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The therapeutic potential of mesenchymal stem cells in a mouse experimental model
Hájková, Michaela
Due to their immunomodulatory and regenerative potential, mesenchymal stem cells (MSCs) represent a promising therapeutic tool for cell-based therapy, organ transplantation or tissue engineering. To improve clinical applicability of MSCs, new methods to increase their delivery and efficacy have been tested in the latest years but the mechanism of observed alterations has not yet been described. In the present project we focused on studying the effect of several factors that can significantly affect the therapeutic success of MSC-based treatment. Initially, we analysed the therapeutic effect of MSCs applied locally on nanofiber scaffold with incorporated cyclosporine A (CsA) in a mouse model of allogeneic skin transplantation. Our results indicate that application of MSCs in the presence of CsA direct M1/M2 macrophage polarization towards regulatory phenotype. This phenotype switching is accompanied by decreased production of nitric oxide (NO) and interferon (IFN-) and increase production of interleukin 10 (IL-10), and may result in suppression of the local inflammatory reaction. The next goal of proposed study was to analyse the effect of the treatment based on MSCs combined with immunosuppressive drugs with different mechanism of action on the balance among distinct T cell subpopulations. We...
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Antitumor activity of IL-2 and IL-7 immunocomplexes in combination with αCTLA-4 and αPD-1 mAbs
Hnízdilová, Tereza ; Kovář, Marek (advisor) ; Hájková, Michaela (referee)
Biological activity of IL-2 and IL-7 in vivo is significantly increased when complexed with some of the respective anti-cytokine mAb. Different immune cell subsets can be preferentially stimulated depending on the anti-IL-2 mAb used to complex IL-2. IL-2/anti-IL-2 mAb S4B6 immunocomplexes (IL-2/S4B6) induce preferential expansion of CD122high cells whereas IL-2/anti-IL-2 mAb JES6-1 immunocomplexes (IL-2/JES6-1) highly selectively stimulate CD25high cells in mice. Similarly, IL-7/anti-IL-7 mAb M25 immunocomplexes (IL-7/M25) possess higher stimulatory activity for both naïve and memory CD8+ T cells in vivo in comparison to free IL-7. CTLA-4 and PD-1 molecules are inhibitory receptors which negatively regulate proliferation, survival and effector functions of T cells. Blocking antibodies against these molecules represent promising immunotherapeutic tool for treatment of malignant diseases. We examined possible synergism of IL-2/S4B6 and αCTLA-4 plus αPD-1 mAbs in tumor-bearing mice. We found that the expansion of recently activated CD8+ T cells driven by IL-2/S4B6 was further augmented by αCTLA-4 plus αPD-1 mAbs. However, these two immunotherapeutic approaches did not show synergistic antitumor activity in any mouse tumor model tested. Next, we showed that IL-7/M25 possessed higher biological activity...
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Performance Management of an Economic Advisory Company
Hájková, Michaela ; Poláchová, Jana (referee) ; Režňáková, Mária (advisor)
The main aim of the thesis is to analyze the performance of the company providing economic services. The first part summarizes the basic information used to evaluate the performance of the company. Next part deals with comparison with competition and evaluation of profitability of selected orders by calculation method Activity-Based Costing. The final part proposes changes in cost management.
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Non-discrimination and equal treatment in Employment relationships in the Czech Republic and in selected EU countries
Hájková, Michaela ; Bělina, Miroslav (advisor) ; Chvátalová, Iva (referee) ; Štefko, Martin (referee)
Non-discrimination and equal treatment in Employment relationships in the Czech Republic and in selected EU countries Abstract Principles of equality, respectively equal treatment and prohibition of discrimination, are prominent in public discourse as well as in practical life, specifically in relationships between employees and employers. It is typical that these principles and their precise content and scope may vary in accordance with cultural, local and historical contexts. In the Czech Republic, arguments relating to equal treatment and prohibition of discrimination in employment relations are not very often heard and resolved by courts; that however does not mean that problems relating to unequal treatment or discrimination would be absent. Employment laws are in many respects driven and influenced by European Union law; ban on discrimination is subject to regulation by a number of Directives, which each Member State must transpose into its national legal framework. When these national laws are interpreted and applied, the primary concern must rest in maintaining consistency with the original regulation while considering any relevant case law passed down by the Court of Justice of the European Union. For the same reasons, it may be interesting to compare, from legislative standpoint and in application...
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Circadian clocks in cells of the immune system
Lavrova, Kseniia ; Bendová, Zdeňka (advisor) ; Hájková, Michaela (referee)
Circadian rhythms affect all physiological processes in the body, including immune function. Circadian oscillations are observed in almost all components of the immune system. This oscillation generates molecular clocks that are in each cell and are synchronized by the main CSN pacemaker with help hormone secretion and neuronal innervation. As a result, the immune system is ready for increased responses to pathogens during the active phase when is higher risk of bruising with it. Macrophages are cells of the natural immune system and main modulators of inflammation. Their activity, including cytokine production, phagocytosis and polarization to M1 and M2 phenotypes is closely linked to the molecular clock. This association between circadian and immune systems has implications for the course of a series of inflammatory diseases, such as arthritis and atherosclerosis. The aim of this thesis is to investigate the effect of circadian system on macrophage function in inflammatory response. Keywords: circadian clocks, circadian genes, macrophage, melatonin, glucocorticoids
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Extracellular vesicles derived from mesenchymal stem cells and their use in the treatment of neurological disorders
Kratochvílová, Anna ; Hájková, Michaela (advisor) ; Holada, Karel (referee)
Extracellular vesicles (EVs) are cell-derived membrane vesicles, which represent an important part of intercellular communication by transferring cytosolic proteins, lipids, and RNAs between cells. It has been proved that mesenchymal stem cells (MSCs) are potent producers of EVs with a therapeutic effect comparable to their parental cells. Moreover, recent findings suggest that EVs may strongly contribute to their physiological function. The aim of this thesis is to introduce extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) as a novel cell-free alternative to the cell-based therapy and focus on their neuroprotective properties studied in various neurological diseases.
