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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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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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Tolerogenic dendritic cells as a novel cell-based therapy in type 1 diabetes
Kroulíková, Zuzana ; Funda, David (advisor) ; Smrž, Daniel (referee)
Utilization of tolerogenic dendritic cells (tolDCs) as a cell-based therapy represents a promising strategy in treatment of autoimmune diseases including type 1 diabetes (T1D). Numerous protocols have been established to generate tolDCs ex vivo and their therapeutic effect has been demonstrated in animal models of autoimmune diseases. In this thesis we compared three different variants of such protocols which are based on the combined treatment of bone marrow- derived DCs with vitamin D and dexamethasone applied at different time points of their maturation towards tolDCs. We assessed the efficiency of these protocols in regards of their effect on the expression of co-stimulatory molecules CD40, CD80, CD86, and MHC II and the chemokine receptor CCR7 on the surface of tolDCs. Then, we evaluated the migration pattern of antigen unloaded tolDCs in vivo as well as their effect on the induction of immune responses and cell proliferation of lymph node cells. This was achieved by labelling of tolDCs with membrane dye PKH26 and by following their migration path by flow cytometry after intraperitoneal (i.p) or subcutaneous (s.c.) injection into either left or right side of the body. On day 1, 3, 5, 7, and 9, the presence of PKH26+ tolDCs was examined in spleen, pancreatic, mesenteric, inguinal and axillary...
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