Institute for Medical Research

University of Belgrade

Group of immunology

Group of immunology was founded in 2007 as the successor of the Group for immunochemistry. The change in the name of the group was a result of the broadening of the research scope, from immunochemical properties of immunoglobulins, immune complexes and lipoproteins to the molecular and cellular mechanisms of immunoregulation.

Before 2007, research work in the Group of immunology was focused on investigation of molecular basis of interactions within the humoral branch of immune response by analysing structural characteristics of immunoglobulins in body fluids of humans and animals under physiological and pathological conditions. The results of studies of molecular mechanisms of malignant alterations in multiple myeloma have provided information on structural characteristics of serum and urinary monoclonal immunoglobulins (paraprotein) in human malignant monoclonal gammopathies, on activity of two inherited immunoglobulin gene locuses, and composition B of cell receptors expressed on peripheral blood lymphocyte in multiple myeloma. In this period significant part of the work were related to the problem of reactivity and specificity of rheumatoid factors, auto anti-immunoglobulin antibodies present in the serum of patients with rheumatoid arthritis. Another major area in the group was investigation of molecular characteristics of immunoglobulin as a part of local immunological defence system on mucosal surfaces. The most important part of this research was dealt with analyses of molecular characteristics of immunoglobulins of oral fluids (salivary and gingival fluid) in parodontopathies.

Since 2007, due to the opening of new research areas the members of the group have introduced, in cooperation and with the help of researches from other institutes and faculties of the University of Belgrade, a number of new methods and techniques: cell culture, modern microscopic techniques, complex physicochemical analyses, and techniques for testing nucleic acids. The main part of current researches is the study of immunomodulatory function of immune complex, mesenchymal stem cells, nutrients, and hormones. As a part of the research into mechanisms of immunoregulation, members of the group participated in research of cell signalling pathways through which proinflammatory cytokines regulate growth and functions of hematopoietic and non-haematopoietic cell of significance for effective immune response. As a part of applied research members of the group have analysed anti-inflammatory role of conventional and newly synthesized steroidal and non-steroidal drugs administered in the form of free molecules or in the form of system for prolonged release based on erythrocyte membranes. Also the group the group have carried out studies of body fluids’ proteins and lipoproteins with the aim of using them as biomarkers of inflammatory diseases in humans and animals. In addition, basic and applied research performed in the group led to the development of a significant number of immunohemical assays.

The group is headed by dr Vesna Ilić, and associates are dr Dragana Marković, Sonja Mojsilović, dr Ivana Drvenica, Marijana Kovacić, and Ana Stančić.

Selected publications

Dobričić V, Drvenica I, Stančić A, Mihailović М, Čudina O, Bugarski D, Ilić V. (2018) Investigation of metabolic properties and effects of 17β-carboxamide glucocorticoids on human peripheral blood leukocytes. Arch Pharm Chem Life Sci. 2018;e1700371.

Bukara K, Jovanić S, Drvenica IT, Stančić A, Ilić V, Rabasović MD, Pantelić D, Jelenković B, Bugarski B, Krmpot AJ. (2017): Mapping of hemoglobin in erythrocytes and erythrocyte ghosts using two photon excitation fluorescence microscopy. J Biomed Opt 22(2):26003.

Kovačić M, Marković D, Maslovarić I, Obrenović S, Grujić-Milanović J, Arsić A, Milanović Z, Savić O, Fratrić N, Ilić V. (2017): Serum proteins and lipids in mild form of calf bronchopneumonia: Candidates for reliable biomarkers. Acta Vet (Belgrade) 67(2): 201-221.

Bjelica J, Jovanović IB, Ilić V, Valčić O, Kirovski D, Gvozdić D, Milanović S. (2017): Effects of selenium and thyroid hormone deficiency on peritoneal macrophages adhesion and occurrence of naturally occurring IgM antibodies in juvenile rats. Acta Vet (Belgrade) DOI:10.1515/acve-2017-0028.

Buač M, Mojsilović S, Mišić D, Vuković D, Savić O, Valčić O, Marković D, Gvozdić D, Ilić V, Fratrić N. (2016): Circulating immune complexes of calves with bronchopneumonia modulate the function of peripheral blood leukocytes: In vitro evaluation. Res Vet Sci 106: 135-142.

