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Tolerogenic dendritic cells as immune interventions in prevention or therapy of type 1 diabetes
Petrovčíková, Diana ; Funda, David (advisor) ; Hrdý, Jiří (referee)
The main aim of this work is to refer a recent summary of the opportunities and pitfalls of the application of tolerogenic dendritic cells in the prevention or therapy of type 1 diabetes (T1D). Tolerogenic dendritic cells (TolDCs) represent a potential tool for the treatment of allergies, transplant rejections and autoimmune diseases, including T1D, due to their capability to specifically inhibit autoimmune reactions without causing general immunosuppression. TolDCs represent a specific group of dendritic cells and are essential in establishing central and peripheral tolerance. This work presents a helpful guide to better understanding the physiology of tolerogenic DCs and an overview of in vitro generation attempts. In addition, the route of application and migration to target organs has been described. Type 1 diabetes (T1D) is a chronic disease resulting from immune-mediated destruction of the insulin-producing beta cells in the pancreas. Animal models have been invaluable in testing innovative medical treatments since the early testing of insulin in dogs almost a century ago. Animal models of type 1 diabetes (T1D) enable the study of the mechanisms underlying its pathogenesis and the potential development of therapeutic interventions. However, there are still significant gaps in our general...
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Modern therapy of chondral defects
Neckař, Pavel ; Havlas, Vojtěch (advisor) ; Zeman, Petr (referee) ; Tuček, Michal (referee)
The thesis describes the application of cultured bone marrow stem cells in the therapy of focal chondral defect of the knee joint. In the experimental part of the work, the goal was to quantitatively and qualitatively compare two sampling sites of bone marrow monocytic aspirates, the iliac crest bone and the proximal tibia, in order to determine a suitable cell source for advanced cell therapy. The sample analysis showed that the amount of monocytic cells and the yield of stem cells from the aspirate obtained were significantly higher in the bone marrow from the iliac crest. We did not find significant qualitative differences between the two sources of stem cells. In the clinical part of the work, I present a description of the surgical procedure and the results of a 1-year follow-up of patients after the implantation of cultured stem cells from the bone marrow, under the name BiCure® orthoMSCp (Bioinova, Prague, Czech Republic), fixed on a commercially available 3D scaffold Chondrotissue® (BioTissue AG, Geneva, Switzerland) using coagulated autologous platelet-rich plasma. The primary objective of the clinical study included the evaluation of the short-term and long-term safety of the applied medical product. The secondary objective of the work included the assessment of the effectiveness of the...
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Tolerogenic dendritic cells in immunotherapy of type 1 diabetes
Grohová, Anna ; Špíšek, Radek (advisor) ; Černý, Jan (referee) ; Hrdý, Jiří (referee)
Type 1 diabetes is characterized by chronic hyperglycaemia leading to life-threatening complication. The pathogenetic mechanism of T1D is the abnormal immune reaction destroying β-cell mass in pancreas. The current therapy is based on the administration of subcutaneous insulin. However, this therapy can not prevent the episodes of transient hyperglycaemia. Thus, the high blood glucose influences negatively cellular metabolism and progressively leads to tissue damage. The cellular therapy brings the new strategy allowing the direct modulation of the abnormal autoimmune reaction. This strategy promises more targeting therapy with less adverse effects. In this thesis we discuss two types of immune-suppressive cells which are candidates for cellular therapy in autoimmune diseases. The first part describes the tolerogenic dendritic cells (tDC) and their stable suppressive phenotype in proinflammatory condition. tDC maintain their stable inhibitory phenotype and are able to suppress antigen- specific T-cell proliferation together with the induction of T-regulatory cells. These properties of tDC are very important for potential clinical application. The thesis also reveals the relation between laboratory parameters of T1D patients and suppressive properties of tDC. The second part of the thesis is focused...
