M Mostarica-Stojković

University of Belgrade, Belgrade, SE, Serbia

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Publications (55)116.49 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is a heterogeneous disease in which diverse genetic, pathological and clinical backgrounds lead to variable therapy response. Accordingly, MS care should be tailored to address disease traits unique to each person. At the core of personalized management is the emergence of new knowledge, enabling optimized treatment and disease-modifying therapies. This overview analyzes the promise of genetic and nongenetic biomarkers in advancing decision-making algorithms to assist diagnosis or in predicting the disease course and therapy response in any given MS patient.
    Biomarkers in Medicine 02/2013; 7(1):59-71. · 3.22 Impact Factor
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    ABSTRACT: Like other helminths, Trichinella spiralis has evolved strategies to allow it to survive in the host organism, including the expression of epitopes similar to those present in either expressed or hidden host antigens. To identify T. spiralis-derived antigens that are evolutionarily conserved in the parasite and its host and that could be responsible for its evasion of the host immune response, we examined the reactivity of six different types of autoantibodies to T. spiralis larvae from muscle. T. spiralis antigens that share epitopes with human autoantigens were identified by assessing the cross-reactivity of autoantibody-containing serum samples with T. spiralis antigens in the absence of specific anti-parasite antibodies. Of the 55 autoantibody-containing human serum samples that we analysed by immunohistological screening, 24 (43.6%) recognised T. spiralis muscle larvae structures such as the subcuticular region, the genital primordium or the midgut. Using Western blots, we demonstrated that the same sera reacted with 24 protein components of T. spiralis muscle larvae excretory-secretory L1 antigens. We found that the human autoantibodies predominantly bound antigens belonging to the TSL1 group; more specifically, the autoantibody-containing sera reacted most frequently with the 53-kDa component. Thus, this protein is a good candidate for further studies of the mechanisms of T. spiralis-mediated immunomodulation.
    Memórias do Instituto Oswaldo Cruz 06/2012; 107(4):503-9. · 1.36 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by unpredictable and variable clinical course. Etiology of MS involves both genetic and environmental factors. New technologies identified genetic polymorphisms associated with MS susceptibility among which immunologically relevant genes are significantly overrepresented. Although individual genes contribute only a small part to MS susceptibility, they might be used as biomarkers, thus helping to identify accurate diagnosis, predict clinical disease course and response to therapy. This review focuses on recent progress in research on MS genetics with special emphasis on the possibility to use single nucleotide polymorphism of candidate genes as biomarkers of susceptibility to disease and response to therapy.
    Immunologic Research 03/2012; 52(1-2):42-52. · 2.96 Impact Factor
  • Miljana Momcilović, Marija Mostarica-Stojković, Djordje Miljković
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    ABSTRACT: Inflammation within the central nervous system (CNS) is strictly controlled and if possible prevented. Such a tight control is necessary due to high sensitivity of nervous tissue to mechanical and biochemical consequences of inflammation. Still, neuroinflammation is a typical feature of a chronic, inflammatory, demyelinating disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). It is assumed that mechanisms that should prevent activation of immune cells at the periphery, in the lymphoid tissues, and/or inflammation within the CNS are inadequately efficient in MS patients. Here, some recent data about the importance of CXCL12 for regulation of neuroinflammation and contribution of its deviant expression within the CNS to EAE and MS pathogenesis are presented.
    Immunologic Research 03/2012; 52(1-2):53-63. · 2.96 Impact Factor
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    ABSTRACT: The aim of the study was to correlate the preoperative activity of Th1 and Th17 cytokine axes with the development of sepsis after radical cystectomy. The study involved twenty patients with the infiltrative transitional cell carcinoma of the urinary bladder without previous radiotherapy/chemotherapy, who underwent open radical cystectomy with urinary diversion. Preoperative plasma concentrations of Th1 cytokines interleukin 12 (IL-12) and interferon gamma (IFN-γ), and Th17 cytokines IL-23 and IL-17, were measured using ELISA. Preoperative expression of mRNA for IL-12p35, IFN-γ, IL-23p19 and IL-17 was quantified by real-time RT-PCR using mRNA extracted from peripheral blood mononuclear cells. Eight patients developed postoperative sepsis, diagnosed within two weeks post-operation as systemic inflammatory response syndrome in the presence of local or systemic infection. The preoperative basal plasma concentrations of Th1 and Th17 cytokines were slightly above the detection limits, with a tendency toward lower concentrations in patients who developed sepsis, but the difference was not significant (p>0.05). The preoperative expression of mRNA encoding IL-12p35 and IL-17 was significantly lower in patients who developed sepsis (p=0.003 and p=0.028, respectively). The similar trend was observed for IL-23p19 and IFN-γ, but the differences did not reach the statistical significance (p=0.051 and p=0.172, respectively). These data suggest that determination of preoperative Th1 and Th17 cytokine mRNA levels might be useful in predicting sepsis development after radical cystectomy.
