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Heterogeneity of antigen-presenting cells in the thymus and its relevance for the establishment of central tolerance
Sýkora, Vojtěch ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
The crucial function of the thymus is the establishment of central tolerance. In this process, developing T-cells are tested for their self-reactivity, since self-reactive T-cells might cause the autoimmunity if they would escape from the thymus to the periphery. Many thymic antigen-presenting cells are essential for establishment of central tolerance. Their role is to present self-antigens to the developing T-cells. Such presentation is capable to reveal the self-reactive potential of T-cells which can be then directly removed or deviated into suppressive T-regulatory cells. In the last several years, a high level of heterogeneity has been described among the thymic antigen-presenting cells and the molecular mechanisms that govern their functions towards enforcement of tolerance began to be uncovered. This thesis summarises recent knowledge in the field of heterogeneity of the thymic antigen-presenting cells and its relevance for establishment of the central tolerance, with the major focus on conventional dendritic cells and post-AIRE medullary thymic epithelial cells. This thesis also outlines recent advances in understanding of functional mechanisms and regulations of maturation of the antigen-presenting cells.
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Úloha osy PD-1/PD-L1 při infekci \kur{Borrelia burgdorferi} u myší
PALOUNKOVÁ, Anna
Borrelia burgdorferi, the causative agent of Lyme disease, induces upregulation of inhibitory immune checkpoint PD-L1 in mice. We studied if the blockade of PD-1/PD-L1 axis by neutralizing antibodies influences the proliferation of T lymphocytes and cytokine milieu in imunological synapsis between murine dendritic cells and T cells in vitro.
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CX3CR1+ migratory dendritic cells in the mechanisms of central tolerance
Březina, Jiří ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Display of thousands of self-antigens in the thymus is fundamental for the establishment of central tolerance as its failure can lead to the development of autoimmunity. Medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs) constitute essential populations of antigen presenting cells (APCs) which present these self-antigens to developing T cells. While mTECs produce and present antigens in self-autonomous manner, DCs can hijack mTEC-derived antigens by the process of cooperative antigen transfer (CAT). It is well found that CAT is essential for working central tolerance, however, the overall heterogeneity of thymic APCs participating in CAT remains unclear. Using transgenic mouse models and multicolor flow cytometry analysis, we determined that APCs involved in CAT are exclusively of CD11c+ phenotype. Within these cells, we identified previously unrecognized CX3CR1+ subset of migratory DCs (mDCs) exhibiting monocyte/macrophage markers. These CX3CR1+ mDCs are more efficient in CAT than their CX3CR1- counterparts and reveal robust antigen presenting properties with the capability to present CAT-acquired antigen. Genetic ablation of CX3CR1+ mDCs resulted in increased cellularity of CD8+ and CD4+ thymocytes, indicating importance of this mDC subset for negative selection of...
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Immunogenic cell death
Šímová, Michaela ; Drbal, Karel (advisor) ; Javorková, Eliška (referee)
According to the danger model, the immune system is activated by endogenous molecules known as danger-associated molecular patterns (DAMP) that are externalized from the interior of a dying cell to the cell surface or released into the extracellular space. Due to the loss of plasma membrane integrity a necrotic cell death as well as several types of proinflammatory programmed cell death are considered to be immunogenic, whereas apoptosis, on contrary, has been initially defined as a tolerogenic type of cell death. However, under certain circumstances, the immune response can be initiated by an apoptotic cell after exnternalization of DAMP molecules by newly described secretory pathways. This phenomenon was observed on tumor cells as a result of some widely used therapeutic modalities and is known as immunogenic cell death (ICD). Nomenclature of selected types of cell death is part of this thesis. The aim of this bachelor thesis is to provide an evidence of the experimental support for ICD theory during in vivo initiation of the immune response. I will evaluate the correlation between ICD and the induced exposure of DAMP molecules on the surface of tumor cells or their secretion to the extracellular space.
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CX3CR1+ migratory dendritic cells in the mechanisms of central tolerance
Březina, Jiří ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Display of thousands of self-antigens in the thymus is fundamental for the establishment of central tolerance as its failure can lead to the development of autoimmunity. Medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs) constitute essential populations of antigen presenting cells (APCs) which present these self-antigens to developing T cells. While mTECs produce and present antigens in self-autonomous manner, DCs can hijack mTEC-derived antigens by the process of cooperative antigen transfer (CAT). It is well found that CAT is essential for working central tolerance, however, the overall heterogeneity of thymic APCs participating in CAT remains unclear. Using transgenic mouse models and multicolor flow cytometry analysis, we determined that APCs involved in CAT are exclusively of CD11c+ phenotype. Within these cells, we identified previously unrecognized CX3CR1+ subset of migratory DCs (mDCs) exhibiting monocyte/macrophage markers. These CX3CR1+ mDCs are more efficient in CAT than their CX3CR1- counterparts and reveal robust antigen presenting properties with the capability to present CAT-acquired antigen. Genetic ablation of CX3CR1+ mDCs resulted in increased cellularity of CD8+ and CD4+ thymocytes, indicating importance of this mDC subset for negative selection of...
