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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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Changes of gut microbiome in patients with inflammatory bowel diseases
Schierová, Dagmar ; Jirásková Zákostelská, Zuzana (advisor) ; Hrdý, Jiří (referee) ; Kohout, Pavel (referee)
(EN) Microbes have coevolved with humans forming symbiotic communities that constantly challenge the immune system and, when imbalanced, could lead to diseases like inflammatory bowel disease (IBD). Patients with IBD suffer from microbial dysbiosis and chronic inflammation which could be potentiated by immune system reaction to the commensal microbiota. In the research presented here, firstly I have focused on the description of the gut and skin microbiome from patients with IBD and secondly, I investigated the process of antimicrobial defense. Patients with IBD on two different biological therapies targeting TNFα, IL-12 and IL-23 cytokines were tracked for changes in their gut and skin microbiome features. Although, neither differences in gut microbial diversity nor composition were linked with the progression of the therapies, an increased similarity to the healthy control group at week 38 of anti-TNFα therapy was found. This shift in microbiome could be considered beneficial and could be attributed to the inflammation reducing effect of the therapy. While analyzing the microbiome features, various patient characteristics were taken into account and the sources microbiome of variability were uncovered, out of which the interindividual variability stood out the most. Regarding the skin microbiome,...
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Maternal allergy status has no impact on neonatal immune responses to allergen stimuli
Lohonková, Adéla ; Hrdý, Jiří (advisor) ; Černý, Jan (referee)
The alarming increasing incidence of allergic diseases leads to the effort to identify the group of markers with prognostic potential pointing reliably to an allergy development at a later age. Identification of such marker or a group of markers pointing to a higher risk of developing an allergy would allow early implementation of preventive measures to block further development of the allergic disease. Umbilical cord blood appears to be the ideal biological material for the search for prognostic markers that are suitable for further study. The ability of umbilical cord blood cells to respond to stimulation by common allergens by producing cytokines according to a pattern dependent on the allergic status of the mother could be the predictive feature sought. The presented study focuses on the determination of cytokines typical for Th1- : interferon gamma (IFN-γ), Th2-: interleukin 5, interleukin 13 (IL-5, IL-13) a regulatory T cells (Tregs): interleukin 10 (IL-10) immunity responses at the level of gene expression by quantitative real-time polymerase chain reaction (qRT-PCR) followed by determination of the protein production itself in the cell culture supernatant. Newborns were divided into two groups according to the allergic status of their mothers: children of healthy mothers (newborns with a...
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Effect of early postnatal supplementation by probiotic bacteria Escherichia coli O83:K24:H31 on proportional and fucntional characteristics of selected cellular population
Věcek, Jan ; Hrdý, Jiří (advisor) ; Funda, David (referee)
The hygiene hypothesis proposes that exposure to microorganisms during the postnatal period is crucial for proper immune system development and may help to prevent development of autoimmune diseases and allergies. Probiotics, live microorganisms with beneficial health effects, could be a safe way to promote the appropriate maturation of the immune system. Early postnatal administration of a specific probiotic strain, Escherichia coli O83:K24:H31 (EcO83), reduces the incidence of allergies later in life. To understand the immunomodulatory features of EcO83, we conducted a bioinformatic analysis of its genome and compared it to two other strains, E. coli Nissle and E. coli K12. Our analysis identified unique genes in EcO83 related to propionate and galactose metabolism, as well as genes that may enhance its ability to thrive in the gastrointestinal tract. Moreover, we transformed EcO83 with luciferase enzymes and observed that it effectively colonizes the gastrointestinal tract of newborn mice but not adult mice. Further analysis of mice treated with EcO83 revealed that the probiotic promotes the expression of genes involved in tight junction formation and increases costimulatory molecules on dendritic cells in the mesenteric lymph nodes (MLN). Induced RORγt+ Tregs in MLN displayed increased...
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The role of gut microbiome and autoimmune mechanisms in patients with anorexia nervosa
Kovářová, Tereza ; Procházková, Petra (advisor) ; Hrdý, Jiří (referee)
In addition to gastroenterological diseases, changes in the composition and diversity of the gut microbiota have been also described in several neurological and psychiatric diseases, including eating disorders. My intention in this work is to clarify whether changes in the composition of the intestinal microbiota may be involved in the development of anorexia nervosa (AN) and whether there is a correlation between these changes and possible immunopathological reactions in patients with anorexia nervosa. The study included 30 acute patients (disease duration up to 3 years), 30 patients with a chronic course of the disease (duration longer than 7 years), and 30 healthy controls. The research included analysis of the gut microbiome using high-throughput sequencing (HTS) and determination of serum levels of autoantibodies against selected neuropeptides regulating food intake (by ELISA). Furthermore, serum levels of biomarkers of microbial translocation through the intestinal barrier, intestinal cell damage, and inflammation were detected by ELISA. The levels of pro- and anti-inflammatory cytokines were measured using Luminex instrument. We also introduced an experimental ABA (activity-based anorexia) mouse model, which may contribute significantly to further investigating mechanisms of anorexia...
