Ivana Stojanovic

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Verified

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• PhD
• Research Professor at University of Belgrade

Type 1 diabetes (T1D) is an autoimmune disease with a strong chronic inflammatory component. One possible strategy for the treatment of T1D is to stimulate the regulatory arm of the immune response, i.e. to promote the function of tolerogenic dendritic cells (tolDC) and regulatory T cells (Treg). Since both cell types have been shown to be responsi...

Aryl Hydrocarbon Receptor (AHR) ligands, upon binding, induce distinct gene expression profiles orchestrated by the AHR, leading to a spectrum of pro- or anti-inflammatory effects. In this study, we designed, synthesized and evaluated three indole-containing potential AHR ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were sh...

Mesenchymal stem cells (MSCs) are known for their immunosuppressive properties. Based on the demonstrated anti-inflammatory effect of mouse MSCs from hair follicles (moMSCORS) in a murine wound closure model, this study evaluates their potential for preventing type 1 diabetes (T1D) in C57BL/6 mice. T1D was induced in C57BL/6 mice by repeated low do...

Innate lymphoid cells type 3 (ILC3s) are the first line sentinels at the mucous tissues, where they contribute to the homeostatic immune response in a major way. Also, they have been increasingly appreciated as important modulators of chronic inflammatory and autoimmune responses, both locally and systemically. The proper identification of ILC3 is...

Recent data indicate the link between the number and function of T regulatory cells (Treg) in the gut immune tissue and initiation and development of autoimmunity associated with type 1 diabetes (T1D). Since type 3 innate lymphoid cells (ILC3) in the small intestine are essential for maintaining FoxP3⁺ Treg and there are no data about the possible...

Cyclophosphamide (CP) is a cytostatic, widely used to treat different carcinomas and autoimmune diseases. It is commonly used in experimental designs modeling immunosuppression in laboratory animals, with different approaches for CP treatment but without a consensus on the dose, timing, and route of administration. We aimed to establish if treatmen...

Wound healing of acute full-thickness injuries and chronic non-healing ulcers leads to delayed wound closure, prolonged recovery period and hypertrophic scarring, generating a demand for an autologous cell therapy and a relevant pre-clinical research models for wound healing. In this study, an immunocompetent model for wound healing was employed us...

Chokeberry has exhibited cardioprotective, anti-bacterial, immunomodulating and anti-cancer properties. Chokeberry extract (CE) was tested in the model of melanoma induced by B16 cells inoculation in C57BL/6 mice. CE treatment that began 7 days before inoculation and continued through the observation period, delayed melanoma appearance and increase...

Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redo...

Aims Rosmarinic acid (RA) is a polyphenol that occurs in plants of the Lamiaceae family. Phenethyl ester of RA (PERA), a novel RA derivative, has been developed and evaluated in vivo in an animal model of type 1 diabetes (T1D). Methods T1D was induced in male C57BL/6 mice using multiple low doses of streptozotocin (STZ) administered intraperitonea...

Gut-associated lymphoid tissue (GALT) is crucial for the maintenance of the intestinal homeostasis, but it is also the potential site of the activation of autoreactive cells and initiation/propagation of autoimmune diseases in the gut and in the distant organs. Type 3 innate lymphoid cells (ILC3) residing in the GALT integrate signals from food ing...

Gut immune cells have been increasingly appreciated as important players in the central nervous system (CNS) autoimmunity in animal models of multiple sclerosis (MS). Among the gut immune cells, innate lymphoid cell type 3 (ILC3) is of special interest in MS research, as they represent the innate cell counterpart of the major pathogenic cell popula...

Obesity, a global health problem nowadays, is a state of low-grade chronic inflammation of adipose tissue (AT) associated with increased adipocyte growth and proliferation and immune cell polarization towards an inflammatory phenotype within the stromal vascular fraction (SVF). Pro-inflammatory cells in the AT produce mediators of inflammation (IL-...

