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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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Effect of bacterial monoassociations (Akkermansia muciniphila) on development of type 1 diabetes and immune parameters in ex-germ-free NOD mice
Němec, Dušan ; Funda, David (advisor) ; Zadražil, Zdeněk (referee)
Type 1 diabetes (T1DM) is an autoimmune condition affecting around 0,4 % of general population and its prevalence is still increasing. T1DM is a multifactorial disease, and it develops under the forces of various environmental and hereditary factors. Gut microbiota is recently one of the most relevant environmental features of autoimmunity, including T1DM. Healthy gut microbiota is characterized especially by its variability. However, there has been an effort to determine critical bacteria that can either drive or suppress T1DM development. Akkermansia muciniphila is among those potentially protective bacteria. This diploma thesis examined changes of immune parameters, such regulatory T cells, NK cells, γδ T cells and expression of IFNγ, IL-10 and IL-17, and their correlation with T1DM onset in A. muciniphila- monoassociated ex-germ-free NOD mice compared to germ-free (GF) and specific-pathogen- free (SPF) controls. Furthermore, the second part of the thesis, NOD-SCID adoptive transfer provided an insight into whether diabetogenic ability of NOD mice-derived splenocytes differ in A. muciniphila vs GF and SPF controls. Minor differences were found in immune parameters among various cell populations, with the most prominent increased IL-10 expression in A. muciniphila-monoassociated mice compared to...
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The effect of gluten-free diet on β-cell residual capacity, immune function and gut microbiome in children with newly diagnosed type 1. diabetes
Neuman, Vít ; Šumník, Zdeněk (advisor) ; Pelikánová, Terezie (referee) ; Škvor, Jaroslav (referee)
The effect of gluten-free diet on β-cell residual capacity, immune function and gut microbiome in children with newly diagnosed type 1. diabetes Abstract The pathophysiology of the onset and progression of type 1 diabetes (T1D) is not fully understood. Gluten has a proinflammatory effect on the immune system and is therefore considered as one of the factors affecting the onset and progression of T1D. The aim of the thesis is to allow a complex insight into the role of the GFD on the residual β-cell capacity, T1D control, gut microbiome, gut permeability, subtypes of immune cells and the effect of gut microbiome transfer into germ-free non-obese diabetic (NOD) mice on the incidence of diabetes. On the group of 45 children with T1D (26 intervention group, 19 control group) we proved the association of the GFD with slower decrease of β-cell residual capacity (the difference in the trend of C-peptide decrease 409 pmol/l/year; p = 0,04) and lower HbA1c (by 7,8 mmol/mol; p=0,02). We also described the changes in the gut bacteria that were differentially abundant after the administration of the GFD and the changes in abundance of the regulatory and effector immune cells. We showed there was no change in the gut permeability with respect to the study group. We also proved that the transfer of human gut microbiota...
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Impact of mesenchymal stem cells on islets revascularization after transplantation into the extracellular matrix
Hudzieczková, Aneta ; Girman, Peter (advisor) ; Černý, Jan (referee)
Pancreatic transplantation is the only possible treatment to induce independence from exogenous insulin administration in type 1 diabetes mellitus. However, the shortage of donor organs remains the main limitation of pancreas transplantations. The goal of the research is the preparation of a bioartificial organ based on cell therapy. Parts of the extracellular matrix obtained by decellularization of the pancreas are used for its preparation. The protein scaffolds prepared in this way are then repopulated by different cell types again. The extracellular matrix provides structural support to cells, mediates signaling for differentiation, proliferation or migration. Mesenchymal stromal cells are used in clinical therapy, have a positive effect on tissue regeneration processes, modulating the function of the extracellular matrix, suppress inflammation and promote angiogenesis. After pancreas decellularization, we repopulated the extracellular matrix with islets, mesenchymal cells and endothelial cells. Then, the pancreas was transplanted subcutaneously into syngeneic diabetic rats to observe islet revascularization. Based on sections of explanted scaffolds, we found out that revascularization of the islets was higher without the endothelial cells in the transplanted extracellular matrix. Key words:...
