TY  - DATA
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Kotur-Stevuljević, Jelena
AU  - Simić, Ljubica
AU  - Sopta, Jelena
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/647
AB  - Supplementary Fig. 1 Sex differences in the clinical and histological presentation of CIA. (a) A line graph indicates daily arthritic score  (mean ± SEM) from the 12th to the 39th day post-immunization (d.p.i.) in male (n = 9) and female (n = 10) CIA rats.  Mann–Whitney U test: * p ≤ 0.05, from the 17th to the 39th d.p.i. (b) Line graph indicates daily arthritic score  (mean ± SEM) from the 13th to the 21st day post-immunization (d.p.i.) in male and female CIA rats. Mann–Whitney U test: n = 8 rats/sex. * p ≤ 0.05.  Photographs show representative arthritic joints (arrows) of hind paws from male and female CIA rats.  (c) Photomicrographs of HE-stained sections of paraffin-embedded joints from male and female CIA rats show replacement  of the normal bone marrow cell populations by inflammatory cells. In females, numerous multinuclear giant cells (red arrows)  are present as opposed to male CIA rats. Original magnification × 400. The bar indicates 100 μm (PNG 2723 kb) Supplementary Fig. 2 Fluorescence minus one controls for flow cytometry analysis of CD11b/CCR2/CX3CR1 staining of splenocytes.  For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single  antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without anti-CX3CR1 or anti-CCR2  Abs within CD11b+ splenocytes (gated as shown in Fig. 3) isolated from CIA rats on the 21st day post-immunization (PNG 98 kb). Supplementary Fig. 3 Fluorescence minus one controls for flow cytometry analysis of CD11b/CD43/CCR2/CX3CR1 staining of peripheral blood cells.  For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single  antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without (upper) CD43 mAb within  CD11b+ peripheral blood cells (gated as shown in Fig. 4a) and (lower) anti-CX3CR1 or anti-CCR2 Abs within CD11b+CD43+  peripheral blood cells isolated from CIA rats on the 21st day post-immunization (PNG 157 kb). Supplementary Fig. 4 Sex differences in the activation of Th cells, Th17 cell function, and frequency of CD40+CD11b+ antigen presenting cells in  draining lymph nodes from CIA rats, popliteal draining lymph nodes (DLNs) were retrieved from male and female CIA rats on the  21st day post-immunization. (a) Scatter plots with bar indicate the frequencies of activated Th cells (CD25+Foxp3-CD4+) and  Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats and the concentration of IL-17 in supernatants of collagen type  II-stimulated and unstimulated (medium) DLN cell cultures from male and female rats (see MATERIAL AND METHODS).  Linear graph shows the correlation between the frequency of activated Th cells (CD25+Foxp3-CD4+) and the frequency of  Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats. Pearson’s r value is shown in the graph. (b) Representative flow  cytometry dot plots show (upper) CD11b staining and (lower) CD40 vs CD11b staining of DLN cells from male and female rats.  Number indicates percent in the region. Scatter plots with bar indicate the frequency and the number of (upper) CD11b+ cells  and (lower) CD40+CD11b+ cells in DLNs of male and female rats. The Number indicates percent in the region. Results are  expressed as mean ± SEM. (c) The linear graph shows the correlation between the frequency of activated Th cells  (CD25+Foxp3-CD4+) and the frequency of CD40+CD11b+ cells in DLNs from CIA rats. Pearson’s r value is shown in the graph.  n = 8 rats/sex. * p ≤ 0.05, ** p ≤ 0.01, and *** p ≤ 0.001 (PNG 590 kb). Supplementary Fig. 5 Gating strategy for activated Th cells and Th17 cells, popliteal draining lymph nodes (DLNs) were retrieved from CIA rats on  the 21st day post-immunization. Flow cytometry dot plots show gating strategy for (a) activated The cells (CD25+Foxp3-CD4+)  and (b) Th17 cells (IL-17+CD4+TCRαβ+) (PNG 101 kb).
PB  - Springer
T2  - Inflammation
T1  - Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0.
EP  - 2331
IS  - 6
SP  - 2312
VL  - 43
UR  - https://hdl.handle.net/21.15107/rcub_intor_647
ER  - 

@misc{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Bufan, Biljana and Nacka-Aleksić, Mirjana and Kosec, Duško and Pilipović, Ivan and Kotur-Stevuljević, Jelena and Simić, Ljubica and Sopta, Jelena and Leposavić, Gordana",
year = "2020",
abstract = "Supplementary Fig. 1 Sex differences in the clinical and histological presentation of CIA. (a) A line graph indicates daily arthritic score  (mean ± SEM) from the 12th to the 39th day post-immunization (d.p.i.) in male (n = 9) and female (n = 10) CIA rats.  Mann–Whitney U test: * p ≤ 0.05, from the 17th to the 39th d.p.i. (b) Line graph indicates daily arthritic score  (mean ± SEM) from the 13th to the 21st day post-immunization (d.p.i.) in male and female CIA rats. Mann–Whitney U test: n = 8 rats/sex. * p ≤ 0.05.  Photographs show representative arthritic joints (arrows) of hind paws from male and female CIA rats.  (c) Photomicrographs of HE-stained sections of paraffin-embedded joints from male and female CIA rats show replacement  of the normal bone marrow cell populations by inflammatory cells. In females, numerous multinuclear giant cells (red arrows)  are present as opposed to male CIA rats. Original magnification × 400. The bar indicates 100 μm (PNG 2723 kb) Supplementary Fig. 2 Fluorescence minus one controls for flow cytometry analysis of CD11b/CCR2/CX3CR1 staining of splenocytes.  For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single  antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without anti-CX3CR1 or anti-CCR2  Abs within CD11b+ splenocytes (gated as shown in Fig. 3) isolated from CIA rats on the 21st day post-immunization (PNG 98 kb). Supplementary Fig. 3 Fluorescence minus one controls for flow cytometry analysis of CD11b/CD43/CCR2/CX3CR1 staining of peripheral blood cells.  For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single  antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without (upper) CD43 mAb within  CD11b+ peripheral blood cells (gated as shown in Fig. 4a) and (lower) anti-CX3CR1 or anti-CCR2 Abs within CD11b+CD43+  peripheral blood cells isolated from CIA rats on the 21st day post-immunization (PNG 157 kb). Supplementary Fig. 4 Sex differences in the activation of Th cells, Th17 cell function, and frequency of CD40+CD11b+ antigen presenting cells in  draining lymph nodes from CIA rats, popliteal draining lymph nodes (DLNs) were retrieved from male and female CIA rats on the  21st day post-immunization. (a) Scatter plots with bar indicate the frequencies of activated Th cells (CD25+Foxp3-CD4+) and  Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats and the concentration of IL-17 in supernatants of collagen type  II-stimulated and unstimulated (medium) DLN cell cultures from male and female rats (see MATERIAL AND METHODS).  Linear graph shows the correlation between the frequency of activated Th cells (CD25+Foxp3-CD4+) and the frequency of  Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats. Pearson’s r value is shown in the graph. (b) Representative flow  cytometry dot plots show (upper) CD11b staining and (lower) CD40 vs CD11b staining of DLN cells from male and female rats.  Number indicates percent in the region. Scatter plots with bar indicate the frequency and the number of (upper) CD11b+ cells  and (lower) CD40+CD11b+ cells in DLNs of male and female rats. The Number indicates percent in the region. Results are  expressed as mean ± SEM. (c) The linear graph shows the correlation between the frequency of activated Th cells  (CD25+Foxp3-CD4+) and the frequency of CD40+CD11b+ cells in DLNs from CIA rats. Pearson’s r value is shown in the graph.  n = 8 rats/sex. * p ≤ 0.05, ** p ≤ 0.01, and *** p ≤ 0.001 (PNG 590 kb). Supplementary Fig. 5 Gating strategy for activated Th cells and Th17 cells, popliteal draining lymph nodes (DLNs) were retrieved from CIA rats on  the 21st day post-immunization. Flow cytometry dot plots show gating strategy for (a) activated The cells (CD25+Foxp3-CD4+)  and (b) Th17 cells (IL-17+CD4+TCRαβ+) (PNG 101 kb).",
publisher = "Springer",
journal = "Inflammation",
title = "Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0.",
pages = "2331-2312",
number = "6",
volume = "43",
url = "https://hdl.handle.net/21.15107/rcub_intor_647"
}