Ethyl pyruvate (EP), a stable form of pyruvate, has shown beneficial effects in animal models of shock, ischemia/reperfusion injury, and sepsis due to its potent anti-oxidant and anti-inflammatory properties. Our recent study demonstrated that EP application prevented the clinical manifestation of type 1 diabetes in mice by augmenting regulatory T...

Chokeberry (Aronia melanocarpa) fruit extracts (CE) are rich in polyphenols and usually exhibit immunomodulatory, anti-viral and anti-bacterial effects. We have previously shown that the CE used in this study activated macrophages and stimulated effector T cell differentiation in vitro. When applied orally to healthy mice, CE increased the proporti...

The DIA-DB is a web server for the prediction of diabetes drugs that uses two different and complementary approaches; a) comparison by shape similarity against a curated database of approved anti-diabetic drugs and experimental small molecules, and b) inverse virtual screening of the input molecules chosen by the users against a set of therapeutic...

Significance: Autoimmune diseases are progressively affecting westernized societies, as the proportion of individuals suffering from autoimmunity is steadily increasing over the past decades. Understanding the role of reactive oxygen species (ROS) in modulation of the immune response in the pathogenesis of autoimmune disorders is of outmost import...

Chokeberry (Aronia melanocarpa) is known for its anti-oxidant, anti-inflammatory and anti-diabetic properties. Since the effects of chokeberry extract on the immune response have been only sporadically assessed, our aim was to investigate chokeberry fruit water extract on the immune response in vivo and in vitro. When administered orally to healthy...

Macrophage migration inhibitory factor (MIF) is a molecule with multiple functions: from enforcing the immune system to fight bacterial infection to the regulation of insulin activity. Also, MIF is expressed by enterocytes that line the intestinal border toward the lumen, and in M cells, where it regulates phagocytosis of antigens from the lumen of...

Type 1 diabetes (T1D) is a multifactorial autoimmune disease that develops as a consequence of macrophage- and T cell-dependent pancreatic β-cell death. Multiple approaches for induction of anti-inflammatory/regulatory mechanisms that would attenuate T1D have been utilized, with little or no beneficial effects. To achieve prolonged stimulation of r...

Pro-inflammatory nature of macrophage migration inhibitory factor (MIF) has been generally related to the propagation of inflammatory and autoimmune diseases. But this molecule possesses many other peculiar functions, unrelated to the immune system, among which is its supportive role in the post-translational modifications of insulin. In this way M...

Polyclonal T regulatory cells (Treg - CD4 ⁺ CD25 ⁺ CD127 low Foxp3 ⁺ ) are used in several protocols for the treatment of type 1 diabetes (T1D), multiple sclerosis and graft-versus host disease in clinical trials. However, general opinion is that autoantigen-specific Treg could be more efficient in autoimmunity suppression due to their direct effec...

Type 1 diabetes (T1D) is an autoimmune disease in which a strong inflammatory response causes the death of insulin-producing pancreatic β-cells, while inefficient regulatory mechanisms allow that response to become chronic. Ethyl pyruvate (EP), a stable pyruvate derivate and certified inhibitor of an alarmin–high mobility group box 1 (HMGB1), exert...

The effect of EP on innate cells proportion and function. (A) F4/80+ cell proportion within the spleen and the pancreatic infiltrates. Representative dot plots for the spleen are shown on the right hand side. (B) The proportion of M1 (F4/80+CD40+) and M2 (F4/80+CD206+) macrophages within the pancreatic infiltrates, with representative dot plots bel...

Negative staining for insulin (A) and HMGB1 (B).

Phenotypic analysis of adaptive immune cells after EP treatment. Representative dot plots of the proportion of cytotoxic lymphocytes (CD8+) or B lymphocytes (B220+ or CD19+) in spleen (A), PLN (B) or pancreatic infiltrates (C). Representative dot plots of the proportion of regulatory B cells (CD19+CD5+IL-10+) within PLN (D) and pancreatic infiltrat...