    European cytokine network. 12/2011; 22(4):169-74.
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis. Dark Agouti rats immunized with spinal cord homogenate (SCH) and carbonyl iron (CI), as an adjuvant, develop severe hyperacute form of EAE. They succumb to EAE earlier and have higher clinical scores and lethality rate in comparison to counterparts immunized with SCH + complete Freund's adjuvant. There is no difference in the number of cells or in histological presentation of the CNS infiltrates of rats immunized with the two adjuvants. However, there are more granulocytes, NK and NKT cells, and less CD4(+) T cells in the spinal cord infiltrates of SCH + CI-immunized animals. Nitric oxide (NO)-generating enzyme inducible NO synthase have higher expression in spinal cord of SCH + CI-immunized rats, and this corresponds to more intensive nitrotyrosine formation in the CNS tissue of these rats. Abundant infiltration of granulocytes and NK cells into the CNS and excessive generation of peroxynitrite within the CNS of SCH + CI-immunized rats might account for the severe neurological deficits induced by immunization with CI. These factors should be closely examined in the fulminant forms of multiple sclerosis and acute disseminated encephalomyelitis, as they could represent a promising targets for therapy.
    Journal of Neurochemistry 05/2011; 118(2):205-14. · 3.97 Impact Factor
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis, a chronic inflammatory and demyelinating disease of the CNS. Albino Oxford (AO) rats are resistant to the induction of EAE, while the disease can be readily induced in Dark Agouti (DA) rats. Here we investigated a potential contribution of the CNS milieu in the limitation of the encephalitogenic autoimmune response. EAE was induced by immunization of the respective rat strains with spinal cord homogenate emulsified in complete Freund's adjuvant. AO rats did not exhibit clinical signs after immunization while DA rats developed severe neurologic deficits. Infiltration of immune cells into spinal cords (SC) was evident in both strains 12-14 days after the immunization. EAE lesions of AO rats contained substantially lower numbers of CD4+ T cells and CD11b+ cells compared to those in DA rats. This went together with lower levels of interferon (IFN)-γ and interleukin (IL)-17 in the cells isolated from SC. We found a dramatic increase of CXCL12 expression in SC tissue and microvessels of AO rats, whereas DA rats markedly decreased the expression of this chemokine within their CNS. Administration of the CXCL12 antagonist AMD3100 to a substrain of AO rats that developed a weak EAE led to earlier onset and exacerbation of the disease. These results suggest a role of CXCL12 in down-regulating autoimmune processes in AO rats during EAE. Therapeutic modulation of CXCL12 could be a promising strategy for the treatment of CNS autoimmunity.
    Immunobiology 04/2011; 216(9):979-87. · 2.81 Impact Factor
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    ABSTRACT: Trichinella spiralis is a helminth that provokes Th2 and anti-inflammatory type responses in an infected host. Our previous studies using Dark Agouti (DA) rats indicated that T. spiralis infection reduced experimental autoimmune encephalomyelitis (EAE) severity in rats. The aim of this study was to analyse the mechanisms underlying EAE suppression driven by T. spiralis infection. Reduced clinical and histological manifestations of the disease were accompanied by increased IL-4 and IL-10 production and decreased IFN-gamma and IL-17 production in draining lymph node cells. This indicates that T. spiralis infection successfully maintains a Th2 cytokine bias regardless of EAE induction. High IL-10 signifies parasite-induced anti-inflammatory and/or regulatory cell responses. Transfer of splenic T cell-enriched population of cells from T. spiralis-infected rats into EAE immunized rats caused amelioration of EAE and in some cases protection from disease development. This population of cells contained higher proportion of CD4(+) CD25(+) Foxp3(+) regulatory cells and produced high level of IL-10 when compared with uninfected rats.