Dimitrijević, M., Arsenović-Ranin, N., Bufan, B., Nacka-Aleksić, M., Kosec, D., Pilipović, I., Kotur-Stevuljević, J., Simić, L., Sopta, J.,& Leposavić, G.. (2020). Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0.. in Inflammation
Springer., 43(6), 2312-2331.
https://hdl.handle.net/21.15107/rcub_intor_647

Dimitrijević M, Arsenović-Ranin N, Bufan B, Nacka-Aleksić M, Kosec D, Pilipović I, Kotur-Stevuljević J, Simić L, Sopta J, Leposavić G. Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0.. in Inflammation. 2020;43(6):2312-2331.
https://hdl.handle.net/21.15107/rcub_intor_647 .

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Bufan, Biljana, Nacka-Aleksić, Mirjana, Kosec, Duško, Pilipović, Ivan, Kotur-Stevuljević, Jelena, Simić, Ljubica, Sopta, Jelena, Leposavić, Gordana, "Supplementary information for the article: Dimitrijević, M.; Arsenović-Ranin, N.; Bufan, B.; Nacka-Aleksić, M.; Kosec, D.;  Pilipović, I.; Kotur-Stevuljević, J.; Simić, L.; Sopta, J.; Leposavić, G. Sex-Based Differences in Monocytic Lineage Cells  Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 2020, 43 (6),  2312–2331. https://doi.org/10.1007/s10753-020-01302-0." in Inflammation, 43, no. 6 (2020):2312-2331,
https://hdl.handle.net/21.15107/rcub_intor_647 .

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Kosec, Duško
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/554
AB  - The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki-67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higher Tfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-gamma /IL-4 production ratio was shifted towards IFN-gamma. Consistently, the serum IgG2a(b)/IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.
PB  - Nature Publishing Group, London
T2  - Scientific Reports
T1  - Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis
IS  - 1
VL  - 10
DO  - 10.1038/s41598-020-58127-y
ER  - 

@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Kosec, Duško and Bufan, Biljana and Nacka-Aleksić, Mirjana and Pilipović, Ivan and Leposavić, Gordana",
year = "2020",
abstract = "The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki-67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higher Tfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-gamma /IL-4 production ratio was shifted towards IFN-gamma. Consistently, the serum IgG2a(b)/IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.",
publisher = "Nature Publishing Group, London",
journal = "Scientific Reports",
title = "Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis",
number = "1",
volume = "10",
doi = "10.1038/s41598-020-58127-y"
}

Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2020). Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis. in Scientific Reports
Nature Publishing Group, London., 10(1).
https://doi.org/10.1038/s41598-020-58127-y

Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis. in Scientific Reports. 2020;10(1).
doi:10.1038/s41598-020-58127-y .

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis" in Scientific Reports, 10, no. 1 (2020),
https://doi.org/10.1038/s41598-020-58127-y . .

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Arsenović-Ranin, Nevena
AU  - Bufan, Biljana
AU  - Nacka-Aleksić, Mirjana
AU  - Kosec, Duško
AU  - Pilipović, Ivan
AU  - Kotur-Stevuljević, Jelena
AU  - Simić, Ljubica
AU  - Sopta, Jelena
AU  - Leposavić, Gordana
PY  - 2020
UR  - http://intor.torlakinstitut.com/handle/123456789/543
AB  - Monocytes' plasticity has an important role in the development of rheumatoid arthritis (RA), an autoimmune disease exhibiting greater prevalence in women. Contribution of this phenomenon to sex bias in RA severity was investigated in rat collagen-induced arthritis (CIA) model of RA. The greater severity of CIA in females (exhibiting signs of bone resorption) was accompanied by the higher blood level of advanced oxidation protein products and a more pro-oxidant profile. Consistently, in females, the greater density of giant multinuclear cells (monocytes/macrophages and osteoclasts) in inflamed joint tissue was found. This correlated with the higher frequencies of CCR2- and CX3CR1- expressing cells (precursors of inflammatory monocytes/macrophages and osteoclasts) among CD11b+ splenocytes. This in conjunction with the enhanced migratory capacity of CD11b+ monocytic cells in females compared with males could be linked with the higher frequencies of CCR2+CX3CR1-CD43(low)CD11b+ and CCR2-CX3CR1+CD43(hi)CD11b+ cells (corresponding to "classical" and "non-classical" monocytes, respectively) and the greater density of CD68+ cells (monocytes/macrophages and osteoclast precursors/osteoclasts) in blood and inflamed paws from female rats, respectively. Consistently, the higher levels of GM-CSF, TNF-alpha and IL-6, IL-1 beta (driving Th17 cell differentiation), and IL-17 followed by the lower level of IL-10 were measured in inflamed paw cultures from female compared with male rats. To the greater IL-17 production (associated with enhanced monocyte immigration and differentiation into osteoclasts) most likely contributed augmented Th17 cell generation in the lymph nodes draining arthritic joints from female compared with male rats. Overall, the study suggests the sex-specific contribution of monocytic lineage cells to CIA, and possibly RA development.
PB  - Springer/Plenum Publishers, New York
T2  - Inflammation
T1  - Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats
EP  - 2331
IS  - 6
SP  - 2312
VL  - 43
DO  - 10.1007/s10753-020-01302-0
ER  - 