The effect of EP on Treg migratory abilities. (A) The proportion of CXCR5+ cells within activated Th cells (CD4+CD25med) or within Treg (CD4+CD25high) from PLN. Representative dot plots show the first gate on either live CD4+CD25med or live CD4+CD25high cells, followed by the gate on CXCR5+. (B) Representative dot plots for CD25highCD103+ proportio...

Phenotypic analysis of adaptive immune cells after EP treatment. Representative dot plots of the proportion of Th (CD4+) and Th1 (CD4+IFN-γ+), Th2 (CD4+IL-4+) and Th17 (CD4+IL-17+) within the spleen (A), PLN (B) and pancreatic infiltrates (C) of MLDS or MLDS+EP-treated mice (first gated on live CD4+ cells, followed by the gate on IFN–γ+, IL-4+, or...

Characterization of Treg after EP treatment. (A) The expression of FoxP3, GITR, PD-1, and CD101 within CD4+CD25high measured by mean fluorescence intensity (MFI), along with representative histograms.

Macrophage migration inhibitory factor (MIF) is a multifunctional protein that is involved in the development of gut-related inflammation. To investigate the role of MIF in the function of the intestinal barrier, we have explored intestinal permeability and gut-associated immune response in MIF-deficient (MIF-KO) mice. The absence of MIF provoked i...

Alzheimer’s disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This stu...

Particulate adjuvants have shown increasing promise as effective, safe and durable agents for the stimulation of immunity, or alternatively, the suppression of autoimmunity. Here we examined the potential of the adjuvant carbonyl iron (CI) for the modulation of organ-specific autoimmune disease - type 1 diabetes (T1D). T1D was induced by multiple l...

Pomegranate peel extract (PPE) was obtained by aqueous-ethanol extraction and was abundant in punicalin, punicalagin and ellagic acid. As these compounds are known to act against inflammation and oxidative stress in synergistic fashion, effects of PPE were tested in vitro on immune cells and in animal models of multiple sclerosis and type 1 diabete...

C57BL/6, BALB/c and NOD mice are among the most frequently used strains in autoimmunity research. NOD mice spontaneously develop type 1 diabetes (T1D) and they are prone to induction of experimental autoimmune encephalomyelitis (EAE). Both diseases can be routinely induced in C57BL/6 mice, but not in BALB/c mice. Also, C57BL/6 mice are generally co...

Cell-based tolerogenic therapy is a promising approach for the treatment of autoimmune diseases and transplant rejection. Regulatory T cells and tolerogenic dendritic cells have been particularly explored in the treatment of various autoimmune disorders in experimental models of disease. Although some of these cells have already been tested in a li...

Type 1 diabetes (T1D) is an autoimmune disorder with a strong inflammatory component. Autoreactive cells specifically target insulin-producing β-cells, which leads to loss of glucose homeostasis. T1D remains incurable and versatile; potentially beneficial therapeutics are being tested worldwide. Possible candidates for the treatment of autoimmune d...

Bovine colostrum is a rich source of nutrients and immunologically active components that play a role in conveying passive immunity to the offspring, protection and maturation of new-born?s gastrointestinal tract. Colostrum has exerted positive effects in diseases affecting gastrointestinal tract, as well as type 2 diabetes (T2D). However, health-p...

Type 1 diabetes (T1D) is an autoimmune disease that develops as a consequence of pancreatic β-cell death induced by proinflammatory mediators. Because Origanum vulgare L. ssp. hirtum (Greek oregano) contains antiinflammatory molecules, we hypothesized that it might be beneficial for the treatment of T1D. An ethyl acetate extract of oregano (EAO) wa...

Nuclear protein 1 (NUPR1) is a transcription cofactor that senses stressful conditions and modulates cellular response by promoting or inhibiting apoptosis. NUPR1 is usually highly expressed in tumor cells where it enables them to adapt and resist environmental stress or chemotherapeutic compounds. NUPR1 can be involved in cell proliferation. Data...

We have recently shown that carbon monoxide releasing molecule (CORM)-A1 prevents type 1 diabetes induced in C57BL/6 mice with multiple low doses of streptozotocin (MLDS) by shifting the Th1/Th17/M1 balance towards a Th2/M2 response. In the present work we tested the hypothesis that CORM-A1 might influence regulatory arm of the immune response, as...