    Parasite Immunology 06/2010; 32(6):450-9. · 2.21 Impact Factor
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    ABSTRACT: Glucocorticoids have been shown to be effective in the treatment of autoimmune diseases of the CNS such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms and the site of glucocorticoids' actions are still not completely defined. The aim of this study was to investigate the in vivo effect of the synthetic glucocorticoid methylprednisolone (MP) on the expression and production of proinflammatory cytokines interferon (IFN)-gamma and interleukin (IL)-17 by cells infiltrating CNS tissue. Experimental autoimmune encephalomyelitis was induced in Dark Agouti (DA) rats by immunization with rat spinal cord homogenate mixed with adjuvants. Commencing on the day when the first EAE signs appeared, DA rats were injected daily for 3 days with MP and/or RU486, an antagonist of glucocorticoid receptor. Cytokine production and gene expression in CNS-infiltrating cells and lymph node cells were measured using ELISA and real time PCR, respectively. Treatment of rats with MP ameliorated EAE, and the animals recovered without relapses. Further, MP inhibited IFN-gamma and IL-17 expression and production in cells isolated from the CNS of DA rats with EAE after the last injection of MP. The observed effect of MP in vivo treatment was not mediated through depletion of CD4+ T cells among CNS infiltrating cells, or through induction of their apoptosis within the CNS. Finally, the glucocorticoid receptor-antagonist RU486 prevented the inhibitory effect of MP on IFN-gamma and IL-17 production both in vitro and in vivo, thus indicating that the observed effects of MP were mediated through glucocorticoid receptor-dependent mechanisms. Taken together, these results demonstrate that amelioration of EAE by exogenous glucocorticoids might be, at least partly, ascribed to the limitation of effector cell functions in the target tissue.
    Journal of Neuroinflammation 12/2009; 6:37. · 4.35 Impact Factor
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    ABSTRACT: The aim of the present study was to analyze the activities of extracellular purine metabolizing enzymes, CD39 (apyrase, EC 3.6.1.5) and CD73 (ecto-5' nucleotidase, EC 3.1.3.5) in experimental autoimmune encephalomyelitis (EAE). The levels of ATP, ADP and AMP hydrolysis were analyzed in the blood serum and in the rat spinal cord plasma membrane preparation 8, 15 and 25 days after induction of EAE. The animals were divided in three groups: control (saline), CFA (adjuvant-only) and EAE (CFA and homogenate of spinal cords). Eight days after immunization, ATP, ADP and AMP hydrolysis in the blood serum and spinal cord membrane preparations were unaffected in EAE compared to both, control and CFA group. In the peak of disease, ATP, ADP and AMP hydrolysis in EAE group showed significant decrease in the blood serum and prominent increase in the spinal cord membrane preparation compared to CFA and control group. At the end of illness, as judged by disappearance of clinical manifestation of EAE, ATP, ADP and AMP hydrolysis, although closer to CFA levels, were still significantly different in respect to the CFA group. Modulation of ATP, ADP and AMP hydrolysis suggests that they operate during EAE and might represent the basis of novel therapeutic strategies in immune-mediated diseases, such as MS.
    Neurochemistry International 10/2009; 55(4):193-8. · 2.66 Impact Factor
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is an animal model of CNS inflammatory and demyelinating disease multiple sclerosis. Mediterranean diet, rich in olive products is associated with lower incidence of multiple sclerosis in South European population. Therefore, the influence of dry olive leaf extract (DOLE) on EAE course was investigated. Spinal cord homogenate and complete Freund's adjuvant were used for the induction of EAE in Dark Agouti rats. DOLE was applied intragastrically once per day, starting from the day of the immunization. Real time PCR and ELISA were used for the determination of IFN-gamma and IL-17 gene expression and production, respectively. DOLE reduced various parameters of EAE severity in DA rats, including cumulative disease index, maximal clinical score and disease duration. Also, DOLE decreased cellularity of the draining lymph nodes and production of IFN-gamma and IL-17 by the cells infiltrating spinal cord of EAE rats. The results presented in this paper strongly suggest that DOLE-enriched diet has a beneficial effect in EAE in rats. Further studies in humans are required in order to investigate if DOLE could be a useful supplementary dietetic for the patients suffering from multiple sclerosis and other neuroinflammatory disorders.
    Clinical nutrition (Edinburgh, Scotland) 05/2009; 28(3):346-50. · 3.27 Impact Factor
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    ABSTRACT: The aim of this study was to compare plasma and urine transforming growth factor-beta1 (TGF-beta1) levels in patients with different stages of Balkan endemic nephropathy (BEN) with those in patients with primary glomerulonephritis (GN) and healthy controls. The study involved 47 patients with BEN (30 with manifest BEN and 17 in the early stage of BEN), 12 patients with GN and 10 healthy controls. Plasma and urine TGF-beta1 was assayed by enzyme-linked immunosorbent assay. The median plasma TGF-beta1 levels differed nonsignificantly between the groups (4,908-6,442 pg/ml), but individual plasma TGF-beta1 levels in BEN patients exhibited the highest dispersion. Median urinary TGF-beta1 excretion (pg/mg creatinine) was significantly higher in patient groups (manifest BEN: 203, early-stage BEN: 341, GN: 775) than in healthy controls (42). No correlation was found between plasma and urine TGF-beta1 levels or between plasma TGF-beta1 levels and creatinine clearance for any of the examined groups. Plasma TGF-beta1 levels in BEN patients extended over the widest range, but no significant differences were found between the median values for the groups. Median urinary TGF-beta1 excretion was significantly higher in patients with BEN and GN than in healthy controls.