@article{
author = "Dimitrijević, Mirjana and Arsenović-Ranin, Nevena and Bufan, Biljana and Nacka-Aleksić, Mirjana and Kosec, Duško and Pilipović, Ivan and Kotur-Stevuljević, Jelena and Simić, Ljubica and Sopta, Jelena and Leposavić, Gordana",
year = "2020",
abstract = "Monocytes' plasticity has an important role in the development of rheumatoid arthritis (RA), an autoimmune disease exhibiting greater prevalence in women. Contribution of this phenomenon to sex bias in RA severity was investigated in rat collagen-induced arthritis (CIA) model of RA. The greater severity of CIA in females (exhibiting signs of bone resorption) was accompanied by the higher blood level of advanced oxidation protein products and a more pro-oxidant profile. Consistently, in females, the greater density of giant multinuclear cells (monocytes/macrophages and osteoclasts) in inflamed joint tissue was found. This correlated with the higher frequencies of CCR2- and CX3CR1- expressing cells (precursors of inflammatory monocytes/macrophages and osteoclasts) among CD11b+ splenocytes. This in conjunction with the enhanced migratory capacity of CD11b+ monocytic cells in females compared with males could be linked with the higher frequencies of CCR2+CX3CR1-CD43(low)CD11b+ and CCR2-CX3CR1+CD43(hi)CD11b+ cells (corresponding to "classical" and "non-classical" monocytes, respectively) and the greater density of CD68+ cells (monocytes/macrophages and osteoclast precursors/osteoclasts) in blood and inflamed paws from female rats, respectively. Consistently, the higher levels of GM-CSF, TNF-alpha and IL-6, IL-1 beta (driving Th17 cell differentiation), and IL-17 followed by the lower level of IL-10 were measured in inflamed paw cultures from female compared with male rats. To the greater IL-17 production (associated with enhanced monocyte immigration and differentiation into osteoclasts) most likely contributed augmented Th17 cell generation in the lymph nodes draining arthritic joints from female compared with male rats. Overall, the study suggests the sex-specific contribution of monocytic lineage cells to CIA, and possibly RA development.",
publisher = "Springer/Plenum Publishers, New York",
journal = "Inflammation",
title = "Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats",
pages = "2331-2312",
number = "6",
volume = "43",
doi = "10.1007/s10753-020-01302-0"
}

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

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

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Bufan, Biljana, Nacka-Aleksić, Mirjana, Kosec, Duško, Pilipović, Ivan, Kotur-Stevuljević, Jelena, Simić, Ljubica, Sopta, Jelena, Leposavić, Gordana, "Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats" in Inflammation, 43, no. 6 (2020):2312-2331,
https://doi.org/10.1007/s10753-020-01302-0 . .

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

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

Nacka-Aleksić, M., Stojić-Vukanić, Z., Pilipović, I., Blagojević, V., Kotur-Stevuljević, J.,& Leposavić, G.. (2020). Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment. in Experimental Gerontology
Pergamon-Elsevier Science Ltd, Oxford., 142.
https://doi.org/10.1016/j.exger.2020.111140

Nacka-Aleksić M, Stojić-Vukanić Z, Pilipović I, Blagojević V, Kotur-Stevuljević J, Leposavić G. Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment. in Experimental Gerontology. 2020;142.
doi:10.1016/j.exger.2020.111140 .

Nacka-Aleksić, Mirjana, Stojić-Vukanić, Zorica, Pilipović, Ivan, Blagojević, Veljko, Kotur-Stevuljević, Jelena, Leposavić, Gordana, "Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment" in Experimental Gerontology, 142 (2020),
https://doi.org/10.1016/j.exger.2020.111140 . .

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

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

Nacka-Aleksić, M., Pilipović, I., Kotur-Stevuljević, J.,& Leposavić, G.. (2019). Sexual dimorphism in thymic senescence. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019
Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade., 85-85.
https://hdl.handle.net/21.15107/rcub_intor_855

Nacka-Aleksić M, Pilipović I, Kotur-Stevuljević J, Leposavić G. Sexual dimorphism in thymic senescence. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019. 2019;:85-85.
https://hdl.handle.net/21.15107/rcub_intor_855 .

Nacka-Aleksić, Mirjana, Pilipović, Ivan, Kotur-Stevuljević, Jelena, Leposavić, Gordana, "Sexual dimorphism in thymic senescence" in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019 (2019):85-85,
https://hdl.handle.net/21.15107/rcub_intor_855 .

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

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

Dimitrijević, M., Arsenović-Ranin, N., Kosec, D., Bufan, B., Nacka-Aleksić, M., Pilipović, I.,& Leposavić, G.. (2019). Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019
Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade., 106-106.
https://hdl.handle.net/21.15107/rcub_intor_856

Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells. in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019. 2019;:106-106.
https://hdl.handle.net/21.15107/rcub_intor_856 .

Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana, "Sexual dimorphism in the severity of rat collagen-induced arthritis: the relevance of T follicular cell help to B cells" in Immunology at the confluence of Multidisciplinary approaches, Abstract book, Hotel Mona plaza, Belgrade December 6th-8th, 2019 (2019):106-106,
https://hdl.handle.net/21.15107/rcub_intor_856 .

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Vujnović, Ivana
AU  - Stojić-Vukanić, Zorica
AU  - Petrović, Raisa
AU  - Kosec, Duško
AU  - Nacka-Aleksić, Mirjana
AU  - Jasnić, Nebojša
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/531
AB  - Pharmacological blockade of alpha(1)-adrenoceptor is shown to influence development of experimental autoimmune encephalomyelitis (EAE), an IL-17-producing CD4+TCR+ (Th17) cell-mediated disease mimicking multiple sclerosis. Considering significance of CD4+ cell priming for the clinical outcome of EAE, the study examined alpha(1)-adrenoceptor-mediated influence of catecholamines, particularly those derived from draining lymph node (dLN) cells (as catecholamine supply from nerve fibers decreases with the initiation of autoimmune diseases) for CD4+ cell priming. The results confirmed diminishing effect of immunization on nerve fiber-derived noradrenaline supply and showed that antigen presenting and CD4+ cells synthesize catecholamines, while antigen presenting cells and only CD4+CD25+Foxp3+ regulatory T cells (Tregs) express alpha(1)-adrenoceptor. The analysis of influence of alpha(1)-adrenoceptor antagonist prazosin on the myelin basic protein (MBP)-stimulated CD4+ lymphocytes in dLN cell culture showed their diminished proliferation in the presence of prazosin. This was consistent with prazosin enhancing effect on Treg frequency and their Foxp3 expression in these cultures. The latter was associated with upregulation of TGF-beta expression. Additionally, prazosin decreased antigen presenting cell activation and affected their cytokine profile by diminishing the frequency of cells that produce Th17 polarizing cytokines (IL-1 beta and IL-23) and increasing that of IL-10-producing cells. Consistently, the frequency of all IL-17A+ cells and those co-expressing GM-CSF within CD4+ lymphocytes was decreased in prazosin-supplemented MBP-stimulated dLN cell cultures. Collectively, the results indicated that dLN cell-derived catecholamines may influence EAE development by modulating interactions between distinct subtypes of CD4+ T cells and antigen presenting cells through alpha(1)-adrenoceptor and consequently CD4+ T cell priming.
PB  - Humana Press Inc, Totowa
T2  - Immunologic Research
T1  - Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor
EP  - 240
IS  - 2-3
SP  - 223
VL  - 67
DO  - 10.1007/s12026-019-09082-y
ER  - 