Type 1 diabetes (T1D), an autoimmune inflammatory disorder, develops as a consequence of pancreatic β-cell destruction and results in hyperglycaemia. Since current T1D therapy mainly involves insulin replacement, the aim of the present study was to evaluate the therapeutic potential of Origanum vulgare L. ssp. hirtum (Greek oregano) leaf extract ri...

Compound A (CpdA), or 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethyl-ammonium chloride, is a stable analog of the hydroxyl phenyl aziridine precursor found in the Namibian shrub Salsola tuberculatiformis Botschantzev. It belongs to the group of so-called "dissociated" GC receptor ligands that downmodulate pro-inflammatory gene expression via the trans...

Background and purpose: Type 1 diabetes is a multifactorial inflammatory disease that develops as a result of deregulated immune responses, causing progressive autoimmune destruction of insulin-producing beta cells of pancreas. 2-((4-acetoxyphenyl)-2-chloro-N-methyl) ethylammonium chloride, compound A (CpdA), is a selective glucocorticoid receptor...

Macrophage migration inhibitory factor is a multifunctional cytokine involved in the regulation of immune processes and also in apoptosis induction. Elevated MIF expression is detrimental for insulin-producing beta cells and MIF inhibition protected beta cells from several cytotoxic insults such as inflammatory cytokines, high fatty acids or high g...

Carbon monoxide (CO) is endogenously produced by heme oxygenase-1 and has profound effects on intracellular signaling processes, generating anti-inflammatory, anti-proliferative and anti-apoptotic effects. A boron-containing compound CORM-A1 is capable of releasing CO in such a way to mimic physiological functions of heme oxygenase-1. Considering t...

Carbon monoxide (CO) is endogenously produced by heme oxygenase-1 and has profound effects on intracellular signaling processes, generating anti-inflammatory, anti-proliferative and anti-apoptotic effects. A boron-containing compound CORM-A1 is capable of releasing CO in such a way to mimic physiological functions of heme oxygenase-1. Considering t...

Recent studies have identified carbon monoxide (CO) as a potential therapeutic molecule for the treatment of autoimmune diseases owing to its anti-inflammatory and anti-apoptotic properties. We explored the efficacy and the mechanisms of action of the CO-releasing molecule (CORM)-A1 in preclinical models of type 1 diabetes. The impact of CORM-A1 on...

Transferrin (Tf) has a major role in T cell activation and proliferation. Here, we investigated whether Tf exerts immunomodulatory effects on T cells and in development of T-cell driven experimental autoimmune encephalomyelitis (EAE). While treatment of concanavalin A-stimulated splenocytes with apotransferrin (ApoTf) did not affect release of IL-1...

Macrophage migration inhibitory factor (MIF)-deficient mice develop glucose intolerance and hyperglycemia, but remain entirely responsive to exogenous insulin in adult age. Furthermore, as a consequence of MIF deficiency, the immune response in these mice is predominantly anti-inflammatory. Since MIF is a natural counter-regulator of glucocorticoid...

Beta cell apoptosis is a hallmark of diabetes. Since we have previously shown that galectin-3 deficient (LGALS3(-/-) ) mice are relatively resistant to diabetes induction, the aim of this study was to examine whether beta cell apoptosis depends on the presence of galectin-3 and to delineate the underlying mechanism. Deficiency of galectin-3, either...

Macrophage migration inhibitory factor (MIF) is implicated in the pathogenesis of several inflammation-related diseases, including obesity and type 2 diabetes (T2D). However, MIF deficiency itself promotes obesity and glucose intolerance in mice. Here we show that the introduction of a high-fat diet (HFD) further aggravates the parameters of obesit...

In diabetes, pancreatic islets are subjected to high levels of inflammatory mediators that can lead to beta cell destruction. We recently showed that pancreatic islet cells derived from MIF-deficient (MIF-KO) mice are resistant to apoptosis induction by the cytotoxic stimuli of cytokines. Here we show that MIF-KO islets under cytokine (IFN-gamma+TN...