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Ethic Consequences of Embryonic Stem Cells Research
Rožánková, Vladimíra ; Ehler, Edvard (advisor) ; Přívratský, Vladimír (referee)
TITLE: Ethic Consequences of Embryonic Stem Cells Research Abstract The thesis deals with stem cell research, especially embryonic cells. First the thesis is devoted to researchand describe the history of stem cells, which focused on embryonicstem cells, which are the central theme of this thesis. This section is also accompanied by visual documentation, for better orientation in the field. The thesis also deals with the issue of stem cell research legislation, focusing in detail on the Czech Republic and Europe. The solution is also the issue of ethical and religious impactofn stem cell research. Key words: law, ethics, embyonic research, cell biology
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Potential of stem cell therapy for diabetic retinopathy
Palacká, Kateřina ; Holáň, Vladimír (advisor) ; Tlapáková, Tereza (referee)
Diabetic retinopathy is retinal disease causing irreversible cell damage and consequently a loss of vision. Current treatment protocols have many limitations and are associated with serious site effects. A possible treatment options for retinal degenerative diseases is a use of stem cells. There are different types of stem cells. These include embryonal stem cells, induced pluripotent stem cells and cells from an adult organism, among which we can include mesenchymal stem cells (MSCs). MSCs can be found in almost all tissues of the adult organism. MSCs can migrate to the site of damage, regulate development of inflammation in retina, suppress the formation of fibrovascular scars and replace damaged cells such as nerve cells, photoreceptors and epithelial pigment cells. Application of MSCs could be a promising treatment for degenerative retinal diseases.
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Generation and application of induced pluripotent stem cells in hematology
Berková, Linda ; Láníková, Lucie (advisor) ; Krulová, Magdaléna (referee)
Induced pluripotent stem cells (iPSC) are one of the key discoveries in cell biology of the last decade. These cells are pluripotent stem cells derived from differentiated somatic cells while having used only four exogenous transcription factors. Pluripotent cells, which can be derived from somatic cells carrying genetic mutation, have a great potential to be used in the testing of new drugs and in discovering molecular mechanisms of genetic disorders. iPSC derived from healthy cells can be used in regenerative medicine. Originally, retroviral vectors were used for delivering reprogramming transcription factors to cells. However such approach is not safe for medicinal use, because of the ability of retroviruses to integrate into the host genome. This fact initiated development of safer delivering methods of transcription factors into the cells. In this work I present the overview of methods which have been used for reprogramming including the most common techniques used to test pluripotency. In addition, I will describe iPSC application options for therapy of genetically determined hematological disorders (sickle cell anemia, β-thalassemia, X-linked chronic granulomatous disease) and for modelling of their molecular mechanism (polycythemia vera). Key words: iPSC, reprogramming, hematological...
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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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Multipotent mesenchymal stromal cells in orthopedic: Potentiation of bone healing
Stehlík, David ; Trč, Tomáš (advisor) ; Janíček, Pavel (referee) ; Sedmera, David (referee)
The aim of the thesis was development of an innovative treatment of bone defects. Human multipotent mesenchymal stromal cells (MSC) play a crucial role in bone healing. Clinical applications of MSC require large amount of cells, which could be obtained by autologous expansion of MSC harvested from bone marrow. As a first step, the standard protocol of MSC expansion based on αMEM medium and fetal bovine serum (FBS) was used. Experiments replacing FBS by pooled human serum (HS) in the culture medium concluded in patenting of a new MSC cultivation protocol (EU 1999250, CR 301141). This one-step cultivation protocol and xenogeneic protein-free cultivation medium is based on CellGro® for Hematopoietic Cells' Medium, HS, human recombinant growth factors, dexamethasone, insulin and ascorbic acid. The preclinical in vitro and in vivo experiments with MSC from both expansion protocols were carried out. Fibrillar polylactic scaffolds were seeded with MSC, cultured, differentiated and implanted in immunodeficient mice (NOD/LtSz-Rag1-). Bone-like mineralized tissue containing vessels was observed. The MSC cultured according to patented method were classified as Advanced-therapy Medicinal Product and has to fulfil the European Medicines Agency regulations to enter the clinical trials. Nevertheless the use of MSC seems...
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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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