@article{
author = "Pilipović, Ivan and Vujnović, Ivana and Stojić-Vukanić, Zorica and Petrović, Raisa and Kosec, Duško and Nacka-Aleksić, Mirjana and Jasnić, Nebojša and Leposavić, Gordana",
year = "2019",
abstract = "Pharmacological blockade of alpha(1)-adrenoceptor is shown to influence development of experimental autoimmune encephalomyelitis (EAE), an IL-17-producing CD4+TCR+ (Th17) cell-mediated disease mimicking multiple sclerosis. Considering significance of CD4+ cell priming for the clinical outcome of EAE, the study examined alpha(1)-adrenoceptor-mediated influence of catecholamines, particularly those derived from draining lymph node (dLN) cells (as catecholamine supply from nerve fibers decreases with the initiation of autoimmune diseases) for CD4+ cell priming. The results confirmed diminishing effect of immunization on nerve fiber-derived noradrenaline supply and showed that antigen presenting and CD4+ cells synthesize catecholamines, while antigen presenting cells and only CD4+CD25+Foxp3+ regulatory T cells (Tregs) express alpha(1)-adrenoceptor. The analysis of influence of alpha(1)-adrenoceptor antagonist prazosin on the myelin basic protein (MBP)-stimulated CD4+ lymphocytes in dLN cell culture showed their diminished proliferation in the presence of prazosin. This was consistent with prazosin enhancing effect on Treg frequency and their Foxp3 expression in these cultures. The latter was associated with upregulation of TGF-beta expression. Additionally, prazosin decreased antigen presenting cell activation and affected their cytokine profile by diminishing the frequency of cells that produce Th17 polarizing cytokines (IL-1 beta and IL-23) and increasing that of IL-10-producing cells. Consistently, the frequency of all IL-17A+ cells and those co-expressing GM-CSF within CD4+ lymphocytes was decreased in prazosin-supplemented MBP-stimulated dLN cell cultures. Collectively, the results indicated that dLN cell-derived catecholamines may influence EAE development by modulating interactions between distinct subtypes of CD4+ T cells and antigen presenting cells through alpha(1)-adrenoceptor and consequently CD4+ T cell priming.",
publisher = "Humana Press Inc, Totowa",
journal = "Immunologic Research",
title = "Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor",
pages = "240-223",
number = "2-3",
volume = "67",
doi = "10.1007/s12026-019-09082-y"
}

Pilipović, I., Vujnović, I., Stojić-Vukanić, Z., Petrović, R., Kosec, D., Nacka-Aleksić, M., Jasnić, N.,& Leposavić, G.. (2019). Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor. in Immunologic Research
Humana Press Inc, Totowa., 67(2-3), 223-240.
https://doi.org/10.1007/s12026-019-09082-y

Pilipović I, Vujnović I, Stojić-Vukanić Z, Petrović R, Kosec D, Nacka-Aleksić M, Jasnić N, Leposavić G. Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor. in Immunologic Research. 2019;67(2-3):223-240.
doi:10.1007/s12026-019-09082-y .

Pilipović, Ivan, Vujnović, Ivana, Stojić-Vukanić, Zorica, Petrović, Raisa, Kosec, Duško, Nacka-Aleksić, Mirjana, Jasnić, Nebojša, Leposavić, Gordana, "Noradrenaline modulates CD4+T cell priming in rat experimental autoimmune encephalomyelitis: a role for the alpha(1)-adrenoceptor" in Immunologic Research, 67, no. 2-3 (2019):223-240,
https://doi.org/10.1007/s12026-019-09082-y . .

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

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

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

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

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

TY  - JOUR
AU  - Nacka-Aleksić, Mirjana
AU  - Pilipović, Ivan
AU  - Kotur-Stevuljević, Jelena
AU  - Petrović, Raisa
AU  - Sopta, Jelena
AU  - Leposavić, Gordana
PY  - 2019
UR  - http://intor.torlakinstitut.com/handle/123456789/540
AB  - The study investigated mechanisms underlying sex differences in thymic involution in Dark Agouti rats. Adverse effects of aging on thymus were more pronounced in males than in females. Thymi from old males exhibited more prominent: (i) fibro-adipose degeneration which correlated with greater intensity of thymic oxidative stress and enhanced thymic TGF- and IL-6 expression and (ii) decline in thymopoiesis, as suggested by the number of the most mature CD4+CD8-/CD4-CD8+ single positive (SP) TCRhigh thymocytes. The greater accumulation of adipose tissue in old male thymus was linked with greater age-related increase in thymic expression of PPAR and STAT3, a transcription factor regulating the expression of PPAR downstream genes, in male than in female rats. In aged thymi of both sexes the early CD4-CD8- double negative (DN) stage of thymocyte development was affected, so relative accumulation of the least mature CD45RC+CD2- cells followed by decreased frequency of their DN and CD4+CD8+ double positive (DP) TCR- descendants was observed. Additionally, in old males, because of the increased thymic expression of Nur77, a nuclear receptor involved in negative selection, and decreased CD90 (a negative regulator of thymocyte selection threshold) MFI on DP TCRint thymocytes, less efficient positive/more efficient negative selection was found. Moreover, in male rats, thymocyte post-selection differentiation/maturation was skewed towards CD4-CD8+ SP TCRhigh cells compared with age-matched females, reflecting, at least partly, greater IL-15 expression in their thymi. The study indicated mechanisms underlying sex-based differences in age-related thymic changes and consequently necessity of sex-specific approaches in designing strategies to rejuvenate thymus.
PB  - Springer, New York
T2  - Biogerontology
T1  - Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation
EP  - 569
IS  - 4
SP  - 545
VL  - 20
DO  - 10.1007/s10522-019-09816-3
ER  - 

