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The effect of aspartate β-hydroxylase inhibition on immune reactions
Krausová, Kateřina ; Šmahel, Michal (advisor) ; Filipp, Dominik (referee)
Aspartate β-hydroxylase (ASPH) is an enzyme that contributes to tumor progression by enhancing the proliferation, migration and invasiveness of cancer cells. Its expression is mostly negligible in normal cells, whereas it is often overexpressed in cancer cells. An inhibitory effect of ASPH on immune cells, specifically on natural killer cells, has also been demonstrated. Thus, the ASPH enzyme could be a new target for cancer immunotherapy. The aim of this thesis was to show the effect of ASPH inhibition on the immune response. Firstly, it was found that ASPH inhibition contributes to the anti-tumor effect of DNA vaccination. The reduction of tumors induced by ASPH inhibition in combination with DNA vaccination was shown to be mainly caused by CD8+ T lymphocytes. Subsequently, the specific activation of T lymphocytes was confirmed by the ELISPOT assay. In case of non-specific activation of T lymphocytes, ASPH inhibition had no effect on the direct activation of CD8+ T lymphocytes. Finally, it was found that plasmacytoid dendritic cells did not contribute to CD8+ T lymphocyte activation after ASPH inhibition. Thus, the results demonstrate that inhibition of ASPH contributes to the activation of adaptive immunity induced by DNA vaccination, but the mechanism of this activation remains unknown.
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Lectin receptor-ligand interaction important in experimental tumor therapy
Grobárová, Valéria ; Černý, Jan (advisor) ; Filipp, Dominik (referee) ; Krulová, Magdaléna (referee)
Lectin-saccharide interactions are involved in many biological processes essential for the survival and proper function of multicellular organisms. C-type lectin-like receptors, predominantly expressed by cells of the innate immune system, recognize saccharide structures on microbes and also aberrant glycosylation pattern of cancer cells. The NKR-P1 receptor family was among the first natural killer (NK) receptor families that were identified, however ligands for some of members remain still elusive. Recently, publications describing N-acetylglucosamine-terminated oligosaccharide structures as possible ligands for NKR-P1 receptor have been subjects for correction/retractions after investigation of the Ethical Committee of the Institute of Microbiology, ASCR, v. v. i. and Charles University in Prague. Re-evaluation of glycodendrimer effect, particularly effect of N-acetyl-D-glucosamine octabranched dendrimer on polyamidoamine scaffold (GN8P), revealed mostly indirect role of NK cells on modulation of immune responses. Properly folded soluble recombinant rat NKR-P1A and mouse NKR-P1C lack binding activity to neoglycoproteins modified with GlcNAc-terminated structures. Moreover, new possible target cell populations (NKT cells and macrophages) for saccharide binding were identified.
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DNA methyltransferase inhibitors and their effect on the activation of genes being of importance to a presentation of the antigen in tumour cells
Cebová, Magdaléna ; Reiniš, Milan (advisor) ; Poljaková, Jitka (referee)
DNA methylation is one of the epigenetic modulations that can be associated with tumour diseases. DNA methyltransferases act as catalysers of the process of DNA methylation and their inhibition could be used as a possible approach to the therapy of tumours. DNA methyltransferase inhibitors are classified into two groups, nucleoside inhibitors that are incorporated into DNA and subsequently form covalent bonds with DNA methyltransferase, and non-nucleoside inhibitors whose action is limited to inhibiting the catalytic site of the DNA methyltransferase. The first objective of this bachelor thesis was to compare the toxicity of DNA methyltransferase inhibitors in mouse tumour cell lines. The results show that the toxicity of nucleoside inhibitors is much higher (due to their incorporation into the DNA) than that of non-nucleoside inhibitors. The second objective was to compare the effect of DNA methyltransferase inhibitors on the expression of MHC (major histoncompatibility complex) class I glycoproteins on the surface of mouse tumour cells. Reduced expression of MHC class I glycoproteins is known to be one of the mechanisms used by the tumour cells to escape the immune system. Our laboratory has shown that some inhibitors (5-azacytidine) increase the expression of MHC I class molecules in MHC...
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