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Study of immunopathological mechanisms of autoimmune uveitis and the determination of new therapeutical options.
Seidler Štangová, Petra ; Svozílková, Petra (advisor) ; Rozsíval, Pavel (referee) ; Farghali, Hassan (referee)
The aim of this work was to gain new knowledge about mechanisms of autoimmune uveitis and to test new therapeutic possibilities that have not yet been studied in uveitis or whose effect is questionable. The main emphasis was placed on the role of microorganisms in the process of uveitis. A mouse model of experimental autoimmune uveitis including a germ-free model was used to achieve the aims and samples of patients' intraocular fluids were analyzed. In the experimental model, the intensity of inflammation was evaluated in vivo clinically and post mortem histologically. The effect of immunomodulatory treatment was evaluated. The intensity of inflammation was compared between groups of germ-free and conventional mice. The therapeutic effect of antibiotics administered to affect microbiome was investigated in conventional mice. In intraocular fluid samples of patients with autoimmune uveitis signs of infection were monitored and levels of cytokines and other factors were evaluated. Evaluation of the effect of immunomodulatory therapy has demonstrated the efficacy of mycophenolate mofetil, which supports its wider use in the treatment of autoimmune posterior uveitis in human medicine. The decrease in bacterial load has led to a decrease in the intensity of inflammation, thereby confirming the importance of...
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Effect of the pretransplantation conditioning on the effectiveness of bone marrow transplantation in a mouse model
Renešová, Nicol ; Šefc, Luděk (advisor) ; Průcha, Miroslav (referee)
Hematologic malignancies are among the most often diagnosed forms of cancers. Treatment regimens often utilise various combination of cytostatic drugs and total body irradiation and subsequent transplantation of hematopoietic stem cells. One of the most common combinations includes ionising radiation with the antineoplastic alkylating agent cyclophosphamide. In this study we used congenic Ly5.2 and L5.1 mouse strains that express different isoforms of CD45 antigen to evaluate the effects of various time interval between cyclophosphamide and irradiation treatments on the viability of hematopoietic stem cells and their viability. This was done by competitive repopulation assay. The results revealed that level of engraftment and subsequent reconstitution of hematopoiesis can significantly vary and depend on the time interval between cyclophosphamide and total body irradiation administrations. The results indicate that patients with hematologic malignancies could possibly benefit from the treatment especially if they received transplants after being irradiated five or seven days after cyclophosphamide because at that time point their own stem cells would be least competitive. Key words: bone marrow transplantation, cyclophosphamide, chimerism, hematopoietic stem cells, ionising radiation
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Impacts of chemotherapy on imunoregulatory gene expression in the tumor microenvironment
Paračková, Zuzana ; Reiniš, Milan (advisor) ; Zajícová, Alena (referee)
Tumor microenvironment is an area, where the local immunosuppressive effects dominate and prevents the immune system to perform its physiological functions. The cells infiltrating the microenvironment have an important function among many cell types since they produce a large quantity of factors suppressing the immune response. In our work, we monitored the immune changes in the microenvironment during tumor growth and chemotherapy. For these purposes, we utilized the methods for analysis of the proportion and phenotype of the distinct populations of immunocytes and for analysis of the total level of expressions of selected genes associated with immunosuppression or with distinct populations of immunocytes. The aim of our work was to discover, using two types of mouse tumors (TRAMP-C2 and TC-1/A9), how 5-azacytidine (5AC), a cytostatic drug with epigenetic activity, affects the proportion of leukocytes infiltrating the tumor microenvironment and, further, whether these changes are accompanied by decreased expression of immunosuppressing genes. In addition, we have also focused on the changes of relative expression of genes encoding markers of lymphoid lines and, on other immunoregulating genes, encoding IL-6, IL-10, IL-12, IL-4 and IFNγ cytokines, in the microenvironment of these tumors....
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