@article{
author = "Nacka-Aleksić, Mirjana and Pilipović, Ivan and Kotur-Stevuljević, Jelena and Petrović, Raisa and Sopta, Jelena and Leposavić, Gordana",
year = "2019",
abstract = "The study investigated mechanisms underlying sex differences in thymic involution in Dark Agouti rats. Adverse effects of aging on thymus were more pronounced in males than in females. Thymi from old males exhibited more prominent: (i) fibro-adipose degeneration which correlated with greater intensity of thymic oxidative stress and enhanced thymic TGF- and IL-6 expression and (ii) decline in thymopoiesis, as suggested by the number of the most mature CD4+CD8-/CD4-CD8+ single positive (SP) TCRhigh thymocytes. The greater accumulation of adipose tissue in old male thymus was linked with greater age-related increase in thymic expression of PPAR and STAT3, a transcription factor regulating the expression of PPAR downstream genes, in male than in female rats. In aged thymi of both sexes the early CD4-CD8- double negative (DN) stage of thymocyte development was affected, so relative accumulation of the least mature CD45RC+CD2- cells followed by decreased frequency of their DN and CD4+CD8+ double positive (DP) TCR- descendants was observed. Additionally, in old males, because of the increased thymic expression of Nur77, a nuclear receptor involved in negative selection, and decreased CD90 (a negative regulator of thymocyte selection threshold) MFI on DP TCRint thymocytes, less efficient positive/more efficient negative selection was found. Moreover, in male rats, thymocyte post-selection differentiation/maturation was skewed towards CD4-CD8+ SP TCRhigh cells compared with age-matched females, reflecting, at least partly, greater IL-15 expression in their thymi. The study indicated mechanisms underlying sex-based differences in age-related thymic changes and consequently necessity of sex-specific approaches in designing strategies to rejuvenate thymus.",
publisher = "Springer, New York",
journal = "Biogerontology",
title = "Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation",
pages = "569-545",
number = "4",
volume = "20",
doi = "10.1007/s10522-019-09816-3"
}

Nacka-Aleksić, M., Pilipović, I., Kotur-Stevuljević, J., Petrović, R., Sopta, J.,& Leposavić, G.. (2019). Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation. in Biogerontology
Springer, New York., 20(4), 545-569.
https://doi.org/10.1007/s10522-019-09816-3

Nacka-Aleksić M, Pilipović I, Kotur-Stevuljević J, Petrović R, Sopta J, Leposavić G. Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation. in Biogerontology. 2019;20(4):545-569.
doi:10.1007/s10522-019-09816-3 .

Nacka-Aleksić, Mirjana, Pilipović, Ivan, Kotur-Stevuljević, Jelena, Petrović, Raisa, Sopta, Jelena, Leposavić, Gordana, "Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation" in Biogerontology, 20, no. 4 (2019):545-569,
https://doi.org/10.1007/s10522-019-09816-3 . .

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  - http://intor.torlakinstitut.com/handle/123456789/518
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
EP  - 3774
IS  - 5
SP  - 3755
VL  - 55
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",
pages = "3774-3755",
number = "5",
volume = "55",
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  - 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  - http://intor.torlakinstitut.com/handle/123456789/516
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
EP  - 53
SP  - 37
VL  - 101
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",
pages = "53-37",
volume = "101",
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  - Nacka-Aleksić, Mirjana
AU  - Stojanović, Marija
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Kosec, Duško
AU  - Leposavić, Gordana
PY  - 2018
UR  - http://intor.torlakinstitut.com/handle/123456789/520
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
IS  - 8
VL  - 13
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",
number = "8",
volume = "13",
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  - Nacka-Aleksić, Mirjana
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Vujnović, Ivana
AU  - Bufan, Biljana
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2017
UR  - http://intor.torlakinstitut.com/handle/123456789/490
AB  - To understand strain-specificities of immune system in aged rats and their immunopathological implications, CD4+T lymphocyte-mediated neuroinflammation in experimental autoimmune encephalomyelitis (EAE) was studied in two strains. Upon immunization for EAE, 22-24-month-old Albino Oxford (AO) rats developed milder neurological deficit of prolonged duration compared with their Dark Agouti (DA) counterparts. Consistently, they exhibited: (i) diminished neuroantigen-specific CD4+T lymphocyte generation in draining lymph nodes (reflecting lower density of high-affinity IL-2 receptor complex on their surface and higher CD4+FoxP3+CD25+regulatory cell frequency); (ii) less favorable spinal cord expression of CXCL12 and CCL2, and consequently diminished infiltration of neuroantigen-specific CD4+T lymphocytes, including highly pathogenic IL-17+IFN-gamma+ones, and inflammatory monocytes into the spinal cord and (iii) subsequently impaired CD4+T lymphocyte reactivation/survival and differentiation into highly pathogenic IL-17+cells (reflecting downregulated expression of IL-1 beta, IL-6 and IL-23/p19). On the other hand, when the neurological deficit reached maximum/plateau, in AO rat spinal cord was found lower CD4+FoxP3+CD25+ cell frequency followed by higher frequency of IL-10-producing CD8+T cells, which most likely also belong to regulatory T lymphocytes. Thus, the altered relation between regulatory T cell and effector CD4+T cell subsets was linked with persistence of mild neuroinflammation in AO rat EAE model. (C) 2017 Elsevier B.V. All rights reserved.
PB  - Elsevier Ireland Ltd, Clare
T2  - Mechanisms of Ageing and Development
T1  - Strain specificities in cellular and molecular immunopathogenic mechanisms underlying development of experimental autoimmune encephalomyelitis in aged rats
EP  - 163
SP  - 146
VL  - 164
DO  - 10.1016/j.mad.2017.03.001
ER  - 

