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Use of polymer prodrugs containing cucurbitacin D for the treatment of experimental tumors
Hrabánková, Klára ; Šírová, Milada (advisor) ; Grobárová, Valéria (referee)
Chemotherapy is still the most widely used anti-cancer treatment. The majority of chemotherapeutics inhibit proliferating cells generally, not selectively cancer cells. The side effects associated with chemotherapy can be partly limited by conjugating a cytotoxic drug with a polymer nanocarrier. Such binding facilitates solubility in aqueous solutions, reduces systemic toxicity; and passively targets the drug directly into the tumour through the enhanced permeability and retention (EPR) effect. This thesis focuses on testing polymer conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) carrying cucurbitacin D (CuD), a naturally occurring compound with potential anti-cancer activity. The mechanism of action is not elucidated yet, but several studies have depicted the inhibitory effect on signal transducer and activator of transcription 3 (STAT3) transcription factor. A STAT3 signalling pathway is overexpressed in several cancer cell lines and is also involved in the differentiation of myeloid- derived suppressor cells (MDSCs). We examined the therapeutic effect of the HPMA copolymers based on CuD in combined therapy with other polymer chemotherapeutics. CuD conjugates have shown in vitro cytotoxic effect on several model cancer cell lines. The combination with conjugates carrying doxorubicin...
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Immunomodulatory and regenerative potential of mesenchymal stem cells in the treatment of degenerative retinal disorders in mice
Palacká, Kateřina ; Heřmánková, Barbora (advisor) ; Grobárová, Valéria (referee)
Retinal degenerative disease are the leading cause of vision loss in adult patients. Important role in the development of these types of disease play gradual death of retinal cells and an inflammatory reaction that leads to the production of cytokines, formation of inflamasome, increased angiogenesis and scar formation. These pathologies result in irreversible degeneration of retinal cells. Retinal pigmenetd epithelium cells, photoreceptors and ganglion cells are the most frequently damaged cell types in this conditions. The available treatments are currently very limited and effective only at the early stages of the disease. Therefore, the use of stem cell- based therapy could be a promising option. For therapeutic purposes it would be possible to use mesenchymal stem cells (MSCs) which may be isolated for example from bone marrow or adipose tissue. MSCs are capable of production of neuroprotective factors, differentiation into the variety of cells types and regulation of immune response. In this study we tested the therapeutic potential of MSC administered locally to the damaged retina in an experimental model of retinal degeneration. We focused on the protective effect of MSCs on photoreceptor cells, regulation of the local immune response and expression of genes for cytokines involved in...
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Effect of Wharton's jelly-derived mesenchymal stem cells secretome in the treatment of rat spinal cord injury
Jančová, Pavlína ; Chudíčková, Milada (advisor) ; Grobárová, Valéria (referee)
As previously shown, transplantation of Wharton's jelly-derived mesenchymal stem cells in the experimental model of spinal cord injury leads to the motor and sensory functions improvement, supports neuroregeneration, angiogenesis and provides immunomodulation. On the other hand, these cells have limited migration and survival capacity, and their therapeutic effect is mediated mostly by their secretome. Therefore, application of mesenchymal stem cells derived conditioned medium is studied as an alternative option for cell therapy. In this thesis, therapeutic effect of repeated intrathecal delivery of human Wharton's jelly-derived mesenchymal stem cells and their conditioned media in the treatment of spinal cord injury was compared. After induction of a balloon ischemic compression lesion, stem cells or conditioned media were administered weekly in three doses. Behavioral analyses were carried out up to nine weeks after spinal cord injury and revealed significant improvement of both treated groups compared to the untreated saline control. Application of stem cells and conditioned media also resulted in a higher amount of spared tissue and enhanced expression of genes related to neuroregeneration, although the size of glial scar was not reduced. Compared to application of stem cells, application of...
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Potential role of skin microbiota in the pathogenesis of dermatological diseases
Mihula, Martin ; Jirásková Zákostelská, Zuzana (advisor) ; Grobárová, Valéria (referee)
The surface of the human body is colonized by a large number of microorganisms whose composition depends not only on external and internal factors, but is also significantly influenced by the topography of human skin. The complex skin microbiota is an essential part of physiological and protective mechanisms of the skin. The change in the dynamics of microbial communities on the skin or in the gastrointestinal tract is currently considered to be part of triggering mechanisms of many skin diseases. Some of the skin inflammatory diseases are directly associated with a shift of skin microbiota composition - for instance atopic dermatitis, acne vulgaris or psoriasis. Gaining and perceiving knowledge about interspecies interactions and their effect on a host could lead to the development of new diagnostic and therapeutic approaches which could make the prevention or treatment of some skin disorders more effective. Key words: skin, skin diseases, skin microbiota, immunity, psoriasis, atopic dermatitis, vitiligo
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Microbiota and inflammatory bowel diseases
Gajdárová, Zuzana ; Kostovčíková, Klára (advisor) ; Grobárová, Valéria (referee)
Inflammatory bowel diseases (IBD) are an autoimmune illnesses affecting gastrointestinal tract. The main types include ulcerative colitis and Crohn's disease. Recently, primary sclerosing cholangitis (PSC) has also been associated with IBD. PSC is a chronic liver disease associated with bile duct stenosis. The exact pathogenesis and etiology of these diseases is not clear, despite the great efforts of the scientific community. They are multifactorial diseases that are associated with dysbiosis of intestinal microbiota. Their diagnosis is based on for patients unpleasant endoscopic examinations and therefore the search for new serum biomarkers is needed and appreciated target of scientific interest. In the first part of diploma thesis, we focused on the reactivity of peripheral blood cells of IBD patients to 10 selected representatives of typical intestinal microbiota: Lactobacillus plantarum, Bifidobacterium adolescentis, Blautia coccoides, Roseburia intestinalis, Eubacterium rectale, Faecalibacterium prausnitzii, Ruminococcus flavefaciens, Bacteroides thetaiotaomicron, Prevotella ruminicola and Escherichia coli. Reactivity of CD, UC and PSC- IBD patients was increased after stimulation with Faecalibacterium, Lactobacillus and Prevotella. However, we got low percentage of cytokine-producing cells,...
