which were resistant to EAE induction, the majority of aged (24-26-month-old) rats developed mild chronic form of EAE. On 16th day post-immunization, when in aged rats the neurological deficit reached plateau, more mononuclear cells, including CD4+ T lymphocytes was retrieved from spinal cord of aged than young rats. The frequencies of IL-17+ and GM-CSF+ cells within spinal cord infiltrating CD4+ lymphocytes were greater in aged rats. To their increased frequency contributed the expansion of GM-CSF + IL-17 + IFN-gamma+ cells, which are highly pathogenic in mice. The expression of the cytokines (IL-1 beta and IL-23/p19) driving GM-CSF + IL-17 + IFN-gamma + cell differentiation in mice was also augmented in aged rat spinal cord mononuclear cells. Additionally, in aged rat spinal cord the expansion of GM-CSF + IL-17-IFN-gamma- CD4+ T lymphocytes was found. Consistently, the expression of mRNAs for IL-3, the cytokine exhibiting the same expression pattern as GM-CSF, and IL-7, the cytokine driving differentiation of GM-CSF + IL-17-IFN-gamma- CD4 + lymphocytes in mice, was upregulated in aged rat spinal cord mononuclear cells, and the tissue, respectively. This was in accordance with the enhanced generation of the brain antigen-specific GM-CSF+ CD4+ lymphocytes in aged rat draining lymph nodes, as suggested by (i) the higher frequency of GM-CSF+ cells (reflecting the expansion of IL-17-IFN-gamma- cells) within their CD4+ lymphocytes and (ii) the upregulated GM-CSF and IL-3 mRNA expression in fresh CD4+ lymphocytes and MBP-stimulated draining lymph node cells and IL-7 mRNA in lymph node tissue from aged rats. In agreement with the upregulated GM-CSF expression in aged rats, strikingly more CD11b + CD45(int) (activated microglia) and CD45(hi) (mainly proinflammatory dendritic cells and macrophages) cells was retrieved from aged than young rat spinal cord. Besides, expression of mRNA for SOCS1, a negative regulator of proinflammatory cytokine expression in innate immunity cells, was downregulated in aged rat spinal cord mononuclear cells. Conclusions: The study revealed that aging may overcome genetic resistance to EAE, and indicated the cellular and molecular mechanisms contributing to this phenomenon in AO rats.",
publisher = "BMC, LONDON",
journal = "Immunity & Ageing",
title = "Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+T cells in aged rats",
volume = "12",
doi = "10.1186/s12979-015-0044-x"
}

Stojić-Vukanić, Z., Nacka-Aleksić, M., Pilipović, I., Vujnović, I., Blagojević, V., Kosec, D., Dimitrijević, M.,& Leposavić, G.. (2015). Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+T cells in aged rats. in Immunity & Ageing
BMC, LONDON., 12.
https://doi.org/10.1186/s12979-015-0044-x

Stojić-Vukanić Z, Nacka-Aleksić M, Pilipović I, Vujnović I, Blagojević V, Kosec D, Dimitrijević M, Leposavić G. Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+T cells in aged rats. in Immunity & Ageing. 2015;12.
doi:10.1186/s12979-015-0044-x .

Stojić-Vukanić, Zorica, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Vujnović, Ivana, Blagojević, Veljko, Kosec, Duško, Dimitrijević, Mirjana, Leposavić, Gordana, "Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+T cells in aged rats" in Immunity & Ageing, 12 (2015),
https://doi.org/10.1186/s12979-015-0044-x . .

TY  - JOUR
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Đikić, Jasmina
AU  - Bufan, Biljana
AU  - Leposavić, Gordana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2325
AB  - The study examined the putative role of ovarian hormones in shaping of rat peripheral T-cell compartment during post-reproductive period. In 20-month-old rats ovariectomized (Ox) at the very end of reproductive period, thymic output, cellularity and composition of major TCR alpha beta+peripheral blood lymphocyte and splenocyte subsets were analyzed. Ovariectomy led to the enlargement of CD8 + peripheral blood lymphocyte and splenocyte subpopulations. This reflected: (i) a more efficient thymic generation of CD8 + cells as indicated by increased number of CD4+CD8+double positive and the most mature CD4CD8+TCR alpha beta(high) thymocytes and CD8 + recent thymic emigrants (RTEs) in peripheral blood, but not in the spleen of Ox rats, and (ii) the expansion of CD8 + memory/activated peripheral blood lymphocytes and splenocytes. The latter was consistent with a greater frequency of proliferating cells among freshly isolated memory/activated CD8 + peripheral blood lymphocytes and splenocytes and increased proliferative response of CD8 + splenocytes to stimulation with plate-bound anti-CD3 antibody. The former could be related to the rise in splenic IL-7 and IL-15 mRNA expression. Although ovariectomy affected the overall number of CD4 + T cells in none of the examined compartments, it increased CD4+FoxP3 + peripheral blood lymphocyte and splenocyte counts by enhancing their generation in periphery. Collectively, the results suggest that ovariectomy-induced long-lasting disturbances in ovarian hormone levels (mirrored in diminished progesterone serum level in 20-month-old rats) affects both thymic CD8 + cell generation and peripheral homeostasis and leads to the expansion of CD4+FoxP3 + cells in the periphery, thereby enhancing autoreactive cell control on account of immune system efficacy to combat infections and tumors.
PB  - Sage Publications Ltd, London
T2  - Experimental Biology and Medicine
T1  - Ovarian hormone level alterations during rat post-reproductive life-span influence CD8+T-cell homeostasis
VL  - 240
IS  - 10
SP  - 1319
EP  - 1332
DO  - 10.1177/1535370215570817
ER  - 

@article{
author = "Arsenović-Ranin, Nevena and Kosec, Duško and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Stojić-Vukanić, Zorica and Đikić, Jasmina and Bufan, Biljana and Leposavić, Gordana",
year = "2015",
abstract = "The study examined the putative role of ovarian hormones in shaping of rat peripheral T-cell compartment during post-reproductive period. In 20-month-old rats ovariectomized (Ox) at the very end of reproductive period, thymic output, cellularity and composition of major TCR alpha beta+peripheral blood lymphocyte and splenocyte subsets were analyzed. Ovariectomy led to the enlargement of CD8 + peripheral blood lymphocyte and splenocyte subpopulations. This reflected: (i) a more efficient thymic generation of CD8 + cells as indicated by increased number of CD4+CD8+double positive and the most mature CD4CD8+TCR alpha beta(high) thymocytes and CD8 + recent thymic emigrants (RTEs) in peripheral blood, but not in the spleen of Ox rats, and (ii) the expansion of CD8 + memory/activated peripheral blood lymphocytes and splenocytes. The latter was consistent with a greater frequency of proliferating cells among freshly isolated memory/activated CD8 + peripheral blood lymphocytes and splenocytes and increased proliferative response of CD8 + splenocytes to stimulation with plate-bound anti-CD3 antibody. The former could be related to the rise in splenic IL-7 and IL-15 mRNA expression. Although ovariectomy affected the overall number of CD4 + T cells in none of the examined compartments, it increased CD4+FoxP3 + peripheral blood lymphocyte and splenocyte counts by enhancing their generation in periphery. Collectively, the results suggest that ovariectomy-induced long-lasting disturbances in ovarian hormone levels (mirrored in diminished progesterone serum level in 20-month-old rats) affects both thymic CD8 + cell generation and peripheral homeostasis and leads to the expansion of CD4+FoxP3 + cells in the periphery, thereby enhancing autoreactive cell control on account of immune system efficacy to combat infections and tumors.",
publisher = "Sage Publications Ltd, London",
journal = "Experimental Biology and Medicine",
title = "Ovarian hormone level alterations during rat post-reproductive life-span influence CD8+T-cell homeostasis",
volume = "240",
number = "10",
pages = "1319-1332",
doi = "10.1177/1535370215570817"
}

Arsenović-Ranin, N., Kosec, D., Nacka-Aleksić, M., Pilipović, I., Stojić-Vukanić, Z., Đikić, J., Bufan, B.,& Leposavić, G.. (2015). Ovarian hormone level alterations during rat post-reproductive life-span influence CD8+T-cell homeostasis. in Experimental Biology and Medicine
Sage Publications Ltd, London., 240(10), 1319-1332.
https://doi.org/10.1177/1535370215570817

Arsenović-Ranin N, Kosec D, Nacka-Aleksić M, Pilipović I, Stojić-Vukanić Z, Đikić J, Bufan B, Leposavić G. Ovarian hormone level alterations during rat post-reproductive life-span influence CD8+T-cell homeostasis. in Experimental Biology and Medicine. 2015;240(10):1319-1332.
doi:10.1177/1535370215570817 .

Arsenović-Ranin, Nevena, Kosec, Duško, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Stojić-Vukanić, Zorica, Đikić, Jasmina, Bufan, Biljana, Leposavić, Gordana, "Ovarian hormone level alterations during rat post-reproductive life-span influence CD8+T-cell homeostasis" in Experimental Biology and Medicine, 240, no. 10 (2015):1319-1332,
https://doi.org/10.1177/1535370215570817 . .