Drvenica I, Bukara K, Ilić V, Mišić D, Vasic B, Gajic R, Djordjević V, Veljović Dj, Belić A, Bugarski B. (2016): Biomembranes from slaughterhouse blood erythrocytes as prolonged release systems for dexamethasone sodium phosphate. Biotechnol Prog 32: 1046-1055.

Bukara K, Drvenica I, Ilić V, Stančić A, Mišić D, Vasić B, Gajić R, Vučetić D, Kiekens F, Bugarski B. (2016): Comparative studies on osmosis based encapsulation of sodium diclofenac in porcine and outdated human erythrocyte ghosts. J Biotechnol 240: 14-22.

Vučetić D, Ilić V, Vojvodić D, Subota V, Todorovi M, Balint B. (2016): Flow cytometry analysis of platelets’ populations is useful in monitoring storage lesions in pooled buffy-coat platelet concentrates. Blood Transfus DOI: 10.2450/2016.0193-16.

Obrenović S, Ristanović E, Čekanac R, Radulović Ž, Ilić V. (2015): Seroprevalence of IgG antibodies against Borrelia burgdorferi in dogs in Belgrade area, Serbia. Acta Vet (Belgrade) 65: 99-110.

Djunic I, Elezovic I, Vucic M, Srdic-Rajic T, Konic-Ristic A, Ilic V, Milic N, Bila J, Suvajdzic-Vukovic N, Virijevic M, Antic D, Vidovic A, Tomin D. (2013): Specific binding of paraprotein to platelet receptors as a cause of platelet dysfunction in monoclonal gammopathies. Acta Haematol 130: 101-107.

Ilić V, Mojsilović S, Marković D, Maslovarić I, Milošević-Jovčić N. (2012): Anion exchange chromatographic distribution of human monoclonal immunoglobulin G is determined by heavy chain subclass and level of sialic acid expression. Hem Ind 66: 531–540.

Kovačević-Filipović M, Ilić V, Vujčić Z, Dojnov B, Stevanov-Pavlović M, Mijačević Z, Božić T. (2012): Serum amyloid A isoforms in serum and milk from cows with Staphylococcus aureus subclinical mastitis. Vet Immunol Immunopathol 145: 120-128.

Fratrić N, Gvozdić D, Vuković D, Savić O, Buač M, Ilić V. (2012): Evidence that calf bronchopneumonia may be accompanied by increased sialylation of circulating immune complexes` IgG. Vet Immunol Immunopathol 150: 161– 168.

Brajović G, Stefanović G, Ilić V, Petrović S, Stefanović N, Nikolić-Jakoba N, Milošević-Jovčić N. (2010): Association of Fibronectin with Hypogalactosylated IgG, in Gingival Crevicular Fluid in Periodontitis. J Periodontol 81: 1472-1480.

Ilić V, Milošević-Jovčić N, Petrović S, Marković D, Stefanović G, Ristić T. (2008): Glycosylation of IgG B cell receptor (IgG BCR) in multiple myeloma: relationship between sialynisation and the signal activity of IgG BCR. Glycoconj J 25:383–392.

Ilić V, Milošević-Jovčić N, Petrović S, Marković D, Bila J, Bošković J, Stefanović G, Marković O, Glibetić M. (2007): Signaling status of IgG B cell receptor (IgG BCR) is indicative for an activated state of circulating B cells in multiple myeloma. Ann Hematol 86: 905-912.

Ilić V, Milošević-Jovčić N, Marković D Petrović S. (2007): A biased Gm haplotype and Gm paraprotein allotype in multiple myeloma suggests a role for the Gm system in myeloma development. Int J Immunogenet 34:119-125.

Stefanović G, Marković D, Ilić V, Brajović G, Petrović S, Milošević-Jovčić N. (2006): Hypogalactosylation of salivary and gingival fluid IgG in patients with advanced periodontitis. J Periodontol 77(11): 1887-1893.

