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Factors affecting the efficacy of anti-tumor therapy by blocking the PD-1/PD-L1 signaling pathway and predictive biomarkers of this treatment
Majerová, Miriam ; Šmahel, Michal (advisor) ; Krulová, Magdaléna (referee)
In recent years there has been a focus on cancer therapies that use patient's immune system instead of invasive traditional methods. One such method of immunotherapy is using checkpoint inhibitors. Blockade of PD-1/PD-L1 signaling pathway is one of main immunotherapy approaches utilizing patient's immune cells to combat cancer cells. Despite of positives that come along with this blockade, many patients do not respond to treatment. Therefore, better understanding of immune mechanisms and factors that affect the efficacy is needed. Finding and summarizing predictive biomarkers play an important role in selection of patients with highest chances of positive outcome and it could result in higher percentage of positively responding patients. It could also prevent patients from experiencing adverse events and unnecessary discomfort. Key words: immune checkpoints, immunotherapy, inhibitors, PD-1, PD-L1, biomarkers
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Thyroid hormones, their importance and exposure to cold
Špínová, Šárka ; Žurmanová, Jitka (advisor) ; Krulová, Magdaléna (referee)
Thyroid hormones are essential mainly for prenatal development and they maintain the homeostasis of many organs and body processes in adulthood. Therefore, the correct function of the regulatory axis between the hypothalamus, pituitary gland and thyroid gland is very important. Lack of these hormones is manifested, for example, by the formation of goiter, cretenism and bradycardia, excess in weight loss, ophthalmopathy, excessive sweating, tachycardia and also goiter formation. A serious problem is also the mutation of thyroid hormone receptors in target tissues. It causes nervous system disorders, hearing, vision, digestive system, incorrect cardiac function, delayed growth and mental development. Thyroid hormones are essential for the formation and activation of brown adipose tissue. This, together with the shivering thermogenesis of skeletal muscle, is involved in facultative thermogenesis, helping homoeothermic mammals to maintain a constant body core temperature. In addition, brown adipose tissue is an important endocrine organ that secretes active substances called batokines upon cold activation. Batokines have beneficial effects in the treatment of obesity, diabetes and cardiovascular disease. So we can assume that cold adaptation could effectively help in the treatment of civilization...
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Differentiation of human M2 monocytes/macrophages and their role in kidney transplantation
Čápová, Barbora ; Stříž, Ilja (advisor) ; Krulová, Magdaléna (referee)
The system of mononuclear phagocytes includes macrophages that modulate their phenotype based on microenvironmental signals. Their properties vary considerably in a differentiated stage. M1 macrophages, which are classically activated (typically by IFN-γ), are involved in phagocytosis and produce some pro-inflammatory cytokines, that can stimulate other immune cells. A phenotypically different cell population are M2 macrophages, which are alternatively activated by exposure by Th2 cytokines. M2 macrophages produce preferentially anti-inflammatory cytokines IL-10, TGF-β and participate in repair and tissue healing. The main aim of this study was to standardize a model of differentiation of THP-1 cells and human monocytes towards the M2 phenotyp using an in vitro model. This is represented in particular by increased expression of CD163 and CD206 molecules. The second aim was to assess the dynamics of expression (and co-expression) of CD163 and CD206 molecules in monocytes of patients after kidney transplantation. Expression of surface markers was determined by flow cytometry. Both THP-1 cells and human monocytes, isolated from buffy coat fraction, were stimulated by IL-4, TNF-α, TGF-β and IL-10. Changes in CD163 and CD206 expression were measured after day 1, day 3 and day 6 of stimulation. The most...
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Parasites and multiple sclerosis: trigger, or treatment?
Parohová, Irena ; Macháček, Tomáš (advisor) ; Krulová, Magdaléna (referee)
Multiple sclerosis (MS) is an inflammatory autoimmune disease and its growth has been recently recorded mostly in developed countries. Its yet unsolved origin contributes to difficulties with therapy of this disease. The influence of parasites in aetiology of MS has also been investigated, although never reliably proven in human trials. On the contrary, data from animal models of MS suggest a rather protective effect towards the disease progression, acquired through parasitic helmith infection. In the host helminths induce a variety of immunoregulatory mechanisms, which alleviate the ongoing inflammation in the central nervous system. These observations within the so-called helminthic therapy (mostly based on the application of whipworm Trichuris suis eggs) have been tested in human patients also. Up to date, results indicate a protective effect of application of T. suis to MS patients, however these clinical studies were executed only on a small number of probands. Besides this, pathological manifestations related to the infection of parasite occured in some cases. A solution could be the identification of specific parasite derived molecules with immunomodulatory potential.
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Study of mechanisms of Sertoli cell survival in xenogeneic organism
Porubská, Bianka ; Krulová, Magdaléna (advisor) ; Anděra, Ladislav (referee)
Sertoli cells (SCs) are somatic cells located in the testes. They are the only cells in direct contact with germ cells and play a key role in process of spermatogenesis. New insights in the biology of SCs are highlighting the immunological function of these cells: germ cells protection by maintaining the immunoprotective niche, creating the blood- testis barrier and local modulation of the immune response to spermatic cells. Immunomodulatory activity of SCs is preserved after their allo- and xenogeneic transplantation, and thus SCs prolongs survival not only of themselves but also of cells transplanted with them. The aim of this thesis was to study the survival and migration of SCs precursors (TSC) in mice recipients. The project is employing the neonatal tolerance phenomenon and evolutionary distinct donor organism, Xenopus tropicalis, to monitor conserved mechanisms of immune system (IS) modulation using SCs. SCs were detectable in the lungs and thymus 7 days after transplantation. The phenotype of immune cells was not altered 30 days after transplantation, however we detected changes in cytokine environment, namely increased levels of cytokines typical for Th2 and Treg immune responses. In vitro experiments further confirmed IS modulation by SCs - changing the phenotype of macrophages to alternatively...