@article{
author = "Nacka-Aleksić, Mirjana and Stojić-Vukanić, Zorica and Pilipović, Ivan and Vujnović, Ivana and Bufan, Biljana and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2017",
abstract = "To understand strain-specificities of immune system in aged rats and their immunopathological implications, CD4+T lymphocyte-mediated neuroinflammation in experimental autoimmune encephalomyelitis (EAE) was studied in two strains. Upon immunization for EAE, 22-24-month-old Albino Oxford (AO) rats developed milder neurological deficit of prolonged duration compared with their Dark Agouti (DA) counterparts. Consistently, they exhibited: (i) diminished neuroantigen-specific CD4+T lymphocyte generation in draining lymph nodes (reflecting lower density of high-affinity IL-2 receptor complex on their surface and higher CD4+FoxP3+CD25+regulatory cell frequency); (ii) less favorable spinal cord expression of CXCL12 and CCL2, and consequently diminished infiltration of neuroantigen-specific CD4+T lymphocytes, including highly pathogenic IL-17+IFN-gamma+ones, and inflammatory monocytes into the spinal cord and (iii) subsequently impaired CD4+T lymphocyte reactivation/survival and differentiation into highly pathogenic IL-17+cells (reflecting downregulated expression of IL-1 beta, IL-6 and IL-23/p19). On the other hand, when the neurological deficit reached maximum/plateau, in AO rat spinal cord was found lower CD4+FoxP3+CD25+ cell frequency followed by higher frequency of IL-10-producing CD8+T cells, which most likely also belong to regulatory T lymphocytes. Thus, the altered relation between regulatory T cell and effector CD4+T cell subsets was linked with persistence of mild neuroinflammation in AO rat EAE model. (C) 2017 Elsevier B.V. All rights reserved.",
publisher = "Elsevier Ireland Ltd, Clare",
journal = "Mechanisms of Ageing and Development",
title = "Strain specificities in cellular and molecular immunopathogenic mechanisms underlying development of experimental autoimmune encephalomyelitis in aged rats",
pages = "163-146",
volume = "164",
doi = "10.1016/j.mad.2017.03.001"
}

Nacka-Aleksić, M., Stojić-Vukanić, Z., Pilipović, I., Vujnović, I., Bufan, B., Dimitrijević, M.,& Leposavić, G.. (2017). Strain specificities in cellular and molecular immunopathogenic mechanisms underlying development of experimental autoimmune encephalomyelitis in aged rats. in Mechanisms of Ageing and Development
Elsevier Ireland Ltd, Clare., 164, 146-163.
https://doi.org/10.1016/j.mad.2017.03.001

Nacka-Aleksić M, Stojić-Vukanić Z, Pilipović I, Vujnović I, Bufan B, Dimitrijević M, Leposavić G. Strain specificities in cellular and molecular immunopathogenic mechanisms underlying development of experimental autoimmune encephalomyelitis in aged rats. in Mechanisms of Ageing and Development. 2017;164:146-163.
doi:10.1016/j.mad.2017.03.001 .

Nacka-Aleksić, Mirjana, Stojić-Vukanić, Zorica, Pilipović, Ivan, Vujnović, Ivana, Bufan, Biljana, Dimitrijević, Mirjana, Leposavić, Gordana, "Strain specificities in cellular and molecular immunopathogenic mechanisms underlying development of experimental autoimmune encephalomyelitis in aged rats" in Mechanisms of Ageing and Development, 164 (2017):146-163,
https://doi.org/10.1016/j.mad.2017.03.001 . .

TY  - JOUR
AU  - Dimitrijević, Mirjana
AU  - Kotur-Stevuljević, Jelena
AU  - Stojić-Vukanić, Zorica
AU  - Vujnović, Ivana
AU  - Pilipović, Ivan
AU  - Nacka-Aleksić, Mirjana
AU  - Leposavić, Gordana
PY  - 2017
UR  - http://intor.torlakinstitut.com/handle/123456789/489
AB  - The study examined (a) whether there is sex difference in spinal cord and plasma oxidative stress profiles in Dark Agouti rats immunised for experimental autoimmune encephalomyelitis (EAE), the principal experimental model of multiple sclerosis, and (b) whether there is correlation between the oxidative stress in spinal cord and neurological deficit. Regardless of rat sex, with the disease development xanthine oxidase (XO) activity and inducible nitric oxide synthase (iNOS) mRNA expression increased in spinal cord, whereas glutathione levels decreased. This was accompanied by the rise in spinal cord malondialdehyde level. On the other hand, with EAE development superoxide dismutase (SOD) activity decreased, while O-2 (-) concentration increased only in spinal cord of male rats. Consequently, SOD activity was lower, whereas O-2 (-) concentration was higher in spinal cord of male rats with clinically manifested EAE. XO activity and iNOS mRNA expression were also elevated in their spinal cord. Consistently, in the effector phase of EAE the concentration of advanced oxidation protein product (AOPP) was higher in spinal cord of male rats, which exhibit more severe neurological deficit than their female counterparts. In as much as data obtained in the experimental models could be translated to humans, the findings may be relevant for designing sex-specific antioxidant therapeutic strategies. Furthermore, the study indicated that the increased pro-oxidant-antioxidant balance in plasma may be an early indicator of EAE development. Moreover, it showed that plasma AOPP level may indicate not only actual activity of the disease, but also serve to predict severity of its course.
PB  - Springer/Plenum Publishers, New York
T2  - Neurochemical Research
T1  - Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit
EP  - 492
IS  - 2
SP  - 481
VL  - 42
DO  - 10.1007/s11064-016-2094-7
ER  - 

@article{
author = "Dimitrijević, Mirjana and Kotur-Stevuljević, Jelena and Stojić-Vukanić, Zorica and Vujnović, Ivana and Pilipović, Ivan and Nacka-Aleksić, Mirjana and Leposavić, Gordana",
year = "2017",
abstract = "The study examined (a) whether there is sex difference in spinal cord and plasma oxidative stress profiles in Dark Agouti rats immunised for experimental autoimmune encephalomyelitis (EAE), the principal experimental model of multiple sclerosis, and (b) whether there is correlation between the oxidative stress in spinal cord and neurological deficit. Regardless of rat sex, with the disease development xanthine oxidase (XO) activity and inducible nitric oxide synthase (iNOS) mRNA expression increased in spinal cord, whereas glutathione levels decreased. This was accompanied by the rise in spinal cord malondialdehyde level. On the other hand, with EAE development superoxide dismutase (SOD) activity decreased, while O-2 (-) concentration increased only in spinal cord of male rats. Consequently, SOD activity was lower, whereas O-2 (-) concentration was higher in spinal cord of male rats with clinically manifested EAE. XO activity and iNOS mRNA expression were also elevated in their spinal cord. Consistently, in the effector phase of EAE the concentration of advanced oxidation protein product (AOPP) was higher in spinal cord of male rats, which exhibit more severe neurological deficit than their female counterparts. In as much as data obtained in the experimental models could be translated to humans, the findings may be relevant for designing sex-specific antioxidant therapeutic strategies. Furthermore, the study indicated that the increased pro-oxidant-antioxidant balance in plasma may be an early indicator of EAE development. Moreover, it showed that plasma AOPP level may indicate not only actual activity of the disease, but also serve to predict severity of its course.",
publisher = "Springer/Plenum Publishers, New York",
journal = "Neurochemical Research",
title = "Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit",
pages = "492-481",
number = "2",
volume = "42",
doi = "10.1007/s11064-016-2094-7"
}

Dimitrijević, M., Kotur-Stevuljević, J., Stojić-Vukanić, Z., Vujnović, I., Pilipović, I., Nacka-Aleksić, M.,& Leposavić, G.. (2017). Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit. in Neurochemical Research
Springer/Plenum Publishers, New York., 42(2), 481-492.
https://doi.org/10.1007/s11064-016-2094-7

Dimitrijević M, Kotur-Stevuljević J, Stojić-Vukanić Z, Vujnović I, Pilipović I, Nacka-Aleksić M, Leposavić G. Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit. in Neurochemical Research. 2017;42(2):481-492.
doi:10.1007/s11064-016-2094-7 .