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Mechanisms of antigen presentation in the etiopathogenesis of celiac disease
Hudec, Michael ; Černá, Marie (advisor) ; Hrdý, Jiří (referee) ; Slavčev, Antonij (referee)
1 ABSTRACT Celiac disease (CeD) is a chronic autoimmune disease that develops as a response of the immune system to the presence of gluten in the small intestine. CeD is manifested not only by classic intestinal symptoms: abdominal pain, constipation or diarrhea, as well as complex less common symptoms: anemia, osteoporosis, psychiatric disorders or menstrual cycle disorders. HLA risk alleles predisposing to origin of celiac disease are HLA-DQ2 (DQA1*05:01 / DQB1*02:01) and HLA-DQ8 (DQA1*03:01 / DQB1*03:02). There are other celiac disease-associated polymorphisms outside of HLA locus (6p21.3) that are located in 5q32 and 19p13 regions with unclear connection to CeD development. HLA class II glycoproteins are expressed on antigen presenting cells (APC) that include dendritic cells, macrophages and B cells. Monocytes are one of several possible dendritic cell precursors that circulate in the bloodstream. Deviations in the frequency of intermediate monocytes are directly associated with autoimmune disorders such as Crohn's disease or rheumatoid arthritis. It is known that the monocytes of CeD patients show pro-inflammatory reaction in the presence of gluten. It means that, in the context of CeD, the response to gluten arises earlier than the activation of gluten-specific T cells. The conventional way of direct...
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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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Biochemical predictors of the treatment failure in pediatric IBD patients
Zárubová, Kristýna ; Bronský, Jiří (advisor) ; Hrdý, Jiří (referee) ; Petrášová, Miroslava (referee)
Up to 20 % of patients with IBD (inflammatory bowel disease) is diagnosed in childhood, the course of the disease tends to often be more severe and the treatment more difficult than in case of adults. Therefore, it is necessary to commence or eventually change the treatment in order to prevent development of complications. Early detection of relapse plays significant role for further course of the disease and general prognosis of the patient. Changes to laboratory parameters (e.g. to the level of fecal calprotectin) can significantly prevent the development of clinical symptoms and may indicate the necessity for control endoscopy, further escalation or change in therapy. The primary focus of this thesis are patients who underwent surgical bowel resection, who constitute one of the risk groups. Studies show that as many as 70 % of patients suffering from Crohn's disease reach the point of bowel surgery within the first 10 years of the diagnosis. According to the results, a promising predictor of relapse of the disease seems to be serum albumin, which may relate to the overall nutritional status of the organism. We have also examined the effectivity of using fecal calprotectin and CRP as relapse predictors. Testing directly in the resected bowel did not prove usability of calprotectin as a predictor,...
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Gut microbiome and autoimmune mechanisms in patients with type 1 narcolepsy
Ježková, Janet ; Roubalová, Radka (advisor) ; Hrdý, Jiří (referee)
Narcolepsy Type 1 (NT1) is a chronic neurological disease characterized by the presence of cataplexy and excessive daytime sleepiness. NT1 probably arises from autoimmune destruction of orexinergic neurons in the hypothalamus. These neurons are the only known producers of the neuropeptides orexin A and B, which are involved in the regulation of sleep and wakefulness. NT1 is often accompanied by comorbidities such as obesity, type 2 diabetes, hormonal disorders, depression, and anxiety. Gut microbiota affects the quality of sleep by the production of various metabolites. It is considered that it may be involved in the pathogenesis of NT1 or in the development of related comorbidities. In our study, we analyzed the gut microbiota composition of 41 NT1 patients and 32 healthy controls using next-generation sequencing. The diversity of patients' gut microbiota did not differ significantly from healthy controls. In patients, we revealed a positive correlation between the abundance of the bacterial family Coriobacteriaceae, BMI, and the disease duration. Besides, we observed a negative correlation between the Coriobacteriaceae family and cholesterol levels, suggesting that these bacteria are involved in host lipid metabolism. Compared to healthy controls, a higher abundance of bacteria from the families...
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The role of innate lymphoid cells in influenza virus infection
Mouyabi, Flaviancia ; Hrdý, Jiří (advisor) ; Kössl, Jan (referee)
Innate lymphoid cells (ILCs) are recently discovered group of innate immune cells. They do not have antigen-specific receptors but they can be activated by cytokines similarly to T lymphocytes. ILCs have a crucial role in the regulation of inflammation, tissue repair, containment of commensals, anti-infection immunity and regulation of tissue homeostasis. The presence of mouse and human ILCs can be detected in the lung during and after influenza virus infection when ILCs contribute to the restoration of damaged lung parenchyma. ILCs directly or indirectly provide protection against viral infections by secretion of various cytokines and co-operation with other cells (e.g. T cells, macrophages). Overall, lung ILCs are important in immune responses and tissue homeostasis, but further studies on this topic are needed to fully understand their role. The aim of this thesis was to specifically characterize these cells, focus on their function in the lung, and describe their role in the course of influenza virus infection.
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