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The effect of intranasal immunization by delipidated Bacillus firmus on immune response in NALT
Hnilicová, Šárka ; Hrdý, Jiří (advisor) ; Hájková, Michaela (referee)
Influenza is a serious illness worldwide, causing high morbidity and mortality. 10-20% of world population fall ill with influenza each year and 250 000 - 500 000 people die annually. The most efficacious protection to date is vaccination. Current vaccines are efficient only one season because of fast mutation rate of influenza virus. The effort to create an effective vaccine faces lack of potent adjuvant, which can adequately stimulate and modulate immune system to protect organism from virus infection. Moreover, todays vaccines administered parenterally do not induce immune response on mucosal surfaces. Bacillus firmus, a Gram-positive non-pathogenic bacterium, has strong immmune-modulating properties and is able to induce cross-protection when administered with influenza virus antigens. Immunization with Bacillus firmus stimulates production of neutralizing antibodies, but other mechanisms of its action remain to be elucidated. To better understand the mechanisms how is antiviral immunity enhanced by Bacillus firmus (delipidated fraction, DBF), the effect of immunization with DBF only was studied on mouse model. In last decade it has become obvious that intranasal immunization can induce both systemic and mucosal immune response and in case of influenza it can induce cross-protection. Therefore...
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Immunogenicity of induced pluripotent stem cells (iPSC)
Tejklová, Tereza ; Drbal, Karel (advisor) ; Hájková, Michaela (referee)
Ectopic expression of several transcription factors into the somatic cells allows us to artificially dedifferentiate them into induced pluripotent stem cells (iPSC), which show great promise in regenerative medicine and personalized disease modelling, as well as diagnostic tools. Unique attribute of iPSC is the possibility of creating autologous cells for each patient, which could be used for transplantation without fear of immune rejection. However, cells differentiated from iPSC generally display decreased expression of MHC I glycoproteins, which leads to the activation of NK cells of innate immunity. T cells, the part of adaptive immunity, are activated after recognition of antigen peptide or foreign MHC I glycoproteins only in co-operation with costimulatory molecules, which are not usually expressed on iPSC. During dedifferentiation, cells keep the epigenetic profile of the source cell, which can result in the abnormal expression of genes within derived cell lines. Overall immunogenicity depends on the method of iPSC preparation, with respect to genomic stability. Another important factor is the immune environment of transplantation site as well as the tissue damage caused during transplantation. This results in the presentation of danger signals (DAMPs), which are then recognized by pattern...
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Antimicrobial properties of mesenchymal stem cells
Černá, Kristýna ; Hájková, Michaela (advisor) ; Vobořil, Matouš (referee)
Mesenchymal stem cells (MSCs) were first isolated from bone marrow. Since that they were isolated from almost every tissue in the body. MSCs are multipotent cells with many properties including self-renewal, differentiation into the cells of all three germ lines, trophic and immunomodulatory abilities, specific migration to the site of injury and recently discovered antimicrobial properties. This properties make them a good candidate for cell therapy because they can be used in treatment of many diseases including bacterial infections. This thesis brings a summary of all discovered antimicrobial properties of MSCs. It is primarily focused on their direct and indirect antimicrobial effect. The direct effect is mediated by a secretion of antimicrobial substances and the indirect effect includes an impact on the activity and functions of macrophages and neutrophils. Extracellular vesicles derived from MSCs constitute separate chapter because they can have both direct and indirect antimicrobial effect. Keywords: mesenchymal stem cells, antibacterial effect, bacteria, antimicrobial peptides
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The therapeutic potential of mesenchymal stem cells in a mouse experimental model
Hájková, Michaela
Due to their immunomodulatory and regenerative potential, mesenchymal stem cells (MSCs) represent a promising therapeutic tool for cell-based therapy, organ transplantation or tissue engineering. To improve clinical applicability of MSCs, new methods to increase their delivery and efficacy have been tested in the latest years but the mechanism of observed alterations has not yet been described. In the present project we focused on studying the effect of several factors that can significantly affect the therapeutic success of MSC-based treatment. Initially, we analysed the therapeutic effect of MSCs applied locally on nanofiber scaffold with incorporated cyclosporine A (CsA) in a mouse model of allogeneic skin transplantation. Our results indicate that application of MSCs in the presence of CsA direct M1/M2 macrophage polarization towards regulatory phenotype. This phenotype switching is accompanied by decreased production of nitric oxide (NO) and interferon (IFN-) and increase production of interleukin 10 (IL-10), and may result in suppression of the local inflammatory reaction. The next goal of proposed study was to analyse the effect of the treatment based on MSCs combined with immunosuppressive drugs with different mechanism of action on the balance among distinct T cell subpopulations. We...
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