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Significance of the major histocompatibility complex for organ transplantation
Ilina, Liudmila ; Slavčev, Antonij (advisor) ; Grobárová, Valéria (referee)
The major histocompatibility system is a region in the human genome located on chromosome 6. HLA genes encode polymorphic cell-surface glycoproteins which are primarily responsible for presentation of self and non-self antigens to T cells. When the T lymphocyte recognizes the MHC-peptide complex as foreign, it activates effector components of the innate and adaptive immune system. Therefore, mismatched HLA antigens can lead to a strong immune response against the donor's tissue. HLA laboratories support transplant programs by evaluation the HLA matching between patients and their potential donors and, based on these data, assist in the evaluation of the risk of rejection and eventual immunological complications after transplantation. The aim of this thesis is to describe the significance of the major histocompatibility complex for the occurrence of cellular and antibody-mediated rejection after solid organ transplantation and discuss the relationship between the degree of HLA matching and graft survival outcomes. Key words HLA, organ transplantation, rejection
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Role of antibodies against HLA and non HLA antigens for organ transplantation.
Svobodová, Eva ; Slavčev, Antonij (advisor) ; Mrázek, František (referee) ; Černá, Marie (referee)
Rejection is a significant complication after transplantation and one of the main reasons for loss of graft function. It is triggered by the response of the organ recipient's immune system based on the recognition of mismatched HLA (Human Leukocyte Antigens) and non-HLA antigens of the donor. All components of the immune system participate in this process, and according to the predominance of individual reactions, rejection can be divided into T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). Rejection can develop immediately after transplantation in an acute form, or as a chronic form during several to tens of years after transplantation. The diagnosis of rejection is determined according to the clinical status, laboratory tests (including the detection of donor-specific antibodies, DSA) and histological findings in biopsies. The knowledge of validated gene expressions from the molecular microscope (MMDX) and other diagnostic tests has been recently applied. Individual phenotypes of rejection are evaluated and revised according to the international pathological classification. This work focuses on the analysis of immunological factors in relation to T-cell and antibody- mediated rejection after organ transplantation. The thesis deals with the determination of DSA in relation...
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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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Significance of the major histocompatibility complex for hemopoietic stem cell transplantation
Graman, Vojtěch ; Slavčev, Antonij (advisor) ; Dobeš, Jan (referee)
The genes of the major histocompatibility complex are located on the short arm of chromosome 6 and encode surface glycoproteins (HLA glycoproteins), which ensure the presentation of self and foreign peptides on the cell surface. These glycoproteins are subsequently recognized by T-lymphocytes and by other cells of the immune system. When the HLA-peptide complex is recognized as foreign, T-lymphocytes and other components of the immune system are activated, and the foreign cell is destroyed. Therefore, in hematopoietic stem cell transplantation (HSCT), HLA incompatibility between donor and recipient causes a strong immune response against the transplanted cells, and is therefore a major criterion in selecting suitable stem cell donors. This work briefly summarizes the current knowledge about the structure and function of HLA class I and class II antigens. The work focuses on HLA typing techniques to help understand the HLA system, which include serological typing methods, as well as modern molecular typing methods based on PCR and next-generation sequencing, and their relevance for HSCT. We also focus on HSCT processes and preparatory therapy, but the main emphasis is on the importance of HLA incompatibilities between stem cell recipients and donors and their effect on HSCT outcome.
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Humoral rejection after kidney transplantation and monitoring antibodies against HLA and non-HLA antigens.
Valhová, Šárka ; Slavčev, Antonij (advisor) ; Mrázek, František (referee)
Kidney transplantation is the treatment of choice for patients with end stage renal failure and is associated with prolonged survival of patients and better quality of life than long-term dialysis. Simultaneously, however, transplantation carries the risk of immunological complications leading to graft rejection. A serious problem in patients after organ transplantation is the development of humoral rejection, which is most often associated with the presence of antibodies specific to HLA antigens, particularly against mismatched HLA antigens of the organ donor. In certain cases antibodies may be specific to antigens expressed on endothelial cells, not on lymphocytes, like MICA, MICB, ICAM, and up till now unidentified tissue-specific antigens. Humoral rejection has significantly worse prognosis for the transplanted kidney than cellular rejection, and therefore its timely diagnosis is of great importance for the subsequent choice of appropriate therapy. The diagnosis of humoral rejection is based on the simultaneous detection of C4d deposits in the peritubular capillaries of the transplanted kidney and the finding of antibodies specific to the mismatched antigens of the donor (donor specific antibodies, DSA). The aim of our retrospective study was to contribute to improvement of the diagnosis of acute and...