 Ćirić D, Milošević-Jovčić N, Ilić V, Petrović S. (2005): A Longitudinal study of the relationship between galactosylation degree of IgG and rheumatoid factor titer and avidity during long-term immunization of rabbits with BSA. Autoimmunity 38: 409-416.

Military Medical Academy

Vojnomedicinska akademija VMA - Immunology and Cell Biology group

The group for Immunology and Cell Biology is performing their research within the projects of Ministry of Education, Science and Technological development at the Institute for the Application of Nuclear Energy (INEP) (project no 175102, academician Miodrag Čolić), and the projects of Medical Faculty of the Military Medical Academy (Prof. Dr Dragana Vučević, Academician Miodrag Čolić).

The research focus includes: 1) immunoregulatory mechanisms in inflammation, 2) development of dendritic cells (DC)-based immunotherapy for cancer and autoimmune diseases and, 3) biocompatibility and immunomodulatory properties of biomaterials and nanomaterials. Different chronic inflammation models are being used to study the cross-talk between immune and nonimmune cells, towards discovery of molecular mechanisms suitable for targeted therapy. The group also apply different protocols for the generation of immunogenic DCs capable of inducing efficient anti-tumor responses in vitro and in vivo in B16 melanoma model. Tolerogenic DCs generated with nanomaterials, stem cells, etc., are being tested for their increased capacity to induce suppressive Treg subpopulations in vitro and in vivo in a model of EAE in rats. Biocompatibility studies of biomaterials (shape-memory alloys, biomimetic composite materials, degradable polymers) and nanomaterials (gold nanoparticles, carbon nanotube, graphene quantum dots, cellulose nanofibrils) enable detection of their adverse immunological effects, and discovery of new ways to improve and apply these materials in state-of-the-art immunotherapy. Therefore, different methods are being applied (cell culture, ELISA, flow cytometry, confocal microscopy, β-counter, SEM, TEM, WB, PCR, etc.) for study on different cell models (L929, Raw, 4T1, PBMC, DC, T, THP-1, U937, CaCo2, etc.), patients cells, and in animal models.

Selected publications

Sergej Tomić, Kristina Janjetović, Dušan Mihajlović, Marina Milenković, et al (2017) Biomaterials 146, 13-28

Sergej Tomić, Vanja Kokol, Dušan Mihajlović, Aleksandar Mirčić, Miodrag Čolić (2016), Scientific reports 6, 31618

Bojan Pavlović, Sergej Tomić, Jelena Đokić, Saša Vasilijić, Dragana Vučević, et al. (2015) Cytotherapy 17 (12), 1763-1776

Tomić S, J Đokić, S Vasilijić, N Ogrinc, R Rudolf, P Pelicon, D Vučević, et al. (2014). PloS one 9:e96584.

Thorne A, S Tomić, B Pavlović, D Mihajlović, T Džopalić, M Čolić. (2014). Cytotherapy

Čolić M, T Džopalić, S Tomić, J Rajković, R Rudolf, G Vuković, A Marinković, P Uskoković. (2014). Carbon 67:273-87..

Mihajlovic D, I Rajkovic, I Chinou, M Colic. (2013). Journal of Functional Foods 5:838-46.

Dokic J, S Tomic, M Markovic, P Milosavljevic, M Colic. (2013). Eur J Immunol 43:1862-72.

Dzopalic T, I Rajkovic, A Dragicevic, M Colic. (2012). Immunol Res 52:20-33.

Tomic S, R Rudolf, M Bruncko, I Anzel, V Savic, M Colic. (2012). Eur Cell Mater 23:58-80.

Dzopalic T, A Dragicevic, B Bozic, I Rajkovic, M Colic. (2012). Exp Biol Med (Maywood) 237:784-92.

Dokic J, S Tomic, S Cerovic, V Todorovic, R Rudolf, M Colic. (2012). J Clin Periodontol 39:807-16.

Dzopalic T, D Vucevic, S Tomic, J Djokic, I Chinou, M Colic. (2011). Food Chemistry 126:1211-7.

Rajkovic I, A Dragicevic, S Vasilijic, B Bozic, T Dzopalic, S Tomic, I Majstorovic, et al. (2011). Immunology 132:217-25.