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The role of neutrophils in preeclampsia
Miková, Eliška ; Hrdý, Jiří (advisor) ; Grobárová, Valéria (referee)
Preeclampsia is currently one of the leading causes of maternal morbidity and mortality. Disease development is caused by multiple factors but the main trigger remains unknown. Preeclamptic placentas are defined by increased inflammatory environment. One of the first cells to enter the site of inflammation are neutrophils. Current studies uncover considerable heterogeneity of neutrophils which used to be considered as terminally differentiated population with a very limited plasticity. Disbalance in the proportional and functional properties of proinflammatory and immunosuppressive neutrophil subpopulations including myeloid derived suppressor cells can lead to severe pregnancy complications such as preeclampsia. Better understanding of the origin of abnormal neutrophil subpopulations and their role in the pathogenesis of preeclampsia could help reveal possible targets for therapeutic intervention. Key words: neutrophil subpopulations, preeclampsia, NETosis, myeloid derived suppressor cells, myeloperoxidase, elastase, PD-L1, inflammation
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Difference in T regulatory cells in cord blood of children of healthy and allergic mothers
Macholdová, Kateřina ; Hrdý, Jiří (advisor) ; Grobárová, Valéria (referee)
Allergic diseases belong to one of the most common diseases and their incidence is increasing worldwide, especially among children and adolescents. The development of an allergic disorder occurs already in the early postnatal period and several factors have been described that can predispose the newborn to an allergic disease. However, the mechanism of allergy development has not yet been fully elucidated. The important immune cells involved in this mechanism are regulatory T cells (Treg). Their function is the formation of central tolerance to autoantigens and peripheral tolerance towards harmless antigens present in the external environment, including allergens. The aim of this work is to compare the proportion and functional properties of Treg in children of healthy mothers (children with low risk of allergic disease development) and children of allergic mothers (children at high risk of allergic disease development). Both the total Treg population and individual subpopulations (natural (n) Treg and induced (i)Treg) in the whole umbilical cord blood of both groups of children were monitored. To assess the functional properties, Treg were isolated from cord blood by magnetic separation and subsequently co-cultured with CD4+CD25-T cells or cord blood mononuclear cells (CBMC) stained with...
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Dietary factors in the development of type 1 diabetes
Fiala, Marek ; Funda, David (advisor) ; Grobárová, Valéria (referee)
Type 1 diabetes mellitus is an autoimmune disease which develops in genetically susceptible individuals and whose incidence rapidly increases, especially in developed countries. Type 1 diabetes is believed to be strongly associated with the environment: viruses, stressful life events or the absence of exposition to antigens in early life increase its incidence. Antigens to which we are expressed continuously are food antigens. Gluten, milk proteins or the intake of vitamin D precursors clearly influence type 1 diabetes pathogenic process. This bachelor's thesis aims to describe our current knowledge on the role of dietary factors in type 1 diabetes, their possible immune mechanisms and also interplay with other environmental factors. Key words: type 1 diabetes, dietary factors, gluten-free diet, immune mechanisms, prevention, NOD mouse, mucosal immunity
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Immune response of different subpopulations of dendritic cells to probiotic strain of E. coli O83:K24:H31
Gorelová, Miroslava ; Hrdý, Jiří (advisor) ; Grobárová, Valéria (referee)
Allergy, as one of the worldwide most frequent pathologies, belongs to illnesses with constantly growing incidence among young children. In genetically predisposed individuals, dendritic cells are able to polarize the immune response of Th2 in contact with the allergen. Postnatal probiotic supplementation could be one the preventive measure to prevent the development of allergic diseases. It has been shown that introduction of selected probiotic strains or mixtures can prevent development of allergy. In this diploma thesis, the capacity of probiotic strain Escherichia coli O83:K24:H31 (E. coli O83) to support maturation of dendritic cells (DC) and polarization of immune responses was tested. Introduction of this probiotic vaccine called Colinfant Newborn appears to be suitable preventive measure, lowering allergy incidence in children with predisposition to development of allergy. The aim of this diploma thesis was to observe capacity of E. coli O83 to support maturation of the two main subpopulations of dendritic cells (myeloid dendritic cells - mDC and plasmacytoid dendritic cells - pDC) in cord blood of newborns of healthy mothers (children with relatively low risk for allergy development) and allergic mothers (children with relatively high risk for allergy development). To achieve this goal,...
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Regulatory CD8+ T lymphocytes
Chadimová, Tereza ; Štěpánek, Ondřej (advisor) ; Grobárová, Valéria (referee)
Regulatory T cells are essential for the maintenance of peripheral immune tolerance, preventing alloimmunity and pathogen-induced immunopathology. While regulatory CD4+ T lymphocytes have been studied for over two decades, the existence of regulatory T lymphocytes in the CD8+ compartment is still controversial. Through the years, multiple CD8+ T lymphocytes subpopulations have been reported to exhibit regulatory activity, yet none has been canonically recognized. The aim of this thesis is to review current knowledge of these putative CD8+ regulatory lymphocytes and evaluate whether or not these subsets can be established as regulatory T cells. The emphasis of this thesis will be put on the phenotypic characteristics, regulatory activity and inhibitory mechanisms of these cells. Keywords: CD8+ Regulatory T lymphocytes, immunological self-tolerance, immunosuppression
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