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Immunogenic cell death
Šímová, Michaela ; Drbal, Karel (advisor) ; Javorková, Eliška (referee)
According to the danger model, the immune system is activated by endogenous molecules known as danger-associated molecular patterns (DAMP) that are externalized from the interior of a dying cell to the cell surface or released into the extracellular space. Due to the loss of plasma membrane integrity a necrotic cell death as well as several types of proinflammatory programmed cell death are considered to be immunogenic, whereas apoptosis, on contrary, has been initially defined as a tolerogenic type of cell death. However, under certain circumstances, the immune response can be initiated by an apoptotic cell after exnternalization of DAMP molecules by newly described secretory pathways. This phenomenon was observed on tumor cells as a result of some widely used therapeutic modalities and is known as immunogenic cell death (ICD). Nomenclature of selected types of cell death is part of this thesis. The aim of this bachelor thesis is to provide an evidence of the experimental support for ICD theory during in vivo initiation of the immune response. I will evaluate the correlation between ICD and the induced exposure of DAMP molecules on the surface of tumor cells or their secretion to the extracellular space.
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Antigen cross-presentation - mechanism and biological significance
Boháčová, Šárka ; Stříšovský, Kvido (advisor) ; Černý, Jan (referee)
iii Abstract Antigen cross-presentation is a process, when dendritic cells present exogenous antigens in context of MHC-I to CD8+ T lymphocytes. Unlike classical antigen presentation, this one goes crosswise, because exogenous antigens are otherwise usually presented on MHC-II and endogenous antigens on MHC-I glycoproteins. Molecular mechanism of cross-presentation has not been well established yet. Two major pathways are considered - vacuolar and cytosolic. In the vacuolar pathway, the internalised antigens are cleaved in the endosome by proteases and then loaded onto MHC-I. In the cytosolic pathway, the internalised antigens leave the endosome to be cleaved by the proteasome in the cytosol. They are then imported into the endoplasmic reticulum (ER) to by loaded onto MHC-I as in classical antigen presentation, or they go back into the endosome where the MHC-I loading machinery is trafficked. This process is mediated by ER proteins including those participating in ERAD, by Rab GTPases regulating vesicular transport, and by structures important for endosome maturation. Cross-presentation is important in medicine, because it ensures activation of CD8+ T lymphocytes against intracellular pathogens and cancer cells, and induction of tolerance at the...
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Subpopulations of lymphocytes in patients with prostate cancer during the immunotherapy by dendritic cell vaccine
Volmová, Martina ; Lašťovička, Jan (advisor) ; Palich Fučíková, Jitka (referee)
The bachelor thesis looks into the issue of cancer immunotherapy and it deals with possible use of immunotherapy by dendritic cell vaccine in patients with prostate cancer, which is now in phase I/II of clinical trials on the Department of Immunology at Faculty hospital Motol. The target of the practical part was to cope with the technology of preparation of blood samples and their measurement by means of the flow cytometry, with subsequent data evaluation and processing. The highlight of this work was the statistical evaluation of obtained data of lymphocyte subpopulations levels in peripheral blood, and their possible correlation with disease progression. The main subject of the research were subpopulations CD3 +, CD4 +, CD8+ , CD16+ , CD19+ and HLA-DR+. The monitoring of these subpopulations in patients treated by dendritic cell vaccine showed the decrease of both leukocyte and lymphocyte levels, reduction of CD4/CD8 index, decrease of relative and absolute numbers of CD4+ cells and significant decrease of both relative and absolute B lymphocyte numbers during the progress of the disease. Powered by TCPDF (www.tcpdf.org)
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Vliv klíštěcích slin na fagocytózu borelií dendritickými buňkami
MARŠÁLKOVÁ, Eliška
In this study we examined the effect of the tick saliva from I. ricinus and the effect of recombinant protein IRS-2 from the saliva of I. ricinus on dendritic cells derived from the mice bone marrow. We studied their effect on the production of cytokines by dendritic cells after the stimulation by B. burgdorferi, their effect on the expression of genes, that participate in phagocytosis, and the impact of the tick saliva on phagocytosis of B. burgdorferi by dendritic cells.
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The effect of tick cystatins on TLR - induced maturation of myeloid dendritic cells
NERADOVÁ, Hana
Tick saliva contains a lot of molecules with antihemostatic and immunosupressive effects.The goal of this thesis is to test the effects of tick salivary cystatins from I.ricinus and I.scapularis on TLR - induced maturation of bone-marrow derived dendritic cells and production of chosen cytokines. Over all, the supressive effect of tick cystatins was observed in relation to TLR-induced maturation of DC. In addition, cystatins enhanced production of IL-10 and attenuated induction of IL-12 cytokines.
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