TY  - JOUR
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Bufan, Biljana
AU  - Stojić-Vukanić, Zorica
AU  - Radojević, Katarina
AU  - Nacka-Aleksić, Mirjana
AU  - Leposavić, Gordana
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2190
AB  - Objective: Considering a causal role of androgens in thymic involution, age-related remodeling of peripheral T-cell compartments in the absence of testicular hormones was evaluated. Methods: Rats were orchidectomized (ORX) at the age of 1 month, and T-peripheral blood lymphocytes (PBLs) and splenocytes from young (75-day-old) and aged (24-month-old) rats were examined for differentiation/activation and immunoregulatory marker expression. Results: In ORX rats, following the initial rise, the counts of CD4+ and CD8+ PBLs diminished with aging. This reflected the decline in thymic export as shown by recent thymic emigrant (RTE) enumeration. Orchidectomy increased the count of both of the major T-splenocyte subsets in young rats, and they (differently from controls) remained stable with aging. The CD4+:CD8+ T-splenocyte ratio in ORX rats shifted towards CD4+ cells compared to age-matched controls. Although in the major T-cell subsets in the blood and spleen from aged ORX rats the numbers of RTEs were comparable to the corresponding values in age-matched controls, the numbers of mature naive and memory/activated cells substantially differed. Compared with age-matched controls, in aged ORX rats the numbers of CD4+ mature naive PBLs and splenocytes were reduced, whereas those of CD4+ memory/activated cells (predictive of early mortality) were increased. Additionally, in spleens from aged ORX rats, despite unaltered thymic export, CD4+CD25+FoxP3+ and natural killer T cell counts were greater than in age-matched controls. Conclusion: (i) Age-related decline in thymopoietic efficacy is not dependent on androgen presence, and (ii) androgens are involved in the maintenance of peripheral T-cell (particularly CD4+ cell) homeostasis during aging.
PB  - Karger, Basel
T2  - NeuroImmunoModulation
T1  - Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way
VL  - 21
IS  - 4
SP  - 161
EP  - 182
DO  - 10.1159/000355349
ER  - 

@article{
author = "Arsenović-Ranin, Nevena and Kosec, Duško and Pilipović, Ivan and Bufan, Biljana and Stojić-Vukanić, Zorica and Radojević, Katarina and Nacka-Aleksić, Mirjana and Leposavić, Gordana",
year = "2014",
abstract = "Objective: Considering a causal role of androgens in thymic involution, age-related remodeling of peripheral T-cell compartments in the absence of testicular hormones was evaluated. Methods: Rats were orchidectomized (ORX) at the age of 1 month, and T-peripheral blood lymphocytes (PBLs) and splenocytes from young (75-day-old) and aged (24-month-old) rats were examined for differentiation/activation and immunoregulatory marker expression. Results: In ORX rats, following the initial rise, the counts of CD4+ and CD8+ PBLs diminished with aging. This reflected the decline in thymic export as shown by recent thymic emigrant (RTE) enumeration. Orchidectomy increased the count of both of the major T-splenocyte subsets in young rats, and they (differently from controls) remained stable with aging. The CD4+:CD8+ T-splenocyte ratio in ORX rats shifted towards CD4+ cells compared to age-matched controls. Although in the major T-cell subsets in the blood and spleen from aged ORX rats the numbers of RTEs were comparable to the corresponding values in age-matched controls, the numbers of mature naive and memory/activated cells substantially differed. Compared with age-matched controls, in aged ORX rats the numbers of CD4+ mature naive PBLs and splenocytes were reduced, whereas those of CD4+ memory/activated cells (predictive of early mortality) were increased. Additionally, in spleens from aged ORX rats, despite unaltered thymic export, CD4+CD25+FoxP3+ and natural killer T cell counts were greater than in age-matched controls. Conclusion: (i) Age-related decline in thymopoietic efficacy is not dependent on androgen presence, and (ii) androgens are involved in the maintenance of peripheral T-cell (particularly CD4+ cell) homeostasis during aging.",
publisher = "Karger, Basel",
journal = "NeuroImmunoModulation",
title = "Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way",
volume = "21",
number = "4",
pages = "161-182",
doi = "10.1159/000355349"
}

Arsenović-Ranin, N., Kosec, D., Pilipović, I., Bufan, B., Stojić-Vukanić, Z., Radojević, K., Nacka-Aleksić, M.,& Leposavić, G.. (2014). Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way. in NeuroImmunoModulation
Karger, Basel., 21(4), 161-182.
https://doi.org/10.1159/000355349

Arsenović-Ranin N, Kosec D, Pilipović I, Bufan B, Stojić-Vukanić Z, Radojević K, Nacka-Aleksić M, Leposavić G. Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way. in NeuroImmunoModulation. 2014;21(4):161-182.
doi:10.1159/000355349 .

Arsenović-Ranin, Nevena, Kosec, Duško, Pilipović, Ivan, Bufan, Biljana, Stojić-Vukanić, Zorica, Radojević, Katarina, Nacka-Aleksić, Mirjana, Leposavić, Gordana, "Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way" in NeuroImmunoModulation, 21, no. 4 (2014):161-182,
https://doi.org/10.1159/000355349 . .

TY  - JOUR
AU  - Leposavić, Gordana
AU  - Perišić-Nanut, Milica
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Arsenović-Ranin, Nevena
AU  - Stojić-Vukanić, Zorica
AU  - Đikić, Jasmina
AU  - Nacka-Aleksić, Mirjana
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2180
AB  - This study explores the role of ovarian hormones in the phenotypic shaping of peripheral T-cell pool over the reproductive lifespan of rats. For this purpose, 2-month-old prepubertally ovariectomised (Ox) rats, showing oestrogen and progesterone deficiency, and 11-month-old Ox rats, exhibiting only progesterone deficiency, were examined for thymus output, and cellularity and composition of major TCR alpha beta+ peripheral blood lymphocyte (PBL) and splenocyte subsets. Although ovariectomy increased thymic output in both 2- and 11-month-old rats, the count of both CD4+ and CD8+ PBLs and splenocytes increased only in the former. In the blood and spleen of 11-month-old Ox rats only the count of CD8+ cells increased. Although ovariectomy affected the total CD4+ count in none of the examined compartments from the 11-month-old rats, it increased CD4+FoxP3+ PBL and splenocyte relative proportions over those in the age-matched controls. The age-related differences in the cellularity and the major subset composition in Ox rats were linked to the differences in the ovarian steroid hormone levels registered in 2- and 11-month-old rats. The administration of progesterone to Ox rats during the seven days before the sacrificing confirmed contribution of this hormone deficiency to the ovariectomy-induced changes in the TCR alpha beta+ PBL and splenocyte pool from 11-month-old rats. The expansion of the CD8+ splenocyte subset in the 11-month-old Ox rats reflected increases in cellularity of memory and, particularly, nave cells. This was due to greater thymic output of CD8+ cells and homeostatic proliferation than apoptosis in 11-month-old Ox rats when compared with age-matched sham-Ox control rats. The homeostatic changes within CD8+ splenocyte pool from 11-month-old Ox rats, most likely, reflected the enhanced splenic IL-7 and TGF-beta mRNA expression. Overall, in adult female rats, circulating oestrogen and progesterone provide maintenance of T-cell counts, a diversity of T-cell repertoire, and the main T-cell subset composition in the periphery. Progesterone deficiency affects mainly the CD8+ lymphocyte compartment through increasing thymic CD8+ cell export and upsetting homeostatic regulation within the CD8+ splenocyte pool. These alterations were reversible through progesterone supplementation.
PB  - Elsevier Gmbh, Urban & Fischer Verlag, Jena
T2  - Immunobiology
T1  - Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency
VL  - 219
IS  - 2
SP  - 118
EP  - 130
DO  - 10.1016/j.imbio.2013.08.004
ER  - 

@article{
author = "Leposavić, Gordana and Perišić-Nanut, Milica and Pilipović, Ivan and Kosec, Duško and Arsenović-Ranin, Nevena and Stojić-Vukanić, Zorica and Đikić, Jasmina and Nacka-Aleksić, Mirjana",
year = "2014",
abstract = "This study explores the role of ovarian hormones in the phenotypic shaping of peripheral T-cell pool over the reproductive lifespan of rats. For this purpose, 2-month-old prepubertally ovariectomised (Ox) rats, showing oestrogen and progesterone deficiency, and 11-month-old Ox rats, exhibiting only progesterone deficiency, were examined for thymus output, and cellularity and composition of major TCR alpha beta+ peripheral blood lymphocyte (PBL) and splenocyte subsets. Although ovariectomy increased thymic output in both 2- and 11-month-old rats, the count of both CD4+ and CD8+ PBLs and splenocytes increased only in the former. In the blood and spleen of 11-month-old Ox rats only the count of CD8+ cells increased. Although ovariectomy affected the total CD4+ count in none of the examined compartments from the 11-month-old rats, it increased CD4+FoxP3+ PBL and splenocyte relative proportions over those in the age-matched controls. The age-related differences in the cellularity and the major subset composition in Ox rats were linked to the differences in the ovarian steroid hormone levels registered in 2- and 11-month-old rats. The administration of progesterone to Ox rats during the seven days before the sacrificing confirmed contribution of this hormone deficiency to the ovariectomy-induced changes in the TCR alpha beta+ PBL and splenocyte pool from 11-month-old rats. The expansion of the CD8+ splenocyte subset in the 11-month-old Ox rats reflected increases in cellularity of memory and, particularly, nave cells. This was due to greater thymic output of CD8+ cells and homeostatic proliferation than apoptosis in 11-month-old Ox rats when compared with age-matched sham-Ox control rats. The homeostatic changes within CD8+ splenocyte pool from 11-month-old Ox rats, most likely, reflected the enhanced splenic IL-7 and TGF-beta mRNA expression. Overall, in adult female rats, circulating oestrogen and progesterone provide maintenance of T-cell counts, a diversity of T-cell repertoire, and the main T-cell subset composition in the periphery. Progesterone deficiency affects mainly the CD8+ lymphocyte compartment through increasing thymic CD8+ cell export and upsetting homeostatic regulation within the CD8+ splenocyte pool. These alterations were reversible through progesterone supplementation.",
publisher = "Elsevier Gmbh, Urban & Fischer Verlag, Jena",
journal = "Immunobiology",
title = "Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency",
volume = "219",
number = "2",
pages = "118-130",
doi = "10.1016/j.imbio.2013.08.004"
}