    Nephron Clinical Practice 02/2009; 111(2):c127-32. · 1.65 Impact Factor
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    Miljana Momčilović, D. Miljković, Marija Mostarica-Stojković
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    ABSTRACT: Brain endothelial cells (BEC) are the major constituents of the blood-brain barrier (BBB), the structure that controls entrance of immune cells into CNS parenchyma. Our aim was to investigate the influence of BEC on production of IL-17 and IFN-γ-cytokines that are important for CNS inflammation. To that end, co-cultivations of the bEnd.3 brain endothelial cell line and lymph node cells (LNC) were performed, and gene expression and production of IL-17 and IFN-γ were determined. It was found that bEnd.3 cells inhibited expression and production of IFN-γ, but not of IL-17. Additionally, bEnd.3 cells also reduced production of the major IFN-γ-promoting cytokine - IL-12 - in LNC. The observed variation in modulation of pro-inflammatory cytokines by BEC could be of importance for the understanding of CNS inflammation.
    Archives of Biological Sciences. 01/2009;
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    ABSTRACT: The role of extracellular purines and purinoreceptors in the pathophysiology of different neurological disorders is the focus of rapidly expanding area of research. Ectonucleotidases are the enzymes with multiple roles in extracellular nucleotides metabolism and regulation of nucleotidebased intercellular signaling. The aim of present study was to investigate the changes in the ATP, ADP and AMP hydrolyzing activities after ribavirin treatment in spinal cord during experimental autoimmune encephalomyelitis (EAE). Our results demonstrate that ribavirin itself had no significant effect on ectoenzyme activities, when tested in vitro and in vivo on spinal cord crude membrane preparation of intact animals. We observed significant increase in ATP, ADP and AMP hydrolyzing activity in the spinal cord crude membrane preparation in EAE animals at 15 days post immunization compared to control animals. The increase was registered at 28 days post immunization, as well. At same time points, ribavirin treatment decreased ATP, ADP and AMP hydrolyzing activity compared to EAE animals. In addition, no significant changes 8 days post immunization was observed between EAE-induced and ribavirin- treated EAE animals and these levels were similar to control level. Thus, we suppose that ribavirin-induced alteration in ectonucleotidase activities is rather due to its suppression of inflammation, than to its direct action on ATP, ADP and AMP hydrolysis.
    General Physiology and Biophysics 01/2009; 28 Spec No:69-76. · 0.85 Impact Factor
  • Neurochemistry International 01/2009; 55(4):193. · 2.66 Impact Factor
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    ABSTRACT: Interferon-gamma (IFN-gamma) and interleukin-17 (IL-17) have been involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). We have carried out a follow-up study of the expression and production of these cytokines, as well as of cells expressing these cytokines during the course of active EAE in Dark Agouti (DA) rats. As a result, IL-17, but not IFN-gamma expression and production had the peak value in draining lymph nodes (DLN) during the induction phase of the disease, and in spinal cords (SC) at the onset of clinical signs of the disease, and then declined toward the resolution of the disease. Also, a significant proportion of IFN-gamma/IL-17 double-positive cells was observed in SC of DA rats in active EAE. Importantly, the highest proportion of IL-17 single positive and double-positive cells, but not of IFN-gamma single positive cells, was observed at the onset of the disease. The observed difference in the kinetics of IFN-gamma and IL-17 expression during active EAE in DA rats suggests different roles these cytokines might have in the pathogenesis of the disease.
    Neuroscience Letters 11/2008; 447(2-3):148-52. · 2.03 Impact Factor
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    ABSTRACT: To determine the mechanism underlying ribavirin induced amelioration of experimental autoimmune encephalomyelitis (EAE), cytokine profiles were evaluated in draining lymph node (DLN) cell culture supernatants and spinal cord obtained from EAE and/or ribavirin-treated EAE Dark Agouti rats. Administration of ribavirin to EAE rats markedly affected the production of pro-inflammatory cytokines IFN-gamma, IL-1beta and TNF-alpha in DLN and spinal cord, thus shifting the balance towards the anti-inflammatory cytokines IL-10 and TGF-beta. These findings suggest that ribavirin attenuates EAE by limiting cytokine-mediated immunoinflammatory events leading to CNS destruction. The conducted experiments provide rationale for ribavirin to be considered as a candidate drug in the development of new therapeutic strategies for the treatment of autoimmune diseases in humans, such as multiple sclerosis.