Tomic S, J Djokic, S Vasilijic, D Vucevic, V Todorovic, G Supic, M Colic. (2011). Stem Cells Dev 20:695-708.

Colic M, R Rudolf, D Stamenkovic, I Anzel, D Vucevic, M Jenko, V Lazic, G Lojen. (2010). Acta Biomater 6:308-17.

Colic M, D Gazivoda, I Majstorovic, A Dragicevic, S Vasilijic, R Rudolf, P Milosavljevic, D Vucevic. (2009). J Dent Res 88:1142-7.

Colic M, D Gazivoda, D Vucevic, S Vasilijic, R Rudolf, A Lukic. (2009). Mol Immunol 47:101-13.

IBISS

University of Belgrade

Department of Immunology

The main research topics of the Department of Immunology, Institute for Biological Research „Siniša Stanković" (IBISS) are organ-specific autoimmune and immunoinflammatory disorders (diabetes type 1 and type 2, and multiple sclerosis) and experimental immunooncology. Our research is predominantly conducted in animal models, but it also involves in vitro studies, as well as samples obtained from human subjects. Basic experimental models of Type 1 diabetes used are diabetes induced in inbred strains of mice and rats by multiple low doses of streptozotocin and spontaneous or accelerated diabetes in NOD mice, whereas type 2 diabetes is induced by high-fat diet. Experimental autoimmune encephalomyelitis (EAE) in Dark Agouti (DA) rats induced with central nervous system antigens is used as an experimental model of multiple sclerosis. Rats of Albino Oxford (AO) strain, resistant to the induction of diabetes and EAE are also involved in the studies. The basic aim of our studies is the discovery of molecular and cellular mechanisms responsible for the initiation, the development and the limitation of an autoimmune response in the diseases. Also, a possibility of pharmacological modulation of the autoimmune response is investigated. Regarding experimental immunooncology, the investigations are mainly focused on the efficacy of natural or synthetic agents in the treatment of transformed and/or immortalized cell lines in vitro, or animal tumor models in vivo. Beside evaluation of drugs' efficacy on the viability of tumor cells, different aspects of immune- and chemo-sensitization are explored.

Selected publications

Diabetology

1. Vujicic M, Nikolic I, Kontogianni VG, Saksida T, Charisiadis P, Vasic B, Stosic-Grujicic S, Gerothanassis IP, Tzakos AG, Stojanovic I. Ethyl Acetate Extract of Origanum vulgare L. ssp. hirtum Prevents Streptozotocin-Induced Diabetes in C57BL/6 Mice. J Food Sci. 2016 81:H1846-53.

2. Vujicic M, Nikolic I, Kontogianni VG, Saksida T, Charisiadis P, Orescanin-Dusic Z, Blagojevic D, Stosic-Grujicic S, Tzakos AG, Stojanovic I. Methanolic extract of Origanum vulgare ameliorates type 1 diabetes through antioxidant, anti-inflammatory and anti-apoptotic activity. Br J Nutr. 2015 113:770-82.

3. Nikolic I, Saksida T, Mangano K, Vujicic M, Stojanovic I, Nicoletti F, Stosic-Grujicic S. Pharmacological application of carbon monoxide ameliorates islet-directed autoimmunity in mice via anti-inflammatory and anti-apoptotic effects. Diabetologia 2014 57:980-90.

Immunooncology

1. Bulatović MZ, Maksimović-Ivanić D, Bensing C, Gómez-Ruiz S, Steinborn D, Schmidt H, Mojić M, Korać A, Golić I, Pérez-Quintanilla D, Momčilović M, Mijatović S, Kaluđerović GN. Organotin(IV)-Loaded Mesoporous Silica as a Biocompatible Strategy in Cancer Treatment. Angew Chem Int Ed Engl. 2014 May;53(23):5982-7.

2. Mijatovic S, Maksimovic-Ivanic D, Timotijevic G, Miljkovic D, Donia M, Libra M, Coco M, McCubrey J, Al-Abed Y, Korac A, Stosic-Grujicic S, Nicoletti F. Induction of caspase-independent apoptotic-like cell death of mouse mammary tumor TA3Ha cells in vitro and reduction of their lethality in vivo by the novel chemotherapeutic agent GIT-27NO. Free Radic Biol Med. 2010;48(8):1090-9.