Leposavić, G., Perišić-Nanut, M., Pilipović, I., Kosec, D., Arsenović-Ranin, N., Stojić-Vukanić, Z., Đikić, J.,& Nacka-Aleksić, M.. (2014). Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency. in Immunobiology
Elsevier Gmbh, Urban & Fischer Verlag, Jena., 219(2), 118-130.
https://doi.org/10.1016/j.imbio.2013.08.004

Leposavić G, Perišić-Nanut M, Pilipović I, Kosec D, Arsenović-Ranin N, Stojić-Vukanić Z, Đikić J, Nacka-Aleksić M. Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency. in Immunobiology. 2014;219(2):118-130.
doi:10.1016/j.imbio.2013.08.004 .

Leposavić, Gordana, Perišić-Nanut, Milica, Pilipović, Ivan, Kosec, Duško, Arsenović-Ranin, Nevena, Stojić-Vukanić, Zorica, Đikić, Jasmina, Nacka-Aleksić, Mirjana, "Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency" in Immunobiology, 219, no. 2 (2014):118-130,
https://doi.org/10.1016/j.imbio.2013.08.004 . .

TY  - JOUR
AU  - Đikić, Jasmina
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Bufan, Biljana
AU  - Kosec, Duško
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2139
AB  - Aging is associated with the decline in immune response to infectious agents and tumors and increasing risk of autoimmunity, but the incidence of autoimmune diseases does not increase in the elderly. To elucidate the cellular and molecular mechanisms influencing clinical expression of autoimmunity in aged animals, the phenotypic and functional characteristics of mononuclear cells isolated from the spinal cords of 3-month-old (young) and 26-month-old (aged) Dark Agouti rats immunized to induce experimental autoimmune encephalomyelitis (EAE) - the model of multiple sclerosis, the most common autoimmune disease of the central nervous system, were examined. Aged rats were less susceptible to EAE induction, and the neurological and histological picture was milder in those rats which developed the clinically manifested disease. At the peak of the disease, several times fewer mononuclear cells and T lymphocytes were isolated from the spinal cords of aged rats compared with the young ones. The frequency of CD4+ cells among TCR alpha beta+ lymphocytes, as well as that of reactivated CD134(OX40)+ cells within its CD4+ T-lymphocyte subpopulation, was less in spinal cords of aged compared with young rats. Additionally, CD134 surface density on CD4+ lymphocytes was decreased in the spinal cord of aged rats. The changes in CD134 expression most likely reflected in part age-related intrinsic changes in CD4+ lymphocytes as the expression of this molecule was also impaired on in vitro stimulated naive CD4+ splenocytes from aged rats compared with young animals. In addition, greater frequency of CD8+ lymphocytes with regulatory phenotypes could also contribute to impaired CD4+ cell reactivation in aged rats. The increased apoptosis of CD4+ cells from aged rats was consistent with their impaired reactivation and it was accompanied by the greater frequency of CD4+CD11b+CD45(int/high) cells, which are supposed to be actively engaged in apoptotic cell phagocytosis and to have immunoregulatory properties. Compared with young rats, following short-term PMA and ionomycin stimulation in vitro, the frequency of IL-17+ and IFN-gamma+CD4+ T lymphocytes among the spinal cord mononuclear cells from aged rats and the cytokine expression density on a per lymphocyte basis were reduced. Additionally, the increase in the proportion of autoregulatory IL-17+IL-10+ cells on the account of proinflammatory IL-17+IFN-gamma+ cells within IL-17+ lymphocytes suggested their lower pathogenic capacity in aged rats. This most likely reflected alterations in the aged rat spinal cord cytokine milieu, which were mirrored in a diminished expression of IL-1 beta mRNA followed by an enhanced expression of IL-6 and TGF-beta mRNA. Overall, the study points to age-related changes in T lymphocytes and other cells from the spinal cord infiltrate which could contribute to the decreased susceptibility of aged rats to the induction of EAE.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Experimental Gerontology
T1  - Age-associated changes in rat immune system: Lessons learned from experimental autoimmune encephalomyelitis
VL  - 58
SP  - 179
EP  - 197
DO  - 10.1016/j.exger.2014.08.005
ER  - 

@article{
author = "Đikić, Jasmina and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Stojić-Vukanić, Zorica and Bufan, Biljana and Kosec, Duško and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2014",
abstract = "Aging is associated with the decline in immune response to infectious agents and tumors and increasing risk of autoimmunity, but the incidence of autoimmune diseases does not increase in the elderly. To elucidate the cellular and molecular mechanisms influencing clinical expression of autoimmunity in aged animals, the phenotypic and functional characteristics of mononuclear cells isolated from the spinal cords of 3-month-old (young) and 26-month-old (aged) Dark Agouti rats immunized to induce experimental autoimmune encephalomyelitis (EAE) - the model of multiple sclerosis, the most common autoimmune disease of the central nervous system, were examined. Aged rats were less susceptible to EAE induction, and the neurological and histological picture was milder in those rats which developed the clinically manifested disease. At the peak of the disease, several times fewer mononuclear cells and T lymphocytes were isolated from the spinal cords of aged rats compared with the young ones. The frequency of CD4+ cells among TCR alpha beta+ lymphocytes, as well as that of reactivated CD134(OX40)+ cells within its CD4+ T-lymphocyte subpopulation, was less in spinal cords of aged compared with young rats. Additionally, CD134 surface density on CD4+ lymphocytes was decreased in the spinal cord of aged rats. The changes in CD134 expression most likely reflected in part age-related intrinsic changes in CD4+ lymphocytes as the expression of this molecule was also impaired on in vitro stimulated naive CD4+ splenocytes from aged rats compared with young animals. In addition, greater frequency of CD8+ lymphocytes with regulatory phenotypes could also contribute to impaired CD4+ cell reactivation in aged rats. The increased apoptosis of CD4+ cells from aged rats was consistent with their impaired reactivation and it was accompanied by the greater frequency of CD4+CD11b+CD45(int/high) cells, which are supposed to be actively engaged in apoptotic cell phagocytosis and to have immunoregulatory properties. Compared with young rats, following short-term PMA and ionomycin stimulation in vitro, the frequency of IL-17+ and IFN-gamma+CD4+ T lymphocytes among the spinal cord mononuclear cells from aged rats and the cytokine expression density on a per lymphocyte basis were reduced. Additionally, the increase in the proportion of autoregulatory IL-17+IL-10+ cells on the account of proinflammatory IL-17+IFN-gamma+ cells within IL-17+ lymphocytes suggested their lower pathogenic capacity in aged rats. This most likely reflected alterations in the aged rat spinal cord cytokine milieu, which were mirrored in a diminished expression of IL-1 beta mRNA followed by an enhanced expression of IL-6 and TGF-beta mRNA. Overall, the study points to age-related changes in T lymphocytes and other cells from the spinal cord infiltrate which could contribute to the decreased susceptibility of aged rats to the induction of EAE.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Experimental Gerontology",
title = "Age-associated changes in rat immune system: Lessons learned from experimental autoimmune encephalomyelitis",
volume = "58",
pages = "179-197",
doi = "10.1016/j.exger.2014.08.005"
}

Đikić, J., Nacka-Aleksić, M., Pilipović, I., Stojić-Vukanić, Z., Bufan, B., Kosec, D., Dimitrijević, M.,& Leposavić, G.. (2014). Age-associated changes in rat immune system: Lessons learned from experimental autoimmune encephalomyelitis. in Experimental Gerontology
Pergamon-Elsevier Science Ltd, Oxford., 58, 179-197.
https://doi.org/10.1016/j.exger.2014.08.005

Đikić J, Nacka-Aleksić M, Pilipović I, Stojić-Vukanić Z, Bufan B, Kosec D, Dimitrijević M, Leposavić G. Age-associated changes in rat immune system: Lessons learned from experimental autoimmune encephalomyelitis. in Experimental Gerontology. 2014;58:179-197.
doi:10.1016/j.exger.2014.08.005 .

Đikić, Jasmina, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Stojić-Vukanić, Zorica, Bufan, Biljana, Kosec, Duško, Dimitrijević, Mirjana, Leposavić, Gordana, "Age-associated changes in rat immune system: Lessons learned from experimental autoimmune encephalomyelitis" in Experimental Gerontology, 58 (2014):179-197,
https://doi.org/10.1016/j.exger.2014.08.005 . .

