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Study of the effect of immunological sdjuvants on experimental treatment of HPV-induced tumors by recombinant VACV and DNA vaccines
Gabriel, Pavel ; Němečková, Šárka (advisor) ; Mělková, Zora (referee) ; Reiniš, Milan (referee)
1 ABSTRACT The success of cancer vaccines depends on factors associated with the vaccine, which define the main parameters of effective immune responses such as its size and quality, as well as on factors related with the host, represented by the immunosuppressive mechanisms that allow the tumor to escape recognition by the immune system or negatively influence the function of effector T-cells. Attenuated, non-replicating viruses are at present preferred as VACV for safety reasons. A problem may arise concerning their lack of immunogenicity. Through the deletions of non-essential genes, vaccination vectors are therefore developed based on attenuated rVACV capable of replication, which induce a strong immune response. Genes of various immunological adjuvants (e.g., genes for cytokines and costimulatory molecules) are inserted into the vectors for the purpose of eliminating the influence of the immunosuppressive mechanisms of tumors. The first part of the work describes our study of the influence of vCCI on biological properties of rVACV derived from the Prague strain. Testing of vCCI deletion and insertion mutants expressing tumor associated protein HPV16 E7 has shown that secreted vCCI attenuated the virus in vivo, which correlated with reduced levels of the corresponding CC chemokines in the blood compared...
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The therapeutic potential of mesenchymal stem cells in a mouse experimental model
Hájková, Michaela ; Krulová, Magdaléna (advisor) ; Hrdý, Jiří (referee) ; Šírová, Milada (referee)
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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Mesenchymal stem cells and their regenerative and immunomodulatory potential
Brychtová, Michaela ; Lysák, Daniel (advisor) ; Horák, Vratislav (referee) ; Raška, Milan (referee)
Mesenchymal stem cells and their regenerative and immunomodulatory potential Abstract Mesenchymal stem cells (MSCs) possess multidirectional regenerative ability, which, together with their immunomodulatory potential, makes them promising cell type for therapy of wide variety of diseases. Despite ongoing research, which proved MSCs application to be safe, reported effect of MSCs administration on patients is not convincingly beneficial yet. In our work we focused on elucidation of MSCs role in regeneration of vital organs, heart and liver, where a large damage is life threatening for patients and any improvement in therapy would save many lives. Similar situation is in Graft versus host disease (GVHD), where MSCs immunomodulatory properties could be beneficial. Role of MSCs in heart regeneration was examined in vitro. Primary adult swine cardiomyocytes (CMCs) were co-cultured with or without swine MSCs for 3 days and morphological and functional parameters (contractions, current, respiration) of CMCs were measured. MSCs showed supportive effect on CMCs survival, especially at day 3 of the experiment, where in co-culture was significantly higher number of viable CMCs with physiological morphology and maintained function. Effect of MSCs on liver regeneration was observed in swine model of chronic liver...
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Human nutrition, Bacteroides fragilis and the immune system
Veigertová, Tereza ; Hrdý, Jiří (advisor) ; Podzimek, Štěpán (referee)
The presence of bacteria in the human body is a crucial factor for immune system development and its appropriate functioning. This bachelor thesis focuses on the beneficial effects of Bacteroides fragilis and explores the possibility of altering its abundance in the colon by dietary intervention. Both Czech and foreign literature was reviewed and the practical part was carried out using a questionnaire survey. The research indicates that it is possible to affect the proportional representation of Bacteroides fragilis in the colon with specific nutrients and dietary habits. Additionally, the theoretical part describes the benefits of this bacterial species on the human immune system. Bacteroides fragilis produces short-chain fatty acids, antimicrobial substances and polysaccharide A, which are the principal components that influence the host. The practical part builds upon the findings of the theoretical part. It investigates the knowledge of a random sample of Czech citizens about the effect of diet on microbiota composition. It also explores people's view on probiotics and their acquaintance with food composition. The conclusion of the thesis is a correlation between the theoretical and practical part. The intestinal microbiota is a relatively compact unit with complex interactions. Diet can not...
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Specifics of the use of opioids as important immunomodulators in the treatment of pain
Švubová, Veronika ; Hejnová, Lucie (advisor) ; Vašek, Daniel (referee)
This work deals with the specifics associated with the use of opioid analgesics in pain relief. In terms of antinociceptive effects, opioids have not yet been surpassed by other available drugs. However the use of these analgesics is quite problematic in many respects. For over 30 years, studies have shown that opioids can adversely affect components of the immune system (IS) and thus the overall condition of the patient. To understand the relationship between opioids and IS, it is necessary to know the mechanisms leading to immunomodulatory processes. Contact with opioids occurs at the cellular interface through interactions with opioid receptors (ORs). Within IS, we encounter all three basic types of OR - μ (MOR), δ (DOR), κ (KOR) and non-classical nociceptin receptors (NOP). Stimulation of these receptors induces activation of signaling cascades in target cells which can lead to dysregulation of cellular processes, thus modulating the immune response. However, the effect of opioids on IS cells may not be exclusively direct. More complex regulatory pathways have been found, involving parts of the central nervous system (CNS), the sympathetic nervous system (SNS), and endocrine-active tissues. Activation of these pathways then affects the activity of whole lymphoid organs. Each cell type within an...