3. Maksimovic-Ivanic D, Mijatovic S, Miljkovic D, Harhaji-Trajkovic L, Timotijevic G, Mojic M, Dabideen D, Cheng KF, McCubrey JA, Mangano K, Al-Abed Y, Libra M, Garotta G, Stosic-Grujicic S, Nicoletti F. The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt. Mol Cancer Ther. 2009;8(5):1169-78.

Neuroimmunology

1. Stanisavljevic S, Dinic M, Jevtic B, Ðedovic N, Momcilovic M, Ðokic J, Golic N, Mostarica Stojkovic M, Miljkovic Ð. Gut microbiota confers resistance of Albino Oxford rats to the induction of experimental autoimmune encephalomyelitis. Front. Immunol. 2018; 9:942. doi: 10.3389/fimmu.2018.00942

2. Jevtic B,  Djedovic N,  Stanisavljevic S,  Gasic U, Misic D, Despotovic J,  Samardzic J,  Miljkovic D,  Timotijevic G, Anti-encephalitogenic effects of cucumber leaf extract. J Funct Food. 2017 Oct; 37:249-262. doi: 10.1016/j.jff.2017.07.060.

3. Miljkovic D, Blaževski J, Petkovic F, Djedovic N, Momcilovic M, Stanisavljevic S, Jevtic B, Mostarica Stojkovic M, Spasojevic I. A comparative analysis of multiple sclerosis-relevant anti-inflammatory properties of ethyl pyruvate and dimethyl fumarate. J Immunology 2015; 2015 Mar 15;194(6):2493-503.

Institute for the Application of Nuclear Energy - INEP

The group of immunoparassiologists  at INEP is continuously studying how the helminth Trichinella spiralis, through its excretory-secretory products (ES L1 antigens), communicates with the host immune  system and thus modulates not only the inflammatory response against itself, but also influences the development of autoimmune disease - experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Diseases that are the consequence of immune system disregulation, like autoimmunity or allergy, take epidemic proportions in highly developed countries, where the prevention of the infection with various pathogens, including parasitic worms, is successfully carried out. In countries where the infection with one or more parasites is high (like in Africa), allergies and autoimmune diseases are very rare. Studies have shown that helminths, as the most complex microorganisms, contribute to the development, regulation and function of the immune system, and are therefore considered masters of immunomodulation. Discovering the immunomodulatory mechanisms by which helminths induce the regulatory network that prevent autoimmunity and allergy and restores homeostasis could help design new approaches for treating these diseases.

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References: https://scholar.google.com/citations?hl=en&user=AdEmlVwAAAAJ&view_op=list_works&sortby=pubdate

Link

IBISS

University of Belgrade

Department of Ecology

Immunotoxicology group

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Immunotoxicology as a discipline originated due to recognition of environmental chemicals and therapeutic drugs potential to alter immune function and increase sensitivity to infections and cancers. Owing to its complexity, the immune system represents a sensitive target for a variety of environmental influences such as xenobiotics, which might change immune function per se, and/or alter host sensitivity to diseases. The aim of our investigations is to examine immunomodulatory effects of selected xenobiotics, namely heavy metal cadmium, as one of the most important environmental pollutants, and widely used anticoagulant warfarin. In order to assess immunotoxicity of cadmium and warfarin, tiered approach composed of a series of assays is used. Using TIER 1 approach, direct effects of selected xenobiotics are evaluated based on changes in cellular and molecular mechanisms of immunity in laboratory rats (exposed to nonlethal doses of these agents) in the context of exposure duration and physiological factor such as host genetic variability. Namely, the effect of acute or prolonged administration of agents (in a way that corresponds to the natural way of xenobiotic entry in the organism) was measured using two inbred rat strains (AO and DA) known to mount qualitatively and/or quantitatively different immune responses to chemical and biological insults. Beside traditional tissues used for immunotoxicological investigations like blood and spleen, effects of xenobiotics on specialized tissues such as gut, skin and lungs (and associated lymph nodes), that are important for maintaining host immune homeostasis, were analyzed as well. TIER 2 approach is applied in order to assess the significance of affected immune activity induced by xenobiotics for host sensitivity/resistance to additional environmental stimulus, as in vivo correlate to disease susceptibility. Changes in the dynamic of development, intensity of innate and specific cellular immune response and resolution of pulmonary infection with opportunistic fungus Aspergillus fumigatus are used for assessment of immunomodulatory cadmium potential to the lungs. Effects of metal/therapeutic drug on skin immune reactivity are estimated based on changes in the hapten-specific immune responses in a model of contact hypersensitivity to dinitrochlorobenzene. Data showed that both cadmium and warfarin affected immune activity/reactivity of examined tissues, which could have its significance for adverse health effects. Generally, these studies are in correlation with modern epidemiological studies which highlight importance of link between exposure to environmental factors and inflammatory/immune mediated diseases.