TY  - JOUR
AU  - Radojević, Katarina
AU  - Rakin, Ana
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Đikić, Jasmina
AU  - Bufan, Biljana
AU  - Vujnović, Ivana
AU  - Leposavić, Gordana
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2182
AB  - The present study, through quantification of tyrosine hydroxylase (TH) expression and catecholamine (CA) content in the presence and in the absence of alpha-methyl-p-tyrosine (AMPT), a TH inhibitor, in adult thymic organ (ATOC) and thymocyte culture, demonstrated that thymic cells produce CAs. In addition, in ATOC an increase in beta(2)-adrenoceptor (AR) mRNA expression and beta(2)-AR thymocyte surface density was registered. Furthermore, AMPT (10(-4) M), as propranolol (10(-4) M), augmented thymocyte apoptosis and diminished thymocyte proliferation in ATOC. Propranolol exerted these effects acting on CD3(high) thymocytes. However, in thymocyte cultures, propranolol (10(-6) M) acting on the same-thymocyte subset exerted the opposing effect on thymocyte apoptosis and ConA-stimulated proliferation. This suggested that, depending on thymocyte microenvironment, differential effects can be induced through the same type of AR. Additionally, arterenol (10(-8) to 10(-6) M), similar to propranolol, diminished apoptosis, but increased ConA-stimulated thymocyte proliferation in thymocyte culture. However, differently from propranolol, arterenol affected manly CD3- thymocyte subset, which harbors majority of alpha(1)-AR+ thymocytes. Additionally, arterenol showed a dose-dependent decrease in efficiency of thymocyte apoptosis and proliferation modulation with the rise in its concentration. Considering greater affinity of arterenol for alpha(1)-ARs than for beta(2)-ARs, the previous findings could be attributable to increased engagement of beta(2)-ARs with the rise of arterenol concentration. Consistently, in the presence of propranolol (10(-6) M), a beta-AR blacker, the arterenol (10(-8) M) effects on thymocytes were augmented. In conclusion, thymic endogenous CAs, acting through distinct AR types and, possible, the same AR type (but in different cell microenvironment) may exert the opposing effects on thymocyte apoptosis/proliferation.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Neuroimmunology
T1  - Effects of catecholamines on thymocyte apoptosis and proliferation depend on thymocyte microenvironment
VL  - 272
IS  - 1-2
SP  - 16
EP  - 28
DO  - 10.1016/j.jneuroim.2014.04.010
ER  - 

@article{
author = "Radojević, Katarina and Rakin, Ana and Pilipović, Ivan and Kosec, Duško and Đikić, Jasmina and Bufan, Biljana and Vujnović, Ivana and Leposavić, Gordana",
year = "2014",
abstract = "The present study, through quantification of tyrosine hydroxylase (TH) expression and catecholamine (CA) content in the presence and in the absence of alpha-methyl-p-tyrosine (AMPT), a TH inhibitor, in adult thymic organ (ATOC) and thymocyte culture, demonstrated that thymic cells produce CAs. In addition, in ATOC an increase in beta(2)-adrenoceptor (AR) mRNA expression and beta(2)-AR thymocyte surface density was registered. Furthermore, AMPT (10(-4) M), as propranolol (10(-4) M), augmented thymocyte apoptosis and diminished thymocyte proliferation in ATOC. Propranolol exerted these effects acting on CD3(high) thymocytes. However, in thymocyte cultures, propranolol (10(-6) M) acting on the same-thymocyte subset exerted the opposing effect on thymocyte apoptosis and ConA-stimulated proliferation. This suggested that, depending on thymocyte microenvironment, differential effects can be induced through the same type of AR. Additionally, arterenol (10(-8) to 10(-6) M), similar to propranolol, diminished apoptosis, but increased ConA-stimulated thymocyte proliferation in thymocyte culture. However, differently from propranolol, arterenol affected manly CD3- thymocyte subset, which harbors majority of alpha(1)-AR+ thymocytes. Additionally, arterenol showed a dose-dependent decrease in efficiency of thymocyte apoptosis and proliferation modulation with the rise in its concentration. Considering greater affinity of arterenol for alpha(1)-ARs than for beta(2)-ARs, the previous findings could be attributable to increased engagement of beta(2)-ARs with the rise of arterenol concentration. Consistently, in the presence of propranolol (10(-6) M), a beta-AR blacker, the arterenol (10(-8) M) effects on thymocytes were augmented. In conclusion, thymic endogenous CAs, acting through distinct AR types and, possible, the same AR type (but in different cell microenvironment) may exert the opposing effects on thymocyte apoptosis/proliferation.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Neuroimmunology",
title = "Effects of catecholamines on thymocyte apoptosis and proliferation depend on thymocyte microenvironment",
volume = "272",
number = "1-2",
pages = "16-28",
doi = "10.1016/j.jneuroim.2014.04.010"
}

Radojević, K., Rakin, A., Pilipović, I., Kosec, D., Đikić, J., Bufan, B., Vujnović, I.,& Leposavić, G.. (2014). Effects of catecholamines on thymocyte apoptosis and proliferation depend on thymocyte microenvironment. in Journal of Neuroimmunology
Elsevier Science BV, Amsterdam., 272(1-2), 16-28.
https://doi.org/10.1016/j.jneuroim.2014.04.010

Radojević K, Rakin A, Pilipović I, Kosec D, Đikić J, Bufan B, Vujnović I, Leposavić G. Effects of catecholamines on thymocyte apoptosis and proliferation depend on thymocyte microenvironment. in Journal of Neuroimmunology. 2014;272(1-2):16-28.
doi:10.1016/j.jneuroim.2014.04.010 .

Radojević, Katarina, Rakin, Ana, Pilipović, Ivan, Kosec, Duško, Đikić, Jasmina, Bufan, Biljana, Vujnović, Ivana, Leposavić, Gordana, "Effects of catecholamines on thymocyte apoptosis and proliferation depend on thymocyte microenvironment" in Journal of Neuroimmunology, 272, no. 1-2 (2014):16-28,
https://doi.org/10.1016/j.jneuroim.2014.04.010 . .

TY  - JOUR
AU  - Arsenović-Ranin, Nevena
AU  - Nacka-Aleksić, Mirjana
AU  - Đikić, Jasmina
AU  - Perišić, Milica
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2057
AB  - The study was aimed to define the putative role of ovarian hormones in shaping thymocyte apoptosis and proliferation during thymic involution. Thymocytes from young adult and middle-aged rats ovariectomized (Ox) before puberty were examined for apoptosis and proliferation. Apoptosis and proliferation were measured in fresh thymocyte suspensions and in their 18-hour cultures, and fresh thymocyte suspensions, respectively. The thymocyte population and the major thymocyte subsets were analyzed following triple staining using anti-CD4 and anti-CD8 monoclonal antibodies and 7-AAD to label apoptotic or proliferating cells. The frequency of apoptotic cells was lower in thymocyte suspensions and cultures from Ox rats of both ages. This reflected in a diminished frequency of apoptotic cells amongst CD4+CD8+ double positive (DP) and CD4+CD8- single positive (SP), and DP cells in young and middle-aged Ox rats, respectively. Additionally, in thymocyte cultures from Ox rats the frequency of apoptotic cells amongst CD4+CD8- and CD4-CD8+ SP cells decreased with age, but increased within DP and CD4-CD8- double negative (DN) subsets, reaching in the former subset from middle-aged Ox rats higher values than in age-matched controls. The frequency of proliferating cells was also lower in Ox rats than in controls. This reflected the lower frequency of cycling cells amongst CD4+CD8- SP and CD4-CD8+ SP thymocytes in young rats, and DP and CD4-CD8+ SP thymocytes in middle-aged rats. Besides, in both SP and DP thymocyte subsets from Ox rats the frequency of proliferating cells declined with age. In conclusion, thymocyte apoptosis and proliferation exhibit ovarian hormone-dependent thymocyte subset specific alterations during thymic involution.
AB  - Cilj istraživanja je bio da se definiše značaj hormona ovarijuma za razvoj promena u apoptozi i proliferaciji timocita tokom involucije timusa. U tom cilju apoptoza i proliferacija timocita ispitivana je kod prepubertetno ovariektomisanih (Ox) mladih (uzrasta 2 meseca) i sredovečnih pacova (uzrasta 11 meseci). Apoptoza je određivana u suspenziji sveže izolovanih timocita i nakon njihove 18- časovne kultivacije, a proliferacija u suspenziji sveže izolovanih timocita. Procenat apoptotičnih i proliferišućih ćelija je određivan u celokupnoj populaciji timocita, i unutar glavnih subpopulacija ovih ćelija, koje su razdvojene na osnovu ekspresije CD4/CD8 molekula, metodom protočne fluorocitometrije, korišćenjem 7-aminoaktinomicina D (7-AAD). Procenat ćelija u apoptozi je bio značajno manji u suspenzijama svežih timocita koji su izolovani iz Ox životinja i u njihovim kulturama nego u onim izolovanim iz kontrolnih životinja. Ovaj nalaz je odražavao smanjenu učestalost ćelija u apoptozi u CD4+CD8+ dvostruko pozitivnoj (DP) i CD4+CD8- jednostruko pozitivnoj (JP) subpopulaciji timocita kod mladih i u DP subpopulaciji kod sredovečnih Ox pacova. U kulturama timocita koji su izolovani iz sredovečnih Ox pacova uočeno je smanjenje učestalosti ćelija u apoptozi unutar subpopulacija CD4+CD8- i CD4-CD8+ JP timocita, a povećanje unutar DP i CD4-CD8- dvostruko negativne (DN) subpopulacije ovih ćelija. Učestalost proliferišućih ćelija je takođe bila niža u suspenzijama timocita izolovanih iz Ox pacova nego u onim izolovanim iz kontrolnih životinja. Ovo je odražavalo smanjenu proliferaciju CD4+CD8- i CD4-CD8+ JP timocita kod mladih, a DP i CD4-CD8+ JP timocita kod sredovečnih pacova. Procentualna zastupljenost proliferišućih ćelija u subpopulacijama JP i DP timocita je bila veća kod mladih nego kod sredovečnih Ox pacova. U zaključku, tokom involucije timusa dolazi do promena u apoptozi i proliferaciji timocita koje su specifične za pojedine subpopulacije timocita i zavisne od prisustva hormona ovarijuma.
PB  - Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd
T2  - Acta veterinaria
T1  - Thymocyte apoptosis and proliferation modeling during rat thymic involution is influenced by ovarian hormones in a thymocyte subset-specific manner
T1  - Hormoni ovarijuma imaju različit uticaj na modelovanje apoptoze i proliferacije unutar različitih subpopulacija timocita tokom involucije timusa
VL  - 63
IS  - 1
SP  - 3
EP  - 21
DO  - 10.2298/AVB1301003A
ER  - 