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The use of immunoregulatory properties of mesenchymal stem cells/ and their therapeutic potential
Javorková, Eliška
Mesenchymal stem cells (MSCs) have the potential to differentiate into various cell types, possess potent immunomodulatory properties and can influence various functions of immune cells. Since the immunomodulatory properties of MSCs can be modified by cytokines, we compered the effect of unstimulated MSCs and MSCs pretreated with interleukin (IL)-1, interferon (IFN)- , transforming growth factor (TGF)- and IL-10 on the development of regulatory T cells (Treg) and T helper 17 (Th17) cells in vitro and on the inflammatory environment in the eye. MSCs can produce significant levels of TGF- and IL-6. These cytokines represent the key factors that reciprocally regulate the development of naive T cells into Treg and Th17 cells. Unstimulated MSCs produce TGF- , but not IL-6, and the production of TGF- can be further enhanced by IL-10 or TGF- . In the presence of IL-1, MSCs secrete significant levels of IL-6, in addition to spontaneous production of TGF- . MSC producing TGF- induced preferentially expression of Foxp3 and activation of Treg lymphocytes, whereas MSCs supernatants containing TGF- together with IL-6 supported ROR t expression and development of Th17 cells. We demonstrated that MSCs and their products effectively control the development of Tregs and Th17 cells in a population of...
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Immunomodulatory properties of mesenchymal stem cells from patients with amyotrophic lateral sclerosis and healthy donors
Matějčková, Nicole
Mesenchymal stem cells (MSC) possess a multilineage differentiation potential and have the ability to regulate reactivity of the immune system. They are usually isolated and expanded from the bone marrow, adipose tissue or umbilical cord. MSC represent promising cell population for the treatment of some severe diseases, such as amyotrofic lateral sclerosis (ALS), due to the combination of regenerative and immunomodulatory properties. The aim of this study is to compare MSC from ALS patients and healthy donors in their phenotype, proliferative activity and mainly their immunomodulatory properties. The assessment of impact of the disease on the properties of MSC is important for their autologous use in clinical trials. In this study we used MSC isolated from bone marrow of 14 ALS patients and 15 patients undergoing mostly orthopedic surgery as control group. We also used MSC stimulated for 24 hours by poinflammatory cytokines. Cells were compared in terms of immunophenotype, differentiation in adipocytes and osteoblasts, metabolic activity, expression of selected genes for immunomodulatory molecules and for inhibition of lymphocyte proliferation. Further experiments were focused on evaluation of immunomodulatory properties of MSC. The effect of MSC on peripheral blood mononuclear cells stimulated...
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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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Mesenchymal stem cells and their effects on regulatory B cells
Smolová, Helena ; Boháčová, Pavla (advisor) ; Stříž, Ilja (referee)
Mesenchymal stem cells (MSC) are multipotent cells with the ability to regulate reactivity of cells of immune system. Regulatory B cells (Bregs) are also capable of modulating immune responses. Both these cell types are able of creating anti-inflammatory and tolerogenic environments and represent potential of cell-mediated therapy for autoimmune diseases and transplantation reactions. The effect of MSC on Bregs activation and function has been only studied in recent years, and mechanisms of their effects are not yet well characterized. However, studies have demonstrated a decrease in effector B lymphocytes and antibody production, and a support of activation of Bregs subpopulation and increased production of anti-inflammatory interleukin 10. Various molecules produced by MSC are involved in Bregs induction. Unfortunately, their effects have not yet been sufficiently described, and different models yields diverse results. In addition to the current studies in experimental models, the first clinical trials on Bregs have been initiated. The positive results suggesting the potential for future use of Bregs for the treatment of autoimmune diseases and transplantation reactions have been obtained in both cases. Key words: regulatory B cells, mesenchymal stem cells, immunomodulation, autoimmune diseases,...
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The effect of vitamin D on the health of children and adolescents
Schönová, Markéta ; Kalvachová, Božena (advisor) ; Zíma, Zdeněk (referee)
The biologically active vitamin D metabolite is essential for the human body. And it is involved in the regulation of the function of most human cells. It is believed to affect up to 900 genes transcription. Thus, its insufficient amount may contribute to the pathogenesis of many diseases. It regulates calcium homeostasis, participates in bone development, and maintains optimal bone status. On the basis of the new knowledge of vitamin D, his out-of-bone effects are currently at the forefront. These relate to the immune system, metabolism, the nervous system, and the effect on the developing fetus. The aim of this work was to create a comprehensive overview of the effect of vitamin D on the young organism. And then, on the basis of questionnaire research, support or refute the hypothesis that children suffer from vitamin D deficiency in winter and spring. The secondary objective of the thesis is to create promotional material that contributes to increasing the interest of parents and older children in this issue and improving their awareness. Based on the knowledge of the effects of vitamin D, a questionnaire survey was conducted with eleven questions related to vitamin D. The research sample consisted of 134 children aged between three and fifteen who were divided into three groups by age. The results of...
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