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Complement-binding antibodies in patients after organ transplantation and their clinical relevance
Kovandová, Barbora ; Slavčev, Antonij (advisor) ; Krulová, Magdaléna (referee)
The diagnosis of antibody-mediated rejection after liver transplantation is complicated, due to the fact that the clinical and pathological signs of this life- threatening complication are often overlapping with non-immunological symptoms, like biliary obstruction, ischemia, thrombosis and others. Furthermore, the transplanted liver is to a great extent resistant to this type of rejection. Like in the transplanted kidney and heart, the main pathological factors of graft injury are antibodies directed to the mismatched HLA antigens of the organ donor, i.e. donor- specific antibodies. Besides analysis of HLA specificity of antibodies, research lately has been directed to define whether these antibodies are complement-binding or not. Literature data on this are however up till now limited. Therefore, the aim of this diploma thesis was to study the clinical relevance of complement-binding antibodies against HLA antigens in patients after liver transplantation. Our preliminary results suggest that there might be a correlation between the presence of complement-binding antibodies and the development of antibody-mediated rejection. This finding may play a role for improvement of the prognosis of patients after liver transplantation. Key words HLA, antibodies, C4d, complement, liver transplantation
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Anterior segment dysgenesis disorders and their molecular genetic cause
Moravíková, Jana ; Lišková, Petra (advisor) ; Krulová, Magdaléna (referee)
Proper eye development depends on expression and mutual regulation of many genes. Anterior segment dysgenesis (ASD) are a highly heterogeneous group of diseases exhibiting all types of Mendelian inheritance, which manifest as combination of congenital abnormalities of the cornea, iris, anterior chamber angle or lens. Screening of genes associated with ASD does not often lead to the identification of the underlying genetic cause implying that there are still novel variants or genes to be discovered. Molecular genetic analysis in 12 probands with ASD using Sanger and whole-exome sequencing were performed. Functional analysis by Exon trapping assay was provided in variants predicted to effect pre-mRNA splicing. Four PAX6 mutations evaluated as pathogenic or likely pathogenic in a heterozygous state were found in four probands c.183C˃G; p.(Tyr61*), c.1032+1G>A, c.1183+1G>T and c.622C>T; p.(Arg208Trp). One proband was found to be a compound heterozygote for c.244A>G; p.(Met82Val) and c.541delG; p.(Glu181Lysfs*26) mutations in FOXE3. In 7 probands, no potentially pathogenic variants were identified. Exon trapping assay confirmed that mutations c.1032+1G>A and c.1183+1G>T have an effect on pre-mRNA splicing of the PAX6 gene. Detailed molecular-genetic analysis in patients with ASD may contribute to...
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Chemokines in kidney transplantation and their production by human macrophages and renal epithelial cells.
Pidhorodetská, Halyna ; Stříž, Ilja (advisor) ; Krulová, Magdaléna (referee)
One of the main effects of pro-inflammatory cytokines is the induction of chemokines and the expression of adhesive molecules that regulate the migration of immune cells to the center of the damage. Chemoattractant gradient also provides a physiological delivery of cells to tissues and lymphatic organs under normal circumstances. Chemokines are chemotactic cytokines that form a very large and diverse group of secreted proteins that have many functions both in processes that maintain homeostasis but also in inflammatory states. Production of some chemokines also has a major effect on graft rejection. Further understanding of the mechanisms involved in the acute rejection chemokine could contribute to improving treatment steps in transplantology. In this diploma thesis, serum chemokine levels were monitored in renal transplant patients, but these measurements did not show significant dynamics. Furthermore, the effect of pro- inflammatory cytokines on the release of chemokines from renal epithelial cells and monocytes was studied. Experiments were performed to monitor the levels of individual chemokines such as ENA-78, IL-8, MCP-1, MIP-1β, RANTES, GRO-α, THP-1 (monocyte/macrophage cell line), RPTEC (renal epithelial cells of proximal tubules) and RA (renal cell tumor lines). TNF-α had an effect on the...
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Genotype influence on development of infections caused by Trypanosomatidae in mouse
Šíma, Matyáš ; Lipoldová, Marie (advisor) ; Krulová, Magdaléna (referee) ; Kolářová, Iva (referee)
Parasitic protists of genera Trypanosoma and Leishmania are members of Trypanosomatidae family. In our studies, we investigated genetic influence on infections caused by these parasites in a mouse model. These diseases are on genetic level controlled by quantitative trait loci (QTLs), when the resulting phenotype is controlled by set of genes with small individual effect. As a mouse model for mapping of QTLs controlling these infections, we used recombinant congenic strains (RCS). Each RCS carry unique set of 12.5% of the genome from donor parental strain on genetic background of other parental strain. For mapping of QTLs controlling infections caused by Trypanosoma brucei brucei (T. b. brucei) and Leishmania tropica (L. tropica) and eosinophil infiltration into inguinal lymph nodes after Leishmania major (L. major) infection, we used RCS from CcS/Dem series, where STS is donor strain and BALB/cHeA is strain of genetic background. First, it was necessary to find suitable model strains for mapping. In all three studies, we selected RCS, which exceeded range of monitored phenotype parameters in comparison with any other tested RCS or parental strains. Mice of RCS CcS-11 showed shorter survival after T. b. brucei infection and strain CcS-9 exhibited higher eosinophil infiltration after L. major infection. For...
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