@article{
author = "Arsenović-Ranin, Nevena and Nacka-Aleksić, Mirjana and Đikić, Jasmina and Perišić, Milica and Kosec, Duško and Pilipović, Ivan and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2013",
abstract = "The study was aimed to define the putative role of ovarian hormones in shaping thymocyte apoptosis and proliferation during thymic involution. Thymocytes from young adult and middle-aged rats ovariectomized (Ox) before puberty were examined for apoptosis and proliferation. Apoptosis and proliferation were measured in fresh thymocyte suspensions and in their 18-hour cultures, and fresh thymocyte suspensions, respectively. The thymocyte population and the major thymocyte subsets were analyzed following triple staining using anti-CD4 and anti-CD8 monoclonal antibodies and 7-AAD to label apoptotic or proliferating cells. The frequency of apoptotic cells was lower in thymocyte suspensions and cultures from Ox rats of both ages. This reflected in a diminished frequency of apoptotic cells amongst CD4+CD8+ double positive (DP) and CD4+CD8- single positive (SP), and DP cells in young and middle-aged Ox rats, respectively. Additionally, in thymocyte cultures from Ox rats the frequency of apoptotic cells amongst CD4+CD8- and CD4-CD8+ SP cells decreased with age, but increased within DP and CD4-CD8- double negative (DN) subsets, reaching in the former subset from middle-aged Ox rats higher values than in age-matched controls. The frequency of proliferating cells was also lower in Ox rats than in controls. This reflected the lower frequency of cycling cells amongst CD4+CD8- SP and CD4-CD8+ SP thymocytes in young rats, and DP and CD4-CD8+ SP thymocytes in middle-aged rats. Besides, in both SP and DP thymocyte subsets from Ox rats the frequency of proliferating cells declined with age. In conclusion, thymocyte apoptosis and proliferation exhibit ovarian hormone-dependent thymocyte subset specific alterations during thymic involution., Cilj istraživanja je bio da se definiše značaj hormona ovarijuma za razvoj promena u apoptozi i proliferaciji timocita tokom involucije timusa. U tom cilju apoptoza i proliferacija timocita ispitivana je kod prepubertetno ovariektomisanih (Ox) mladih (uzrasta 2 meseca) i sredovečnih pacova (uzrasta 11 meseci). Apoptoza je određivana u suspenziji sveže izolovanih timocita i nakon njihove 18- časovne kultivacije, a proliferacija u suspenziji sveže izolovanih timocita. Procenat apoptotičnih i proliferišućih ćelija je određivan u celokupnoj populaciji timocita, i unutar glavnih subpopulacija ovih ćelija, koje su razdvojene na osnovu ekspresije CD4/CD8 molekula, metodom protočne fluorocitometrije, korišćenjem 7-aminoaktinomicina D (7-AAD). Procenat ćelija u apoptozi je bio značajno manji u suspenzijama svežih timocita koji su izolovani iz Ox životinja i u njihovim kulturama nego u onim izolovanim iz kontrolnih životinja. Ovaj nalaz je odražavao smanjenu učestalost ćelija u apoptozi u CD4+CD8+ dvostruko pozitivnoj (DP) i CD4+CD8- jednostruko pozitivnoj (JP) subpopulaciji timocita kod mladih i u DP subpopulaciji kod sredovečnih Ox pacova. U kulturama timocita koji su izolovani iz sredovečnih Ox pacova uočeno je smanjenje učestalosti ćelija u apoptozi unutar subpopulacija CD4+CD8- i CD4-CD8+ JP timocita, a povećanje unutar DP i CD4-CD8- dvostruko negativne (DN) subpopulacije ovih ćelija. Učestalost proliferišućih ćelija je takođe bila niža u suspenzijama timocita izolovanih iz Ox pacova nego u onim izolovanim iz kontrolnih životinja. Ovo je odražavalo smanjenu proliferaciju CD4+CD8- i CD4-CD8+ JP timocita kod mladih, a DP i CD4-CD8+ JP timocita kod sredovečnih pacova. Procentualna zastupljenost proliferišućih ćelija u subpopulacijama JP i DP timocita je bila veća kod mladih nego kod sredovečnih Ox pacova. U zaključku, tokom involucije timusa dolazi do promena u apoptozi i proliferaciji timocita koje su specifične za pojedine subpopulacije timocita i zavisne od prisustva hormona ovarijuma.",
publisher = "Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd",
journal = "Acta veterinaria",
title = "Thymocyte apoptosis and proliferation modeling during rat thymic involution is influenced by ovarian hormones in a thymocyte subset-specific manner, Hormoni ovarijuma imaju različit uticaj na modelovanje apoptoze i proliferacije unutar različitih subpopulacija timocita tokom involucije timusa",
volume = "63",
number = "1",
pages = "3-21",
doi = "10.2298/AVB1301003A"
}

Arsenović-Ranin, N., Nacka-Aleksić, M., Đikić, J., Perišić, M., Kosec, D., Pilipović, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2013). Thymocyte apoptosis and proliferation modeling during rat thymic involution is influenced by ovarian hormones in a thymocyte subset-specific manner. in Acta veterinaria
Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd., 63(1), 3-21.
https://doi.org/10.2298/AVB1301003A

Arsenović-Ranin N, Nacka-Aleksić M, Đikić J, Perišić M, Kosec D, Pilipović I, Stojić-Vukanić Z, Leposavić G. Thymocyte apoptosis and proliferation modeling during rat thymic involution is influenced by ovarian hormones in a thymocyte subset-specific manner. in Acta veterinaria. 2013;63(1):3-21.
doi:10.2298/AVB1301003A .

Arsenović-Ranin, Nevena, Nacka-Aleksić, Mirjana, Đikić, Jasmina, Perišić, Milica, Kosec, Duško, Pilipović, Ivan, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Thymocyte apoptosis and proliferation modeling during rat thymic involution is influenced by ovarian hormones in a thymocyte subset-specific manner" in Acta veterinaria, 63, no. 1 (2013):3-21,
https://doi.org/10.2298/AVB1301003A . .

TY  - JOUR
AU  - Perišić, Milica
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Nacka-Aleksić, Mirjana
AU  - Đikić, Jasmina
AU  - Arsenović-Ranin, Nevena
AU  - Leposavić, Gordana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1915
AB  - The study explored the putative role of ovarian hormones in the peripubertal remodelling of peripheral T-cell compartment. Ovariectomy at age of 1 month enhanced the peripubertal rise in CD4+ and CD8+ cell numbers in peripheral blood (PB) and spleen from 2-month-old rats. This reflected maintenance of thymopoietic efficiency at the prepubertal level (judging by numbers of the most mature CD4+ and CD8+ thymocytes and recent thymic emigrants) and alterations in T-cell survival/proliferation in the periphery. Compared with age-matched controls, the frequency of apoptotic cells among CD8+ peripheral blood lymphocytes (PBLs) and CD4+ and CD8+ splenocytes was diminished in ovariectomized (Ox) rats, at least partly, due to lower CD95 surface density. The diminished frequency of the apoptotic T splenocytes could also be associated with the rise in the amount of splenic IL-7 mRNA. Additionally, the latter finding was consistent with the augmented proliferation of CD4+ and CD8+ splenocytes. However, the enhanced proliferation of these cells could also be linked to the rise in IL-2 receptor surface density. This increase was related to the enhanced splenic TNF-alpha mRNA expression. Additionally, ovariectomy led to the phenotypic alterations in the major PBL and splenic T-cell subsets by diminishing/preventing the peripubertal changes in the frequency of cells at distinct stages of post-thymic differentiation/maturation (recent thymic emigrants, mature naive and memory cells), and by decreasing the frequency of NKT cells within peripheral CD8+ subsets. In addition to numerical and phenotypic changes in T-cell compartment (due to the lack of ovarian hormone action at both the thymic and peripheral level), Ox rats exhibited a much larger delayed-type hypersensitivity (DTH) response compared with age-matched controls. This suggested the augmented T-cell-mediated immune response in Ox rats compared with aged-matched controls.
PB  - Elsevier Gmbh, Urban & Fischer Verlag, Jena
T2  - Immunobiology
T1  - Role of ovarian hormones in T-cell homeostasis: From the thymus to the periphery
VL  - 218
IS  - 3
SP  - 353
EP  - 367
DO  - 10.1016/j.imbio.2012.05.009
ER  - 