Recent studies identified carbon monoxide (CO) as a potential therapeutic molecule due to its anti-inflammatory and anti-apoptotic abilities. CO-releasing molecule CORM-A1 is a compound designed to liberate controlled quantities of CO in the cellular systems. However, its biological activity in autoimmune type 1 diabetes (T1D) has not been examined...

Although several reports suggest a potentially deleterious role of macrophage migration inhibitory factor (MIF) in type 2 diabetes (T2D) pathology, it is still unclear how this pro-inflammatory cytokine acts on pancreatic beta cells. The aim of the present study was to evaluate MIF effects on murine beta cells in the in vitro settings mimicking T2D...

Background and aims: Galectin-3 (Gal-3) is β-galactoside-binding lectin expressed in variety of tissues and cell types and has diverse functions, including promotion of inflammatory response and triggering apoptosis. However, the precise role of Gal-3 in type 1 diabetes remains obscure. Since we have previously shown that Gal-3 deficient (Gal-3-/-)...

The transferrin (Tf) family of iron binding proteins includes important endogenous modulators of the immune function that may modulate autoimmune diseases. To define more clearly the role of apotransferrin (apoTf) in type 1 diabetes we determined the impact of this protein on type 1 diabetes as investigated in islet cells, animal models and patient...

During pathogenesis of diabetes, pancreatic islets are exposed to high levels of cytokines and other inflammatory mediators that induce deterioration of insulin-producing beta cells. Macrophage migration inhibitory factor (MIF) plays a key role in the onset and development of several immunoinflammatory diseases and also controls apoptotic cell deat...

During evolution, beta cells adapted to a sole aim: the production and stimulus-dependent secretion of insulin. This acquired specificity was accompanied by a loss of protection mechanisms predisposing beta cell to a high vulnerability. Among beta cell-damaging molecules, a new one has been identified recently: macrophage migration inhibitory facto...

We recently demonstrated that macrophage migration inhibitory factor deficient (MIF − / −) mice exhibited a higher susceptibility to lethal systemic Aspergillus fumigatus infections than genetically matched, wild-type (WT) C57BL/6 mice, and displayed altered cytokine profiles in the spleen when challenged by sublethal infections. In this report we...

The immunomodulatory and anticarcinogenic activity of the freshwater bryozoan Hyalinella punctata methanolic extract (MEx) was evaluated in vitro on selected biosystems for the first time. Murine lymphocytes and macrophages were used for testing of MEx effects on cell proliferation and nitric oxide (NO) production, respectively, while human cancer...

As a result of chronic exposure to high levels of free fatty acids, glucose and inflammatory mediators β-cell apoptosis occurs at the end stage of obesity-associated type 2 diabetes (T2D). One potentially deleterious molecule for β-cell function associated with T2D and obesity in humans is macrophage migration inhibitory factor (MIF). Therefore, th...

Inflammation plays an important role in protective immunity against fungi, including the opportunistic pathogen, Aspergillus fumigatus. The balance between pro-inflammatory and anti-inflammatory cytokines is a key determinant of infection outcome. Since macrophage migration inhibitory factor (MIF) is an upstream regulator of many cytokines, we anal...

_ We have recently demonstrated the beneficial effects of dry olive leaf extract (DOLE) in two preclinical models of type 1 diabetes. Here we analyze the potential mechanisms underlying diabetes amelioration at the level of lymph node drainage. Treatment of C57BL/6 mice with DOLE during induction of diabetes with multiple low doses of streptozotoci...

In this study, we investigated splenic and lung cell responses to nonlethal systemic Aspergillus fumigatus infection in mice. Apart from basic indices of spleen and lung cell activity, IL-17 expression by cells from both tissues was determined and compared to the expression of IFN-gamma and IL-4. Progressive decrease in tissue fungal burden correla...