    International Immunopharmacology 10/2008; 8(9):1282-90. · 2.42 Impact Factor
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    ABSTRACT: Numerous studies have shown immunostimulatory and anti-tumor effects of water and standardized aqueous ethanol extracts derived from the medicinal mushroom, Coriolus versicolor, but the biological activity of methanol extracts has not been examined so far. In the present study we investigated the anti-tumor effect of C. versicolor methanol extract (which contains terpenoids and polyphenols) on B16 mouse melanoma cells both in vitro and in vivo. In vitro treatment of the cells with the methanol extract (25-1600 microg/ml) reduced melanoma cell viability in a dose-dependent manner. Furthermore, in the presence of the methanol extract (200 microg/ml, concentration IC(50)) the proliferation of B16 cells was arrested in the G(0)/G(1) phase of the cell cycle, followed by both apoptotic and secondary necrotic cell death. In vivo methanol extract treatment (i.p. 50 mg/kg, for 14 days) inhibited tumor growth in C57BL/6 mice inoculated with syngeneic B16 tumor cells. Moreover, peritoneal macrophages collected 21 days after tumor implantation from methanol extract-treated animals exerted stronger tumoristatic activity ex vivo than macrophages from control melanoma-bearing mice. Taken together, our results demonstrate that C. versicolor methanol extract exerts pronounced anti-melanoma activity, both directly through antiproliferative and cytotoxic effects on tumor cells and indirectly through promotion of macrophage anti-tumor activity.
    Food and Chemical Toxicology 06/2008; 46(5):1825-33. · 3.01 Impact Factor
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    ABSTRACT: Helminth infection has a potent systemic immunomodulatory effect on the host immune response, which also affects the development of autoimmune diseases. We investigated the dose-dependent influence of Trichinella spiralis infection on experimental autoimmune encephalomyelitis (EAE). Our model of concomitant T. spiralis infection and EAE demonstrates that established infection of Dark Agouti (DA) rats with the parasite causes amelioration of the clinical course of induced EAE in a dose-dependent way. Infection with T. spiralis L1 stage muscle larvae (TSL1) reduced the severity of the autoimmune disease as judged by lower maximal clinical score, cumulative index, duration of illness and degree of mononuclear cell infiltration in T. spiralis infected animals compared to control, EAE-induced group. This study provides a valuable model of worm infection to investigate helminth-induced regulatory mechanisms for optimal benefit to the host.
    Experimental Parasitology 05/2008; 118(4):641-7. · 2.15 Impact Factor
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and the helpful tool in preclinical testing of various substances considered for treatment of this human CNS disease. Ribavirin (R) and tiazofurin (T) are purine nucleoside analogues, with the broad spectrum of anti-viral, anti-tumoral and anti-inflammatory properties. We proposed that combined treatment with RT, administrated during the effector phase of EAE, would attenuate disease severity, both clinically and pathologically. Ribavirin was given daily at a dosage of 30 mg/kg and tiazofurin was given at a dosage of 10 mg/kg every other day for 15 days. We detected amelioration of clinical signs and faster recovery in the RT group compared to the control group. Immunohistochemical analyses revealed that RT treatment decrease the number of T cells, macrophages and microglia. In the controls, we detected reactive type of microglia, while in the RT group we noticed ramified/resting form. Demyelination areas and axonal damage were not recorded in the RT group, in contrast to the control group where multiple areas of demyelination zones and axonal loss were found. RT combination treatment suppresses ongoing EAE, prevents demyelination and axonal loss, and therefore may well be the potential therapy for the treatment of MS.
    Journal of the Neurological Sciences 05/2008; 267(1-2):76-85. · 2.24 Impact Factor

Publication Stats

413 Citations
116.49 Total Impact Points

Institutions

  • 1988–2013
    • University of Belgrade
      • • Institute of Microbiology and Immunology
      • • Institute for Biological Research Sinisa Stankovic
      Belgrade, SE, Serbia
  • 2009
    • Klinički centar Srbije
      Beograd, Central Serbia, Serbia
  • 2006–2008
    • Institute for Educational Research, Belgrade, Serbia
      Beograd, Central Serbia, Serbia