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Project 173047

Title: Mechanisms of the immune response to parasitic infection, or exposure to parasite antigens, and the concomitant modulation and/or prevention of unrelated diseases (2011-)
Funding: Ministry of Education, Science and Technological Development of the Republic of Serbia
Realization by: Institute for the Application of Nuclear Energy, University of Belgrade
Project leader: Ljiljana Sofronić-Milosavljević, PhD, Full Research Professor, INEP

Subject and description: The miraculous world of parasites 
Chronic inflammatory disorders, like autoimmune diseases, take epidemic proportions in highly developed countries, where the prevention of the infection with various pathogens, including parasitic worms, is successfully carried out. Studies have shown that parasites, 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 the parasitic worms induce the regulatory network that prevent autoimmunity and allergy and restore homeostasis could help design new approaches for treating a wide range of inflammatory disorders that, in addition to allergies and autoimmune diseases, include cardiovascular disease, metabolic disorders and ageing. Trichinella, as one of them, during co-evolution established an “agreement” with host organism not to harm each other, by creating an environment that is unsuitable for development of autoimmune diseases and allergic disorders. Immunomodulatory molecules among Trichinella products could trigger the “Trichinella clock”, aiming to reverse pathogenic immune responses and ameliorate chronic inflammatory disorders.
The group of immunoparasitologists 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). ES L1 antigens induce tolerogenic dendritic cells (ES L1 tolDCs) that drive T cell response towards mixed Th2/Th1 and the regulatory type, shown for the first time by our group, on animal and human model. ES L1 tolDCs, applied into healthy animals, created an immune status that resembles the one observed in live infection, while in EAE-induced animals ES L1 tolDCs significantly alleviated the disease. Prophylactic application of native ES L1 antigens ameliorates EAE, but the mechanisms underlying this phenomenon are somewhat different from those initiated with the ES L1 tolDCs. Translation of knowledge from the animal to human model includes the work on both DCs derived from peripheral blood monocytes of healthy individuals and monocytes of patients with MS, in aim to test the potential of the ES L1 antigens to redirect immune response from pro-inflammatory to anti-inflammatory type. The study of the interaction between glycoproteins within ES L1 antigens and DCs encompasses investigation of the significance of individual antigen components, as well as their sugar structures for the polarization of the immune response. It also includes determination of the receptors on the surface of the DCs responsible for binding of ES L1 antigens (TLR2, TLR4, DC-SIGN) and the signaling pathways triggered by these interactions.
Into the miraculous world of actions that parasite uses to protect the host organism from various pathological changes, belongs also the ability of T. spiralis to successfully slow down the tumor growth. Our research so far has shown that infection with T. spiralis significantly limits the growth of mouse melanoma B16 in vivo, while ES L1 affected tumor cells multiplication in vitro.
Applied research in the field of Trichinella and Trichinellosis: Determination of Trichinella species and its prevalence in Serbia showed in this century (by molecular analyses at INEP) that, in addition to T. spiralis (which infect domestic swine, horse, wild animals and human), there is also T. britovi presence predominantly in wild animals. Thanks to the cooperation between National Reference Laboratory for Trichinellosis INEP (NRLT INEP), and the physicians and veterinarians, T. britovi was recently, for the first time, identified as the cause of human outbreak in Zlatibor District. Due to the regional activities NRLT INEP provided expertise and proved the presence of mixed T. britovi and T. pseudospiralis infection in one domestic swine in BIH.
In aim to expand existing IVD product line for the detection of anti-Trichinella antibodies, 2 new, highly specific and sensitive diagnostic test were developed and validated in our laboratory: 1. ELISA test for specific IgE detection in humans (as a tool which can discriminate between newly acquired infection and old one), and 2. competitive ELISA test for detection of specific antibodies, regardless of the type of Trichinella and the species of the host.
The NRLT, along with other competent institutions, continuously monitors and reports on the presence and spread of Trichinella infection in humans and animals in Serbia. NRLT, INEP, has been recognized as a part of a network of national reference laboratories in Europe, coordinated by the European Reference Laboratory for Parasites at the Istituto superiore di Sanita (EURLP, ISS, Rome, It) and provide EURLP with above mentioned reports.

Research team:
Ljiljana Sofronić-Milosavljević, MD, PhD, Full Research Professor, Head of Department, Project leader
Alisa Gruden-Movsesijan, PhD, molecular biologist,  Principal Research Fellow
Nataša Ilić, PhD, molecular biologist, Senior Research Associate
Saša Vasilev, PhD, Research Associate
Ivana Mitić, MD, PhD, Research Associate
Jelena Cvetković, PhD, Research Associate
Marija Gnjatović, PhD, Research Assistant
Edoardo Pozio, PhD, Director of the Division of Gastroenteric and Tissue Parasitic Diseases, Istituto Superiore di Sanitr, Rome, Italy, edoardo.pozio@iss.it
Richard Grencis, PhD, Chair in Immunology, Faculty of Life Science, University of Manchester, UK, richard.k.grencis@manchester.ac.uk
Aleksandra Todorović, Research Trainee
Sofija Glamočlija, Research Trainee
Ljiljana Sabljić, Research Trainee