Export Date: 18 October 2014

Studies of systemic and pulmonary Aspergillus fumigatus infection demonstrated differential susceptibility of inbred mice of various genetic background to lethal outcome, with an opposite pattern of Th1 cytokine interferon-γ (IFN-γ) and Th2 cytokine interleukin-4 (IL-4) in susceptible vs resistant mice. We have shown recently reciprocal IFN-γ and I...

The health-promoting effects of various constituents of the olive tree (Olea europaea) are mainly associated with hypoglycaemic and insulin-sensitising activities and have been widely demonstrated in the metabolic syndrome and type 2 diabetes. However, their biological activity in autoimmune type 1 diabetes (T1D) is poorly characterised. Therefore,...

Anticancer activities of various extracts of the medicinal mushroom, Ganoderma lucidum, have been widely demonstrated and are mainly associated with the presence of different bioactive polysaccharides and triterpenoids. We have evaluated and compared in vitro and in vivo the antitumor effects of two preparations from Ganoderma lucidum: a methanol e...

Retinoids have a variety of biological activities, including immunomodulatory action in a number of inflammatory and autoimmune conditions. Considering the pathogenesis of type 1 diabetes mellitus (T1D), in this study we examined the potential role for retinoids, etretinate and all-trans-retinoic acid (ATRA) in preclinical models of human T1D. When...

Diabetes is characterized by progressive failure of insulin producing beta cells. It is well known that both saturated fatty acids and various products of immune cells can contribute to the reduction of beta cell viability and functionality during diabetes pathogenesis. However, their joint action on beta cells has not been investigated, so far. Th...

Anticancer activities of various extracts of the medicinal mushroom, Ganoderma lucidum, have been widely demonstrated and are mainly associated with the presence of different bioactive polysaccharides and triterpenoids. We have evaluated and compared in vitro and in vivo the antitumor effects of two preparations from Ganoderma lucidum: a methanol e...

Macrophage migration inhibitory factor (MIF) is a multipotent cytokine implicated in the pathogenesis of numerous inflammatory and autoimmune disorders. Since anti-cytokine therapy is considered to be a promising therapeutic strategy, selective targeting of MIF with either anti-MIF antibody or specific chemical MIF inhibitors might offer new therap...

Interleukin (IL)-17 is a pro-inflammatory cytokine produced by recently described T helper type 17 (Th17) cells, which have critical role in immunity to extracellular bacteria and the pathogenesis of several autoimmune disorders. IL-6 and transforming growth factor (TGF)-beta are crucial for the generation of Th17 cells in mice, while the productio...

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...

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine of the innate immune system that plays a major role in the induction of immunoinflammatory responses. To examine the role of endogenous MIF in the pathogenesis of type 1 diabetes (TID) we evaluated the effects of administration of neutralizing anti-MIF antibodies to NOD mice...

We recently showed that attenuation of inflammatory cytokine MIF with pharmacological inhibitor ISO-1 down-regulates the immune-mediated diabetes in mice. Here we explore the effects of MIF neutralization by ISO-1 on the local inflammatory pathway of the disease. In vivo treatment of mice with ISO-1 inhibited the expression of pro-inflammatory cyto...

Astrocytes play important roles in the complex and as yet not very well understood net of interactions among resident and infiltrating cells during central nervous system (CNS) inflammation. In such an intricate network, cytokines represent an essential means for intercellular communication, and astrocytes are able to affect their generation and/or...

We have presently studied the in vitro, ex vivo and in vivo immunopharmacological effects of VGX-1027 [(S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid]. This compound reduced the secretion of IL-1beta, TNF-alpha and IL-10 from purified murine macrophages stimulated "in vitro" with lipopolysaccharide (LPS), and it also modified the signaling path...

Interleukin-17 (IL-17) is a pro-inflammatory cytokine, produced by recently described Th17 cells which have critical role in immunity to extracellular bacteria and pathogenesis of sev-eral autoimmune disorders. IL-6 and TGF-β are crucial for the generation of Th17 cells, while the production of IL-17 is supported by IL-1b, IL-15, IL-23 or TNF-α. In...