|
|
Markers of transplantation tolerance in kidney transplantation
Krepsová, Eva ; Viklický, Ondřej (advisor) ; Krejčí, Karel (referee) ; Živný, Jan (referee)
Long-term renal graft acceptance still requires long-term immunosuppressive therapy, which is accompanied by many adverse effects. Contrarily insufficient immunosuppression could lead to graft rejection and its failure. Therefore, research continues for biomarkers that reflect a patient's immunological status and thus allowing for individualized immunosuppressive therapy. In our study we showed lower incidence of acute rejection in kidney transplant recipients treated with rabbit anti-thymocyte globulin (rATG) or basiliximab induction within the first three months after transplantation. The rATG induction caused profound decrease of recipient's peripheral blood T and NK cells, as well as transcripts that are exclusively expressed by these cell types together with expansion of regulatory T cells (Tregs) among CD4+ T cells. In rATG group the increase of two transcripts associated with rejection (MAN1A1 and TLR5) was also observed in early post-transplant period. After the basiliximab induction we transiently detected CD4+CD25low/-FoxP3+ cell population along with disappearance of CD4+CD25+FoxP3+ Tregs. Basiliximab induction resulted in a transient increase in CD4+FoxP3+ Tregs, accompanied by the highest peripheral expression levels of markers associated with operational tolerance (FOXP3 and TCAIM)....
|
|
|
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....
|
|
|
Snižují regulační T lymfocyty riziko autoimmunity indukované CD8+ T lymfocyty?
Chadimová, Tereza ; Štěpánek, Ondřej (advisor) ; Šenolt, Ladislav (referee)
5 Regulatory T cells (Tregs) are essential for the maintenance of peripheral self-tolerance and prevention of autoimmunity by suppressing the response of self-reactive CD8+ and CD4+ T cells. However, while interactions of Tregs with CD4+ T cells have been extensively studied, their effect on the self-tolerance of CD8+ T cells has not been explored in detail. The main aim of this diploma project was to provide evidence whether and how Tregs prevent autoimmunity induced by CD8+ T cells. We used an experimental mouse model of autoimmune diabetes allowing us to acutely deplete Tregs and titrate the number of self-reactive T cells, self- antigen affinity, and self-antigen doses. We found out that Tregs play an important role in the prevention of CD8+ T-cell mediated autoimmunity. Moreover, we revealed that Tregs suppress both high-affinity T cells that escape negative selection and relatively weakly self-reactive, but numerous, positively selected T cells. Tregs do so by increasing requirement for the number of self-reactive CD8+ T cells required for the autoimmunity induction. Intriguingly, presence of Tregs does not impact threshold for self-antigen. Moreover, for the first time, we showed that Tregs can suppress CD8+ T-cell-mediated autoimmunity in the absence of conventional CD4+ T cells. This means that...
|
|
|
Immunomodulatory properties of TES
Holečková, Markéta ; Hrdý, Jiří (advisor) ; Macháček, Tomáš (referee)
Toxocara canis and Toxocara cati are parasitic roundworms. Their definite hosts are canines or felines. Human infection is also possible and in that case these parasites cause human toxocariasis. Larvae of Toxocara spp. in the host release proteins called TES (Toxocara Excretory-Secretory antigens). The main role of these proteins is to ensure long-term survival of the parasite in the body of the host. The surface of the larvae is covered by coat made of some of those proteins, which increases the parasite's chances of survival. Other proteins secreted by Toxocara spp affect production of cytokines of the infected organism and parasite modulates the immune response to infection by that. Presence of the larvae results in inhibition of immune response based on Th1 cells and promotes Th2 immune response, during which levels of IgE and eosinophiles are elevated. Production of regulatory T lymphocytes is also stimulated. Key words Toxocara spp., toxocariasis, TES, immunomodulation, regulatory T lymphocytes, cytokines
|
|
|
Regulační T lymfocyty a nádorová onemocnění
SKALIČKOVÁ, Markéta
The main aim of this thesis was to study the role of regulatory T cells in cancer. Their presence, importance, and mechanism of their action were studied as well. The practical part was focused on reduction of bigger tumors and suppressing regulatory T-cell effects. The combination of TLR agonists, agonistic CD40 antibody and anti-CTLA-4 was studied on a mouse model of pancreatic adenocarcinoma.