Dimitrijević, Mirjana, Kotur-Stevuljević, Jelena, Stojić-Vukanić, Zorica, Vujnović, Ivana, Pilipović, Ivan, Nacka-Aleksić, Mirjana, Leposavić, Gordana, "Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit" in Neurochemical Research, 42, no. 2 (2017):481-492,
https://doi.org/10.1007/s11064-016-2094-7 . .

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  - http://intor.torlakinstitut.com/handle/123456789/484
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
EP  - 185
IS  - 1-2
SP  - 169
VL  - 431
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",
pages = "185-169",
number = "1-2",
volume = "431",
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  - Stojić-Vukanić, Zorica
AU  - Bufan, Biljana
AU  - Pilipović, Ivan
AU  - Vujnović, Ivana
AU  - Nacka-Aleksić, Mirjana
AU  - Petrović, Raisa
AU  - Arsenović-Ranin, Nevena
AU  - Leposavić, Gordana
PY  - 2016
UR  - http://intor.torlakinstitut.com/handle/123456789/460
AB  - There are little data on modulatory effects of estrogens on rat dendritic cell (DC) responses to inflammatory stimuli, and consequently their ability to activate and polarize CD4+ T lymphocyte-mediated immune responses. Splenic conventional DCs from young female Albino Oxford rats were activated in vitro with LPS (TLR4 agonist) or R848 (TLR7/8 agonist) in the presence and absence of 17 beta-estradiol (E2), and their allostimulatory and CD4+ lymphocyte polarizing ability in mixed leukocyte culture (MLC) were studied. Irrespective of the E2 presence, LPS and R848 up-regulated the expression of MHC II on DCs, so they exhibited enhanced allostimulatory capacity in co-culture with CD4+ lymphocytes. On the other hand, E2 promoted stimulatory action of both TLRs on OX62+ DC IL-23 production, augmented their stimulatory effects on IL-6 and IL-1 beta production, but diminished their enhancing effects on the expression IL-10 and IL-27 by DCs. Consequently, in MLC, OX62+ DCs activated/matured in the co-presence of E2 and either LPS or R848 increased the levels of IL-17, the signature Th17 cell cytoldne, when compared with those activated/matured in the absence of E2. GM-CSF levels were also increased in these MLC. Given that the expression of IL-7 mRNA was diminished in DCs activated/matured in the co presence of E2 and TLR, this increase most likely did not reflect enhanced differentiation of Th cells producing GM-CSF only (Th-GM). Conclusions: E2 augments capacity of LPS- and R848-activated/matured DCs from young rat spleen to induce differentiation of IL-17- and GM-CSF-producing cells. (C) 2016 Elsevier B.V. All rights reserved.
PB  - Elsevier, Amsterdam
T2  - International Immunopharmacology
T1  - Estradiol enhances capacity of TLR-matured splenic dendritic cells to polarize CD4+lymphocytes into IL-17/GM-CSF-producing cells in vitro
EP  - 253
SP  - 244
VL  - 40
DO  - 10.1016/j.intimp.2016.09.001
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Bufan, Biljana and Pilipović, Ivan and Vujnović, Ivana and Nacka-Aleksić, Mirjana and Petrović, Raisa and Arsenović-Ranin, Nevena and Leposavić, Gordana",
year = "2016",
abstract = "There are little data on modulatory effects of estrogens on rat dendritic cell (DC) responses to inflammatory stimuli, and consequently their ability to activate and polarize CD4+ T lymphocyte-mediated immune responses. Splenic conventional DCs from young female Albino Oxford rats were activated in vitro with LPS (TLR4 agonist) or R848 (TLR7/8 agonist) in the presence and absence of 17 beta-estradiol (E2), and their allostimulatory and CD4+ lymphocyte polarizing ability in mixed leukocyte culture (MLC) were studied. Irrespective of the E2 presence, LPS and R848 up-regulated the expression of MHC II on DCs, so they exhibited enhanced allostimulatory capacity in co-culture with CD4+ lymphocytes. On the other hand, E2 promoted stimulatory action of both TLRs on OX62+ DC IL-23 production, augmented their stimulatory effects on IL-6 and IL-1 beta production, but diminished their enhancing effects on the expression IL-10 and IL-27 by DCs. Consequently, in MLC, OX62+ DCs activated/matured in the co-presence of E2 and either LPS or R848 increased the levels of IL-17, the signature Th17 cell cytoldne, when compared with those activated/matured in the absence of E2. GM-CSF levels were also increased in these MLC. Given that the expression of IL-7 mRNA was diminished in DCs activated/matured in the co presence of E2 and TLR, this increase most likely did not reflect enhanced differentiation of Th cells producing GM-CSF only (Th-GM). Conclusions: E2 augments capacity of LPS- and R848-activated/matured DCs from young rat spleen to induce differentiation of IL-17- and GM-CSF-producing cells. (C) 2016 Elsevier B.V. All rights reserved.",
publisher = "Elsevier, Amsterdam",
journal = "International Immunopharmacology",
title = "Estradiol enhances capacity of TLR-matured splenic dendritic cells to polarize CD4+lymphocytes into IL-17/GM-CSF-producing cells in vitro",
pages = "253-244",
volume = "40",
doi = "10.1016/j.intimp.2016.09.001"
}

Stojić-Vukanić, Z., Bufan, B., Pilipović, I., Vujnović, I., Nacka-Aleksić, M., Petrović, R., Arsenović-Ranin, N.,& Leposavić, G.. (2016). Estradiol enhances capacity of TLR-matured splenic dendritic cells to polarize CD4+lymphocytes into IL-17/GM-CSF-producing cells in vitro. in International Immunopharmacology
Elsevier, Amsterdam., 40, 244-253.
https://doi.org/10.1016/j.intimp.2016.09.001

Stojić-Vukanić Z, Bufan B, Pilipović I, Vujnović I, Nacka-Aleksić M, Petrović R, Arsenović-Ranin N, Leposavić G. Estradiol enhances capacity of TLR-matured splenic dendritic cells to polarize CD4+lymphocytes into IL-17/GM-CSF-producing cells in vitro. in International Immunopharmacology. 2016;40:244-253.
doi:10.1016/j.intimp.2016.09.001 .