Selected publications:

Mirkov I, Popov Aleksandrov A, Demenesku J, Ninkov M, Mileusnic D, Zolotarevski L, Subota V, Kataranovski D, Kataranovski M. Intestinal toxicity of oral warfarin intake in rats. Food Chem Toxicol. 2016;94:11–8.

Ninkov M, Popov Aleksandrov A, Mirkov I, Demenesku J, Mileusnic D, Jovanovic Stojanov S, Golic N, Tolinacki M, Zolotarevski L, Kataranovski D, Brceski I, Kataranovski M. Strain differences in toxicity of oral cadmium intake in rats. Food Chem Toxicol. 2016;96:11–23.

Demenesku J, Popov Aleksandrov A, Mirkov I, Ninkov M, Zolotarevski L, Kataranovski D, Brceski I, Kataranovski M. Strain differences of cadmium-induced toxicity in rats: Insight from spleen and lung immune responses. Toxicol Lett. 2016;256:33–43.

Subota V, Mirkov I, Demenesku J, Popov Aleksandrov A., Ninkov M., Mileusnic D., Kataranovski D., Kataranovski M. Transdermal toxicity of topically applied anticoagulant rodenticide warfarin in rats. Environ Toxicol Pharmacol. 2016;41:232–40.

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Mirkov I., Popov Aleksandrov A., Ninkov M., Mileusnic D., Demenesku J., Zolotarevski L., Subota V., Stefik D., Kataranovski D., Kataranovski M. Strain differences in intestinal toxicity of warfarin in rats. Environ Toxicol Pharmacol. 2016;48:175–82.

Popov Aleksandrov A., Mirkov I., Zolotarevski L., Ninkov M., Mileusnic D., Kataranovski D., Kataranovski M. Oral warfarin intake affects skin inflammatory cytokine responses in rats. Environ Toxicol Pharmacol. 2017;54: 93–98.

Popov Aleksandrov A., Mirkov I., Ninkov M., Mileusnic D., Demenesku J., Subota V., Kataranovski D., Kataranovski M. Effects of warfarin on biological processes other than haemostasis: A review. Food Chem Toxicol. 2018;13:19–32.

Tucovic D., Popov Aleksandrov A., Mirkov I., Ninkov M., Kulas J., Zolotarevski L., Vukojevic V., Mutic J., Tatalovic N., Kataranovski M. Oral cadmium exposure affects skin immune reactivity in rats. Ecotoxicol Environ Safe. 2018;164:12–20.

Kulas J., Mirkov I., Tucovic D., Zolotarevski L., Glamoclija J., Veljović K., Tolinački M., Golić N., Kataranovski M. Pulmonary Aspergillus fumigatus Infection in Rats Affects Gastrointestinal Homeostasis. Immunobiology 2019;224:116–23.

Kulas J., Ninkov M., Tucovic D., Popov Aleksandrov A., Ukropina M., Cakic Milosevic M., Mutic J., Kataranovski M., Mirkov I. Subchronic oral cadmium exposure exerts both stimulatory and suppressive effects on pulmonary inflammatory/immune reactivity in rats. Biomed. Environ. Sci., 2019;doi: 10.3967/bes2019.043.