@article{
author = "Perišić, Milica and Stojić-Vukanić, Zorica and Pilipović, Ivan and Kosec, Duško and Nacka-Aleksić, Mirjana and Đikić, Jasmina and Arsenović-Ranin, Nevena and Leposavić, Gordana",
year = "2013",
abstract = "The study explored the putative role of ovarian hormones in the peripubertal remodelling of peripheral T-cell compartment. Ovariectomy at age of 1 month enhanced the peripubertal rise in CD4+ and CD8+ cell numbers in peripheral blood (PB) and spleen from 2-month-old rats. This reflected maintenance of thymopoietic efficiency at the prepubertal level (judging by numbers of the most mature CD4+ and CD8+ thymocytes and recent thymic emigrants) and alterations in T-cell survival/proliferation in the periphery. Compared with age-matched controls, the frequency of apoptotic cells among CD8+ peripheral blood lymphocytes (PBLs) and CD4+ and CD8+ splenocytes was diminished in ovariectomized (Ox) rats, at least partly, due to lower CD95 surface density. The diminished frequency of the apoptotic T splenocytes could also be associated with the rise in the amount of splenic IL-7 mRNA. Additionally, the latter finding was consistent with the augmented proliferation of CD4+ and CD8+ splenocytes. However, the enhanced proliferation of these cells could also be linked to the rise in IL-2 receptor surface density. This increase was related to the enhanced splenic TNF-alpha mRNA expression. Additionally, ovariectomy led to the phenotypic alterations in the major PBL and splenic T-cell subsets by diminishing/preventing the peripubertal changes in the frequency of cells at distinct stages of post-thymic differentiation/maturation (recent thymic emigrants, mature naive and memory cells), and by decreasing the frequency of NKT cells within peripheral CD8+ subsets. In addition to numerical and phenotypic changes in T-cell compartment (due to the lack of ovarian hormone action at both the thymic and peripheral level), Ox rats exhibited a much larger delayed-type hypersensitivity (DTH) response compared with age-matched controls. This suggested the augmented T-cell-mediated immune response in Ox rats compared with aged-matched controls.",
publisher = "Elsevier Gmbh, Urban & Fischer Verlag, Jena",
journal = "Immunobiology",
title = "Role of ovarian hormones in T-cell homeostasis: From the thymus to the periphery",
volume = "218",
number = "3",
pages = "353-367",
doi = "10.1016/j.imbio.2012.05.009"
}

Perišić, M., Stojić-Vukanić, Z., Pilipović, I., Kosec, D., Nacka-Aleksić, M., Đikić, J., Arsenović-Ranin, N.,& Leposavić, G.. (2013). Role of ovarian hormones in T-cell homeostasis: From the thymus to the periphery. in Immunobiology
Elsevier Gmbh, Urban & Fischer Verlag, Jena., 218(3), 353-367.
https://doi.org/10.1016/j.imbio.2012.05.009

Perišić M, Stojić-Vukanić Z, Pilipović I, Kosec D, Nacka-Aleksić M, Đikić J, Arsenović-Ranin N, Leposavić G. Role of ovarian hormones in T-cell homeostasis: From the thymus to the periphery. in Immunobiology. 2013;218(3):353-367.
doi:10.1016/j.imbio.2012.05.009 .

Perišić, Milica, Stojić-Vukanić, Zorica, Pilipović, Ivan, Kosec, Duško, Nacka-Aleksić, Mirjana, Đikić, Jasmina, Arsenović-Ranin, Nevena, Leposavić, Gordana, "Role of ovarian hormones in T-cell homeostasis: From the thymus to the periphery" in Immunobiology, 218, no. 3 (2013):353-367,
https://doi.org/10.1016/j.imbio.2012.05.009 . .

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Bufan, Biljana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Perišić-Nanut, Milica
AU  - Leposavić, Gordana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1980
AB  - It is well-established that almost all cellular components of innate and adaptive immunity undergo age-related remodelling. The findings on age-related changes in both human and mouse dendritic cells (DCs) are conflicting, whereas there are no data on the influence of aging on rat DCs. In an attempt to fill this gap, freshly isolated splenic DCs expressing CD103 (alpha(OX-62) integrin), a DC specific marker recognized by MRC OX62 monoclonal antibody, from 3- (young) and 26-month-old (aged) Albino Oxford rats were examined for subset composition, expression of activation/differentiation markers (CD80, CD86 and CD40 and MHC II molecules) and endocytic capacity using flow cytometric analysis (FCA). In addition, splenic OX62+ DCs cultured in the presence or absence of LPS were analysed for the activation marker and TNF-alpha, IL-6, IL-12, IL-23, TGF-beta 1, IL-10 expression using FCA, RT-PCR and ELISA, respectively. Moreover, the allostimulatory capacity of OX62+ DCs and IFN-gamma, IL-4 and IL-17 production by CD4+ T cells in mixed leukocyte reaction was quantified using FCA and ELISA, respectively. It was found that aging: i) shifts the CD4+:CD4- subset ratio in the OX62+ DCs population towards the CD4- subset and ii) influences DCs maturation (judging by activation marker expression and efficiency of endocytosis) by affecting the expression of intrinsic (TNF-alpha and IL-10) and extrinsic maturation regulators. Furthermore, in LPS-matured OX62+ DCs from aged rats expression of TNF-alpha, IL-12, IL-23 and IL-6 was increased, whereas that of IL-10 was diminished compared with the corresponding cells from young rats. Moreover, in MLR, OX62+ DCs from aged rats exhibited enhanced Th1/Th17 driving force and diminished allostimulatory capacity compared with those from young rats.
PB  - Springer, New York
T2  - Biogerontology
T1  - Aging affects AO rat splenic conventional dendritic cell subset composition, cytokine synthesis and T-helper polarizing capacity
VL  - 14
IS  - 4
SP  - 443
EP  - 459
DO  - 10.1007/s10522-013-9444-5
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Bufan, Biljana and Arsenović-Ranin, Nevena and Kosec, Duško and Pilipović, Ivan and Perišić-Nanut, Milica and Leposavić, Gordana",
year = "2013",
abstract = "It is well-established that almost all cellular components of innate and adaptive immunity undergo age-related remodelling. The findings on age-related changes in both human and mouse dendritic cells (DCs) are conflicting, whereas there are no data on the influence of aging on rat DCs. In an attempt to fill this gap, freshly isolated splenic DCs expressing CD103 (alpha(OX-62) integrin), a DC specific marker recognized by MRC OX62 monoclonal antibody, from 3- (young) and 26-month-old (aged) Albino Oxford rats were examined for subset composition, expression of activation/differentiation markers (CD80, CD86 and CD40 and MHC II molecules) and endocytic capacity using flow cytometric analysis (FCA). In addition, splenic OX62+ DCs cultured in the presence or absence of LPS were analysed for the activation marker and TNF-alpha, IL-6, IL-12, IL-23, TGF-beta 1, IL-10 expression using FCA, RT-PCR and ELISA, respectively. Moreover, the allostimulatory capacity of OX62+ DCs and IFN-gamma, IL-4 and IL-17 production by CD4+ T cells in mixed leukocyte reaction was quantified using FCA and ELISA, respectively. It was found that aging: i) shifts the CD4+:CD4- subset ratio in the OX62+ DCs population towards the CD4- subset and ii) influences DCs maturation (judging by activation marker expression and efficiency of endocytosis) by affecting the expression of intrinsic (TNF-alpha and IL-10) and extrinsic maturation regulators. Furthermore, in LPS-matured OX62+ DCs from aged rats expression of TNF-alpha, IL-12, IL-23 and IL-6 was increased, whereas that of IL-10 was diminished compared with the corresponding cells from young rats. Moreover, in MLR, OX62+ DCs from aged rats exhibited enhanced Th1/Th17 driving force and diminished allostimulatory capacity compared with those from young rats.",
publisher = "Springer, New York",
journal = "Biogerontology",
title = "Aging affects AO rat splenic conventional dendritic cell subset composition, cytokine synthesis and T-helper polarizing capacity",
volume = "14",
number = "4",
pages = "443-459",
doi = "10.1007/s10522-013-9444-5"
}

Stojić-Vukanić, Z., Bufan, B., Arsenović-Ranin, N., Kosec, D., Pilipović, I., Perišić-Nanut, M.,& Leposavić, G.. (2013). Aging affects AO rat splenic conventional dendritic cell subset composition, cytokine synthesis and T-helper polarizing capacity. in Biogerontology
Springer, New York., 14(4), 443-459.
https://doi.org/10.1007/s10522-013-9444-5

Stojić-Vukanić Z, Bufan B, Arsenović-Ranin N, Kosec D, Pilipović I, Perišić-Nanut M, Leposavić G. Aging affects AO rat splenic conventional dendritic cell subset composition, cytokine synthesis and T-helper polarizing capacity. in Biogerontology. 2013;14(4):443-459.
doi:10.1007/s10522-013-9444-5 .

Stojić-Vukanić, Zorica, Bufan, Biljana, Arsenović-Ranin, Nevena, Kosec, Duško, Pilipović, Ivan, Perišić-Nanut, Milica, Leposavić, Gordana, "Aging affects AO rat splenic conventional dendritic cell subset composition, cytokine synthesis and T-helper polarizing capacity" in Biogerontology, 14, no. 4 (2013):443-459,
https://doi.org/10.1007/s10522-013-9444-5 . .