Stojić-Vukanić, Zorica, Bufan, Biljana, Pilipović, Ivan, Vujnović, Ivana, Nacka-Aleksić, Mirjana, Petrović, Raisa, Arsenović-Ranin, Nevena, Leposavić, Gordana, "Estradiol enhances capacity of TLR-matured splenic dendritic cells to polarize CD4+lymphocytes into IL-17/GM-CSF-producing cells in vitro" in International Immunopharmacology, 40 (2016):244-253,
https://doi.org/10.1016/j.intimp.2016.09.001 . .

TY  - JOUR
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Vujnović, Ivana
AU  - Nacka-Aleksić, Mirjana
AU  - Petrović, Raisa
AU  - Arsenović-Ranin, Nevena
AU  - Dimitrijević, Mirjana
AU  - Leposavić, Gordana
PY  - 2016
UR  - http://intor.torlakinstitut.com/handle/123456789/457
AB  - Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+ IFN-gamma+, IL-17+ IFN-gamma-, and IL-17-IFN-gamma+ cells accompanied by higher frequency of IL-17-IFN-gamma- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+ IFN-gamma+ Th17 cells in SC) on GM-CSF+ IFN-gamma+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+ IFN-gamma+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1 beta, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45(hi) cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms controlling (auto) reactive CD4+ lymphocyte expansion/differentiation into the cells with pathogenic phenotype and migration of the latter to the SC contribute to AO rat resistance to EAE.
PB  - Public Library Science, San Francisco
T2  - PLoS One
T1  - GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis
IS  - 11
VL  - 11
DO  - 10.1371/journal.pone.0166498
ER  - 

@article{
author = "Stojić-Vukanić, Zorica and Pilipović, Ivan and Vujnović, Ivana and Nacka-Aleksić, Mirjana and Petrović, Raisa and Arsenović-Ranin, Nevena and Dimitrijević, Mirjana and Leposavić, Gordana",
year = "2016",
abstract = "Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+ IFN-gamma+, IL-17+ IFN-gamma-, and IL-17-IFN-gamma+ cells accompanied by higher frequency of IL-17-IFN-gamma- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+ IFN-gamma+ Th17 cells in SC) on GM-CSF+ IFN-gamma+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+ IFN-gamma+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1 beta, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45(hi) cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms controlling (auto) reactive CD4+ lymphocyte expansion/differentiation into the cells with pathogenic phenotype and migration of the latter to the SC contribute to AO rat resistance to EAE.",
publisher = "Public Library Science, San Francisco",
journal = "PLoS One",
title = "GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis",
number = "11",
volume = "11",
doi = "10.1371/journal.pone.0166498"
}

Stojić-Vukanić, Z., Pilipović, I., Vujnović, I., Nacka-Aleksić, M., Petrović, R., Arsenović-Ranin, N., Dimitrijević, M.,& Leposavić, G.. (2016). GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis. in PLoS One
Public Library Science, San Francisco., 11(11).
https://doi.org/10.1371/journal.pone.0166498

Stojić-Vukanić Z, Pilipović I, Vujnović I, Nacka-Aleksić M, Petrović R, Arsenović-Ranin N, Dimitrijević M, Leposavić G. GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis. in PLoS One. 2016;11(11).
doi:10.1371/journal.pone.0166498 .

Stojić-Vukanić, Zorica, Pilipović, Ivan, Vujnović, Ivana, Nacka-Aleksić, Mirjana, Petrović, Raisa, Arsenović-Ranin, Nevena, Dimitrijević, Mirjana, Leposavić, Gordana, "GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis" in PLoS One, 11, no. 11 (2016),
https://doi.org/10.1371/journal.pone.0166498 . .

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  - http://intor.torlakinstitut.com/handle/123456789/431
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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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
EP  - 31
SP  - 15
VL  - 152
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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.",
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",
pages = "31-15",
volume = "152",
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  - 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  - http://intor.torlakinstitut.com/handle/123456789/430
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  - 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  - http://intor.torlakinstitut.com/handle/123456789/448
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 - Beograd
T1  - Aging impairs endocytic capacity of splenic dendritic cells from dark agouti rats and alters their response to TLR4 stimulation
EP  - 55
IS  - 1
SP  - 30
VL  - 65
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 - Beograd",
title = "Aging impairs endocytic capacity of splenic dendritic cells from dark agouti rats and alters their response to TLR4 stimulation",
pages = "55-30",
number = "1",
volume = "65",
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 - Beograd
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 - Beograd. 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 - Beograd, 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  - http://intor.torlakinstitut.com/handle/123456789/444
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. (C) 2014 Elsevier B.V. All rights reserved.
PB  - Elsevier Science Bv, Amsterdam
T2  - Journal of Neuroimmunology
T1  - Age-related changes in spleen of Dark Agouti rats immunized for experimental autoimmune encephalomyelitis
EP  - 135
SP  - 123
VL  - 278
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. (C) 2014 Elsevier B.V. All rights reserved.",
publisher = "Elsevier Science Bv, Amsterdam",
journal = "Journal of Neuroimmunology",
title = "Age-related changes in spleen of Dark Agouti rats immunized for experimental autoimmune encephalomyelitis",
pages = "135-123",
volume = "278",
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  - http://intor.torlakinstitut.com/handle/123456789/442
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. (C) 2014 Elsevier B.V. All rights reserved.
PB  - Elsevier, 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
EP  - 35
IS  - 1
SP  - 24
VL  - 24
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. (C) 2014 Elsevier B.V. All rights reserved.",
publisher = "Elsevier, 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",
pages = "35-24",
number = "1",
volume = "24",
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, 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  - 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  - http://intor.torlakinstitut.com/handle/123456789/429
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
EP  - 1332
IS  - 10
SP  - 1319
VL  - 240
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",
pages = "1332-1319",
number = "10",
volume = "240",
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  - 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  - http://intor.torlakinstitut.com/handle/123456789/427
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. (C) 2015 Elsevier Inc. All rights reserved.
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
EP  - 118
SP  - 101
VL  - 49
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. (C) 2015 Elsevier Inc. All rights reserved.",
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",
pages = "118-101",
volume = "49",
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  - 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  - http://intor.torlakinstitut.com/handle/123456789/421
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. (C) 2013 Elsevier GmbH, All rights reserved.
PB  - Elsevier Gmbh, Munich
T2  - Immunobiology
T1  - Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency
EP  - 130
IS  - 2
SP  - 118
VL  - 219
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. (C) 2013 Elsevier GmbH, All rights reserved.",
publisher = "Elsevier Gmbh, Munich",
journal = "Immunobiology",
title = "Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency",
pages = "130-118",
number = "2",
volume = "219",
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, Munich., 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 . .