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Roles of environmental factors and microbiome in type 1 diabetes
Novotná, Kateřina ; Funda, David (advisor) ; Cahová, Monika (referee)
Type 1 diabetes mellitus (T1DM) is an insulin-dependent autoimmune disease. Its onset is characterized by an autoreactive self-destruction of β-cells within pancreatic islets. T1DM is influenced by multiple genetic predispositions, but since the incidence of the disease has increased dramatically in the past decades, especially in developed, western-type countries, the importance of the environmental factors has become obvious. There are various significant environmental influences that need to be addressed in the equation of variables. This bachelor thesis deals with the environmental variables and their mechanisms in T1DM and focuses on several areas of interest. It introduces frequently used spontaneous animal model of T1DM, pathogenetic mechanisms and T-cells in T1DM as well as regulatory immune cells and their mechanisms, in the light of hygiene and another hypothesis. Next it addresses the role of intestinal microbiota, dietary factors, mucosal immunity, their mechanisms and interactions in T1DM and extends to other, less researched, but important environmental variables such as circadian rhythm in connection with circadian gene expression depending on the rhythmicity of light/dark rotation and timing of food intake throughout the day, psychological/oxidative stress, and the effects of...
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Mucosal immunity in upper respiratory tract diseases and autoimmunity diseases
Fundová, Petra ; Tlaskalová - Hogenová, Helena (advisor) ; Prokešová, Ludmila (referee) ; Bártová, Jiřina (referee)
Mucosal immune system comprises not only the major compartment of the immune system but also important interface with the outer environment. It is responsible in maintaining an intricate balance with the danger and non-danger stimuli of the outer world by employing specific anatomical features and unique functional mechanisms. Mucosal immune system has been long understudied, perhaps due to the limited accessibility, and its biological importance is thus still underevaluated. However, it has become evident that it is important to study mucosal immune system not only in local mucosal affections but also when uncovering pathogenic mechanisms and novel prevention strategies of organ specific autoimmune diseases such as type 1 diabetes. Thus, the first, more clinically oriented part of this thesis is focused on mucosal immune system of the upper respiratory tract in disease conditions - in nasal polyposis (NP). Because there is a substantial accumulation of eosinophils and neutrophils in the most frequent type of NP, we investigated and described increased expression of chemokine receptors CCR1 and CCR3 in NP versus nasal mucosa. Both innate immune mechanisms as well as homeostasis of epithelial cells may participate in NP. We have documented increased numbers of iNOS-positive and insulin-like growth...
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Effect of gluten-free diet on immune cell subsets in the NOD mouse model of type 1 diabetes
Tejklová, Tereza ; Funda, David (advisor) ; Krulová, Magdaléna (referee)
Type 1 diabetes (T1D) is an autoimmune disease leading to destruction of insulin-secreting pancreatic -cells. Environmental factors e.g. exposures to infections, dietary components play a substantial role in etiopathogenesis of T1D and are responsible for rapid increase of T1D incidence in past decades, preferentially in developed countries. Despite long record of T1D research no causative cure or efficient prevention exists. While gluten displays proinflammatory properties, gluten-free diet (GFD) has been documented by several studies as a strong diabetes- preventive environmental factor in spontaneous animal models of T1D, mostly in NOD mouse. The aim of this thesis is to better characterize effects of GFD on the immune system of NOD mouse. Using flow cytometry, we compared effects of GFD vs standard (STD) Altromin diets on NK cell subsets, Tregs, as well as other regulatory cell subsets and their cytokine profile in prediabetic SPF NOD females that were exposed to the diets since "in utero". A reference diabetes incidence in NOD females in our SPF facility kept on STD and GFD was recorded. Diabetes-preventive capacity of GFD were tested by using the NOD-SCID model of diabetes transfer, in which splenocytes from at-onset NOD females kept on GFD or STD were transferred to NOD-SCID recipients....
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