TY  - JOUR
AU  - Arsenović-Ranin, Nevena
AU  - Perišić, Milica
AU  - Bufan, Biljana
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Leposavić, Gordana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1976
AB  - The study was undertaken to assess the effects of ovarian hormone withdrawal in prepubertal age on thymopoiesis in 2- (young) and 11-month-old (middle-aged) rats. In ovariectomized (Ox) rats, irrespective of age, thymic weight and cellularity were greater than in age-matched controls, but the values of both parameters exhibited the age-related decline. In addition, although thymopoietic efficiency was increased in both groups of Ox rats when compared with age-matched controls, thymopoiesis exhibited the age-related decline mirrored in the lower numbers of both CD4+ and CD8+ recent thymic emigrants in peripheral blood. This reflected the prethymic changes affecting bone marrow progenitor generation/entry and the thymic alterations encompassing the impaired progenitor progression through early pre-T-cell receptor developmental stages (defined by CD45RC/CD2 expression) and, possibly, a more pronounced decrease in the proliferation of the most mature thymocytes. Apart from the changes at thymocyte level, in Ox rats the age-related alterations in thymic stroma (substantiated in a prominent loss of thymic epithelial cells) were registered. Ovariectomy-induced changes in thymic lymphoid and epithelial component, most probably, influenced each other leading to the increase in thymic expression of interleukin-6 and interleukin-7 mRNAs along with time after ovariectomy. Collectively, the study showed that the withdrawal of ovarian hormones in prepubertal age increases the efficiency of thymopoiesis in young adult rats, but does not prevent decline in thymopoiesis occurring with age.
PB  - Royal Soc Medicine Press Ltd, London
T2  - Experimental Biology and Medicine
T1  - Ovarian hormone withdrawal in prepubertal developmental stage does not prevent thymic involution in rats
VL  - 238
IS  - 6
SP  - 641
EP  - 657
DO  - 10.1177/1535370213489475
ER  - 

@article{
author = "Arsenović-Ranin, Nevena and Perišić, Milica and Bufan, Biljana and Stojić-Vukanić, Zorica and Pilipović, Ivan and Kosec, Duško and Leposavić, Gordana",
year = "2013",
abstract = "The study was undertaken to assess the effects of ovarian hormone withdrawal in prepubertal age on thymopoiesis in 2- (young) and 11-month-old (middle-aged) rats. In ovariectomized (Ox) rats, irrespective of age, thymic weight and cellularity were greater than in age-matched controls, but the values of both parameters exhibited the age-related decline. In addition, although thymopoietic efficiency was increased in both groups of Ox rats when compared with age-matched controls, thymopoiesis exhibited the age-related decline mirrored in the lower numbers of both CD4+ and CD8+ recent thymic emigrants in peripheral blood. This reflected the prethymic changes affecting bone marrow progenitor generation/entry and the thymic alterations encompassing the impaired progenitor progression through early pre-T-cell receptor developmental stages (defined by CD45RC/CD2 expression) and, possibly, a more pronounced decrease in the proliferation of the most mature thymocytes. Apart from the changes at thymocyte level, in Ox rats the age-related alterations in thymic stroma (substantiated in a prominent loss of thymic epithelial cells) were registered. Ovariectomy-induced changes in thymic lymphoid and epithelial component, most probably, influenced each other leading to the increase in thymic expression of interleukin-6 and interleukin-7 mRNAs along with time after ovariectomy. Collectively, the study showed that the withdrawal of ovarian hormones in prepubertal age increases the efficiency of thymopoiesis in young adult rats, but does not prevent decline in thymopoiesis occurring with age.",
publisher = "Royal Soc Medicine Press Ltd, London",
journal = "Experimental Biology and Medicine",
title = "Ovarian hormone withdrawal in prepubertal developmental stage does not prevent thymic involution in rats",
volume = "238",
number = "6",
pages = "641-657",
doi = "10.1177/1535370213489475"
}

Arsenović-Ranin, N., Perišić, M., Bufan, B., Stojić-Vukanić, Z., Pilipović, I., Kosec, D.,& Leposavić, G.. (2013). Ovarian hormone withdrawal in prepubertal developmental stage does not prevent thymic involution in rats. in Experimental Biology and Medicine
Royal Soc Medicine Press Ltd, London., 238(6), 641-657.
https://doi.org/10.1177/1535370213489475

Arsenović-Ranin N, Perišić M, Bufan B, Stojić-Vukanić Z, Pilipović I, Kosec D, Leposavić G. Ovarian hormone withdrawal in prepubertal developmental stage does not prevent thymic involution in rats. in Experimental Biology and Medicine. 2013;238(6):641-657.
doi:10.1177/1535370213489475 .

Arsenović-Ranin, Nevena, Perišić, Milica, Bufan, Biljana, Stojić-Vukanić, Zorica, Pilipović, Ivan, Kosec, Duško, Leposavić, Gordana, "Ovarian hormone withdrawal in prepubertal developmental stage does not prevent thymic involution in rats" in Experimental Biology and Medicine, 238, no. 6 (2013):641-657,
https://doi.org/10.1177/1535370213489475 . .

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Radojević, Katarina
AU  - Kosec, Duško
AU  - Perišić-Nanut, Milica
AU  - Stojić-Vukanić, Zorica
AU  - Arsenović-Ranin, Nevena
AU  - Leposavić, Gordana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1877
AB  - The study was undertaken considering that: i) androgens affect beta(2)-adrenoceptor (AR)-mediated catecholamine (CA) action in many tissues; and ii) peripubertal changes in both circulating androgen and thymic CA levels are implicated in rat thymic involution. Its aims were to: i) explore putative effects of the late prepubertal orchidectomy on thymic CA:beta(2)-AR complex in young adult rats, and ii) delineate the direct effects of testicular hormone withdrawal on the CA:beta(2)-AR complex from those elicited secondarily through altered influence of this complex components on each other's availability. Upon showing that prepubertal orchidectomy augmented the efficacy of thymopoiesis through increasing the thymocyte surface density of Thy-1, whose expression is negatively regulated by beta(2)-AR-mediated signaling, we examined the effects of orchidectomy and 14-day-long propranolol (PROP) treatment in orchidectomized (ORX) and sham-ORX rats on thymic norepinephrine (NE) concentration and metabolism and beta(2)-AR expression. Orchidectomy, despite an increase in the average NE amount per thymocyte and total thymocyte NE content diminished thymic NE concentration. This decrease reflected the diminished density of CA-synthesizing nerve fibers, CD68 + macrophages, cortical (aminopeptidase A+), and medullary (UEA-1+) thymic epithelial cells (TECs) and their CA content (probably due to lessened TH expression accompanied by increased MAO-A expression). Moreover, orchidectomy decreased the surface beta(2)-AR expression on thymocytes, CD68+ macrophages and OX-62+ dendritic cells, but increased its expression on the TECs. In sham-ORX rats, PROP reduced thymic NE concentration by diminishing TH expression in the thymic cells. Additionally, PROP in thymocytes and thymic stromal cells diminished and enhanced the beta(2)-AR mRNA expression, respectively. However, in ORX rats PROP did not significantly affect CA(NE):beta(2)-AR complex components. This indicated that prepubertal orchidectomy affects ability of young adult rats to respond to beta-AR blockade by altering thymic NE and beta(2)-AR availability. Collectively, the results showed that testicular hormones contribute to alterations in thymus/thymopoiesis during the critical peripubertal period by shaping modulatory sympathetic influence and CA autocrine/paracrine action within the organ.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Neuroimmunology
T1  - Gonadal hormone dependent developmental plasticity of catecholamine:beta 2-adrenoceptor signaling complex in male rat thymus: Putative implications for thymopoiesis
VL  - 265
IS  - 1-2
SP  - 20
EP  - 35
DO  - 10.1016/j.jneuroim.2013.09.021
ER  - 

@article{
author = "Pilipović, Ivan and Radojević, Katarina and Kosec, Duško and Perišić-Nanut, Milica and Stojić-Vukanić, Zorica and Arsenović-Ranin, Nevena and Leposavić, Gordana",
year = "2013",
abstract = "The study was undertaken considering that: i) androgens affect beta(2)-adrenoceptor (AR)-mediated catecholamine (CA) action in many tissues; and ii) peripubertal changes in both circulating androgen and thymic CA levels are implicated in rat thymic involution. Its aims were to: i) explore putative effects of the late prepubertal orchidectomy on thymic CA:beta(2)-AR complex in young adult rats, and ii) delineate the direct effects of testicular hormone withdrawal on the CA:beta(2)-AR complex from those elicited secondarily through altered influence of this complex components on each other's availability. Upon showing that prepubertal orchidectomy augmented the efficacy of thymopoiesis through increasing the thymocyte surface density of Thy-1, whose expression is negatively regulated by beta(2)-AR-mediated signaling, we examined the effects of orchidectomy and 14-day-long propranolol (PROP) treatment in orchidectomized (ORX) and sham-ORX rats on thymic norepinephrine (NE) concentration and metabolism and beta(2)-AR expression. Orchidectomy, despite an increase in the average NE amount per thymocyte and total thymocyte NE content diminished thymic NE concentration. This decrease reflected the diminished density of CA-synthesizing nerve fibers, CD68 + macrophages, cortical (aminopeptidase A+), and medullary (UEA-1+) thymic epithelial cells (TECs) and their CA content (probably due to lessened TH expression accompanied by increased MAO-A expression). Moreover, orchidectomy decreased the surface beta(2)-AR expression on thymocytes, CD68+ macrophages and OX-62+ dendritic cells, but increased its expression on the TECs. In sham-ORX rats, PROP reduced thymic NE concentration by diminishing TH expression in the thymic cells. Additionally, PROP in thymocytes and thymic stromal cells diminished and enhanced the beta(2)-AR mRNA expression, respectively. However, in ORX rats PROP did not significantly affect CA(NE):beta(2)-AR complex components. This indicated that prepubertal orchidectomy affects ability of young adult rats to respond to beta-AR blockade by altering thymic NE and beta(2)-AR availability. Collectively, the results showed that testicular hormones contribute to alterations in thymus/thymopoiesis during the critical peripubertal period by shaping modulatory sympathetic influence and CA autocrine/paracrine action within the organ.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Neuroimmunology",
title = "Gonadal hormone dependent developmental plasticity of catecholamine:beta 2-adrenoceptor signaling complex in male rat thymus: Putative implications for thymopoiesis",
volume = "265",
number = "1-2",
pages = "20-35",
doi = "10.1016/j.jneuroim.2013.09.021"
}

