|
|
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.
|
|
|
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.
|
|
|
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...
|
|
|
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.
|
|
|
Terapeutické využití dendritických buněk
Svobodová, Hana
Dendritic cells (DC) are the most effective antigen presenting cells. They are able to detect the presence of the antigen and ensure the transmission of information to the lymph nodes where T lymphocytes are stimulated by these mechanisms. DC mature after encountering the antigen, wander to the lymph nodes and other secondary lymphatic organs, and change from antigen-binding cells to active antigen presenting cells. They are also critical for regulating of immune response that affect the differentiation of T cells towards the Th1 or Th2 response. Cultivation of dendritic cells in vitro enables manipulation with these cells and discovering new therapies for controlling human diseases. Their specific properties have a great potential to be used not only for antitumor therapy but also in the treatment of infectious, autoimmune and allergic diseases. In particular, the induction of CD8+ T cells by activating the immune system can contribute to inhibition of tumor growth and increase patient survival. Encouraging results were also reported using immature dendritic cells in transplantology.
|
|
|
Biologická charakteristika dendritických buněk
Coufalová, Karmela
This thesis deals about characteristics of dendritic cells. Dendritic cells are antigen presenting cells that can stimulate naive T and B cells and they can regulate immune response of organism. They differ from other cells in that they can express MHC I and MHC II molecules and in that they do not have surface immunoglobulines or lymphocytic and monocytic characters. Dendritic cells are spread nearly through all tissues of the organism. There are two main pathways myeloid and lymphoid. Dendritic cells have two forms: immature (tolerogenic) and matture (immunoregulatory). Follicular dendritic cells are special case of dendritic cells. They are morphologically similar to dendritic cells, but they have not the same origin. Dendritic cells can represent vector for immunotherapy of allergic diseases, infections, autoimmune diseases, tumor immunotherapy and they can play role also in transplantology. Recently, research deals with antitumor vaccination.
|
|
|
Izolace krevních monocytů skotu pro účely kultivace dendritických buněk
Coufalová, Karmela
Monocytes are a population of mononuclear lekocytes. The aim of this thesis was to select a suitable methodology for the isolation of monocytes and their cultivation into dendritic cells. For the experiment, bovine blood was taken from vena jugularis externa. This blood was used to isolate monocytes based on the density gradient of OptiPrep solution and Histopaque solution. The results showed that the method of isolation based on the density gradient of the Histopaque solution and the magnetic separation appeared to be a more efficient method. The monocyte population was cultured for 72 hours. Cells were analyzed by light microscopy and CD14 positive cells appeared to be transformed into dendritic cells. The purity of these cell population was determined by flow cytometry. Dendritic cells have a wide range of utility mainly in immunotherapy of various diseases and also play an important role in cancer therapy.
|
|
|
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...
|
|
|
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.
|
|
|
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...
|
guest ::