|
|
|
Markers of transplantation tolerance in kidney transplantation
Krepsová, Eva ; Viklický, Ondřej (advisor) ; Krejčí, Karel (referee) ; Živný, Jan (referee)
Long-term renal graft acceptance still requires long-term immunosuppressive therapy, which is accompanied by many adverse effects. Contrarily insufficient immunosuppression could lead to graft rejection and its failure. Therefore, research continues for biomarkers that reflect a patient's immunological status and thus allowing for individualized immunosuppressive therapy. In our study we showed lower incidence of acute rejection in kidney transplant recipients treated with rabbit anti-thymocyte globulin (rATG) or basiliximab induction within the first three months after transplantation. The rATG induction caused profound decrease of recipient's peripheral blood T and NK cells, as well as transcripts that are exclusively expressed by these cell types together with expansion of regulatory T cells (Tregs) among CD4+ T cells. In rATG group the increase of two transcripts associated with rejection (MAN1A1 and TLR5) was also observed in early post-transplant period. After the basiliximab induction we transiently detected CD4+CD25low/-FoxP3+ cell population along with disappearance of CD4+CD25+FoxP3+ Tregs. Basiliximab induction resulted in a transient increase in CD4+FoxP3+ Tregs, accompanied by the highest peripheral expression levels of markers associated with operational tolerance (FOXP3 and TCAIM)....
|
|
|
Impact of the regulatory T cells detection and differences in expession of tumor antigens in ovarian cancer
Kloudová, Kamila ; Sojka, Luděk (advisor) ; Čáp, Michal (referee)
Regulatory T cells (Treg) play a key role in maintaining the immune tolerance. They suppress development of autoimmune diseases and contribute to maintaining the homeostasis of the immune system. Expansion and excessive ability of regulatory T cells to suppress the immune response is increasingly observed also at many types of cancer. Due to the active inhibition of the antitumor immune response Treg contribute to tumor progression. Specific phenotype based detection and analysis of Treg functional properties may contribute to the successful monitoring of Treg accounts and to the effective cancer immunotherapy itself. Tumor cells express high amounts of so-called tumor antigens, which may play a key role in the antitumor immune response. Expression level of the tumor antigens gives the evidence about relevancy of each antigen in the specific immune response and efficiency of cancer immunotherapy. These data are obviously important to be obtained from the tumor cell lines as well as primary tumor cells. In the first part of the thesis I was focusing on the quantitative analysis of regulatory T cells in tumor tissue and peripheral blood of patients with ovarian cancer. For this purpose I used the newly introduced methyl-sensitive quantitative PCR (MS-qPCR) method and compare the data with the widely...
|
|
|
The role of the immune system in colorectal and ovarian cancer
Kocián, Petr ; Hoch, Jiří (advisor) ; Prausová, Jana (referee) ; Žaloudík, Jan (referee)
Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome cansignificantly vary among patients within the same stage. Data collected from largecohorts of human cancers has demonstrated the impact of immune-classification, which has a prognostic value that may add largely to the significance of the AJCC/UICC TNM-classification. In our study we examined the immune cells that infiltrated the tumor tissues of colorectal and ovarian cancer patients. In a cohort of newly diagnosed colorectal cancer patients we examined the correlations between the KRAS mutational status, patterns of tumor-infiltrating immune cells and the presence of tumor recurrence. Our data suggest that colorectal cancer patients with low levels of tumor-infiltrating lymphocytes, a high CD1a/DC-LAMP tumor-infiltrating dendritic cells ratio, and a KRAS mutation in codon 13 are at a high risk of disease recurrence. In ovarian cancer patients we focused on the dynamics of the tumor-infiltrating...
|
|
|
Regulatory T lymfocytes and their role in cancer
Kloudová, Kamila ; Sojka, Luděk (advisor) ; Schierová, Michaela (referee)
Regulatory T lymphocytes (Treg) are the population of CD4+CD25+Foxp3+ T cells. Treg have an irreplaceable role in the regulation of immune system thereby contributing to immunological tolerance and to suppression of peripheral autoreactivity. Formation, development and correct function of Treg depend on expression of key transcription factor Foxp3, which is used as a specific Treg marker. In humans, Treg exist in two different subpopulations. Each of these subpopulations differs functionally and in point of formation. Naturally occurring Treg (nTreg) are formed in thymus to maintain peripheral tolerance. Induced Treg (iTreg) are formed in periphery by the activation of naive CD4+ T lymphocytes. After discovering that Treg cells play important role in development and progression of cancer, many research groups restored Treg issue. Treg are expressed in significantly higher amounts in cancer patients, when compared with healthy controls and in these patients Treg can effectively inhibit antitumor immune response with possible fatal consequences. Therefore Treg become one of the main cancer immunotherapy barriers and substances depleting or modulating Treg activity would increase effectiveness of anti-cancer vaccines. Keywords Regulatory T cells, Foxp3, cancer, immunotherapy
|
guest ::