Pilipović, I., Radojević, K., Kosec, D., Perišić-Nanut, M., Stojić-Vukanić, Z., Arsenović-Ranin, N.,& Leposavić, G.. (2013). Gonadal hormone dependent developmental plasticity of catecholamine:beta 2-adrenoceptor signaling complex in male rat thymus: Putative implications for thymopoiesis. in Journal of Neuroimmunology
Elsevier Science BV, Amsterdam., 265(1-2), 20-35.
https://doi.org/10.1016/j.jneuroim.2013.09.021

Pilipović I, Radojević K, Kosec D, Perišić-Nanut M, Stojić-Vukanić Z, Arsenović-Ranin N, Leposavić G. Gonadal hormone dependent developmental plasticity of catecholamine:beta 2-adrenoceptor signaling complex in male rat thymus: Putative implications for thymopoiesis. in Journal of Neuroimmunology. 2013;265(1-2):20-35.
doi:10.1016/j.jneuroim.2013.09.021 .

Pilipović, Ivan, Radojević, Katarina, Kosec, Duško, Perišić-Nanut, Milica, Stojić-Vukanić, Zorica, Arsenović-Ranin, Nevena, Leposavić, Gordana, "Gonadal hormone dependent developmental plasticity of catecholamine:beta 2-adrenoceptor signaling complex in male rat thymus: Putative implications for thymopoiesis" in Journal of Neuroimmunology, 265, no. 1-2 (2013):20-35,
https://doi.org/10.1016/j.jneuroim.2013.09.021 . .

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Radojević, Katarina
AU  - Perišić, M.
AU  - Kosec, Duško
AU  - Nacka-Aleksić, Mirjana
AU  - Đikić, Jasmina
AU  - Leposavić, Gordana
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1631
AB  - Glucocorticoids have been shown to modulate the expression of noradrenaline metabolizing enzymes and beta(2)- and alpha(1B)-adrenoceptors in a tissue- and cell- specific manner. In the thymus, apart from extensive sympathetic innervation, a regulatory network has been identified that encompasses catecholamine-containing non-lymphoid and lymphoid cells. We examined a putative role of adrenal- and thymus-derived glucocorticoids in modulation of rat thymic noradrenaline levels and adrenoceptor expression. Seven days postadrenalectomy, the thymic levels of mRNAs encoding tyrosine hydroxylase, dopamine beta-hydroxylase, monoamine oxidase-A and, consequently, noradrenaline were decreased. Catecholamine content was diminished in autofluorescent nerve fibres (judging by the intensity of fluorescence) and thymocytes (considering HPLC measurements of noradrenaline and the frequency of tyrosine hydroxylase-positive cells), while it remained unaltered in non-lymphoid autofluorescent cells. In addition, adrenalectomy diminished the thymocyte expression of beta(2)- and alpha(1B)-adrenoceptors at both mRNA and protein levels. Administration of ketoconazole (an inhibitor of glucocorticoid synthesis/action; 25 mg kg(-1) day(-1), s.c.) to glucocorticoid-deprived rats increased the thymic levels of tyrosine hydroxylase, dopamine beta-hydroxylase and, consequently, noradrenaline. The increased intensity of the autofluorescent cell fluorescence in ketoconazole-treated rats indicated an increase in their catecholamine content, and suggested differential glucocorticoid-mediated regulation of catecholamines in thymic lymphoid and non-lymphoid cells. In addition, ketoconazole increased the thymocyte expression of alpha(1B)-adrenoceptors. Thus, this study indicates that in the thymus, as in some other tissues, glucocorticoids not only act in concert with cateholamines, but they may modulate catecholamine action by tuning thymic catecholamine metabolism and adrenoceptor expression in a cell-specific manner. Additionally, the study indicates a role of thymus-derived glucocorticoids in this modulation.
PB  - Wiley-Blackwell, Hoboken
T2  - Experimental Physiology
T1  - Catecholaminergic signalling through thymic nerve fibres, thymocytes and stromal cells is dependent on both circulating and locally synthesized glucocorticoids
VL  - 97
IS  - 11
SP  - 1211
EP  - 1223
DO  - 10.1113/expphysiol.2012.064899
ER  - 

@article{
author = "Pilipović, Ivan and Radojević, Katarina and Perišić, M. and Kosec, Duško and Nacka-Aleksić, Mirjana and Đikić, Jasmina and Leposavić, Gordana",
year = "2012",
abstract = "Glucocorticoids have been shown to modulate the expression of noradrenaline metabolizing enzymes and beta(2)- and alpha(1B)-adrenoceptors in a tissue- and cell- specific manner. In the thymus, apart from extensive sympathetic innervation, a regulatory network has been identified that encompasses catecholamine-containing non-lymphoid and lymphoid cells. We examined a putative role of adrenal- and thymus-derived glucocorticoids in modulation of rat thymic noradrenaline levels and adrenoceptor expression. Seven days postadrenalectomy, the thymic levels of mRNAs encoding tyrosine hydroxylase, dopamine beta-hydroxylase, monoamine oxidase-A and, consequently, noradrenaline were decreased. Catecholamine content was diminished in autofluorescent nerve fibres (judging by the intensity of fluorescence) and thymocytes (considering HPLC measurements of noradrenaline and the frequency of tyrosine hydroxylase-positive cells), while it remained unaltered in non-lymphoid autofluorescent cells. In addition, adrenalectomy diminished the thymocyte expression of beta(2)- and alpha(1B)-adrenoceptors at both mRNA and protein levels. Administration of ketoconazole (an inhibitor of glucocorticoid synthesis/action; 25 mg kg(-1) day(-1), s.c.) to glucocorticoid-deprived rats increased the thymic levels of tyrosine hydroxylase, dopamine beta-hydroxylase and, consequently, noradrenaline. The increased intensity of the autofluorescent cell fluorescence in ketoconazole-treated rats indicated an increase in their catecholamine content, and suggested differential glucocorticoid-mediated regulation of catecholamines in thymic lymphoid and non-lymphoid cells. In addition, ketoconazole increased the thymocyte expression of alpha(1B)-adrenoceptors. Thus, this study indicates that in the thymus, as in some other tissues, glucocorticoids not only act in concert with cateholamines, but they may modulate catecholamine action by tuning thymic catecholamine metabolism and adrenoceptor expression in a cell-specific manner. Additionally, the study indicates a role of thymus-derived glucocorticoids in this modulation.",
publisher = "Wiley-Blackwell, Hoboken",
journal = "Experimental Physiology",
title = "Catecholaminergic signalling through thymic nerve fibres, thymocytes and stromal cells is dependent on both circulating and locally synthesized glucocorticoids",
volume = "97",
number = "11",
pages = "1211-1223",
doi = "10.1113/expphysiol.2012.064899"
}

Pilipović, I., Radojević, K., Perišić, M., Kosec, D., Nacka-Aleksić, M., Đikić, J.,& Leposavić, G.. (2012). Catecholaminergic signalling through thymic nerve fibres, thymocytes and stromal cells is dependent on both circulating and locally synthesized glucocorticoids. in Experimental Physiology
Wiley-Blackwell, Hoboken., 97(11), 1211-1223.
https://doi.org/10.1113/expphysiol.2012.064899

Pilipović I, Radojević K, Perišić M, Kosec D, Nacka-Aleksić M, Đikić J, Leposavić G. Catecholaminergic signalling through thymic nerve fibres, thymocytes and stromal cells is dependent on both circulating and locally synthesized glucocorticoids. in Experimental Physiology. 2012;97(11):1211-1223.
doi:10.1113/expphysiol.2012.064899 .

Pilipović, Ivan, Radojević, Katarina, Perišić, M., Kosec, Duško, Nacka-Aleksić, Mirjana, Đikić, Jasmina, Leposavić, Gordana, "Catecholaminergic signalling through thymic nerve fibres, thymocytes and stromal cells is dependent on both circulating and locally synthesized glucocorticoids" in Experimental Physiology, 97, no. 11 (2012):1211-1223,
https://doi.org/10.1113/expphysiol.2012.064899 . .