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HLA neshody u pacientů po opakované transplantaci ledviny a incidence akutní buněčné a protilátkami zprostředkované rejekce.
Karasová, Alexandra ; Slavčev, Antonij (advisor) ; Ambrůzová, Zuzana (referee)
Kidney transplantation is the most appropriate treatment for end-stage kidney failure. The risk of graft failure in retransplanted patients is generally higher than in first-transplant patients due to immunological and non-immunological reasons. An important risk factor to consider for retransplant patients is their sensitization, i.e. the presence of antibodies directed to HLA antigens of previous donor(s). For that reason, a project called Forbidden (Non-acceptable) Antigens was launched by IKEM with the aim of reducing the incidence of acute cellular and antibody-mediated rejection in retransplant patients. Work on the project was carried out between the years 2011-2013. Forbidden antigens were defined as mismatched HLA antigens of previous kidney donor(s) against which patients waiting for retransplantation produced antibodies. The aim of this diploma thesis is to evaluate whether the incidence of rejection is lower in patients with forbidden HLA antigens in comparison with a control cohort, where no forbidden antigens are defined. 234 patients (162 males and 72 females) were included in the study. Almost all tested patients were producing HLA antibodies (90.2%) and forbidden antigens were determined in 71.4% of patients. In a control group of 267 patients waiting for their first transplantation, the...
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Epigenetic regulation of HLA class II genes in relation to senescence of organism
Říhová, Adéla ; Kotrbová - Kozak, Anna Katarzyna (advisor) ; Slavčev, Antonij (referee)
Introduction: Glycoproteins of the major histocompatibility complex (MHC) are an irreplaceable part of immune response regulation and immune homeostasis maintenance. The regulation of the expression plays an important role in adaptive immune response. Recently, DNA methylation in regulatory areas, crucial for DNA availability to transcription factors, is one of the most researched mechanisms of this type of regulation. The DNA methylation is, among others, related to the aging processes. Increased predisposition age-related immunosenescence in higher age could result from the changes in methylation status of regulatory areas of MHC class II genes. Aims: The aim of this thesis is to analyze the methylation status of regulatory areas of DQB1 gene and to compare the differences between generations and specific alleles. The differences in the levels of DQB1 gene mRNA transcription between generations and specific alleles is also compared. Methods: Both DNA and RNA were isolated from blood samples obtained from donors of three different age groups. DNA was genotypized and modified by bisulfite conversion. The regulatory areas of DQB1 genes were then amplified and subcloned into bacteria. The positive clones were selected and subjected to DNA methylation analysis. RNA was reverse transcribed into cDNA...
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Laboratory Diagnostics and HLA Typization of Patients with Rheumatoid Artritis.
Škoda, Marek ; Půtová, Ivana (advisor) ; Slavčev, Antonij (referee)
This work studies the relationship between DRB1 alleles and production of clinically most important autoantibodies in patients with rheumatoid arthritis (RA). A group of 81 patients with RA were diagnosed in immunological laboratory and genotyped. The prevalence of most often tested analytes were determined: antinuclear antibodies (ANA), rheumatoid factor (RF), anti-CCP antibodies and anti-MCV antibodies. HLA-DRB1 alleles were detected using PCR-SSP low resolution. The aim of this study was to determine the frequency of DRB1 alleles in Czech patients and to investigate the relationship between DRB1 alleles and production of particular antibodies. The frequency of HLA-DRB1*01 and HLA-DRB1*04 alleles was significantly increased in RA patients compared to healthy subjects. In contrast, the frequency of DRB1*15 allele was significantly reduced. Studying the relationship between DRB1 alleles and presence of antibodies showed a significantly increased frequency of DRB1*04 allele in patients with positive ACPA antibodies (anti-CCP, anti-MCV). Regarding other antibodies (ANA, RF), no relationship between their production and presence of DRB1 alleles was found. Comparison of anti-CCP and anti-MCV antibodies levels between groups of RA patients with the presence and absence of DRB1*04 alleles showed no difference....
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Immunopathological and immunogenetic aspects of haematopietic stem cell and solid organ transplantations
Jindra, Pavel ; Boudová, Ludmila (advisor) ; Fakan, František (referee) ; Slavčev, Antonij (referee)
The genetic diversity of KIR genes and genotypes resembles of the HLA. Although the genes encoding KIR and HLA are located in different chromosomes and segregate independently, there is some evidence of some kind of co-evolution. Therefore, one could expect reduced KIR diversity within the HLA restricted population. A total of 41 unrelated individuals homozygous for ancestral HLA haplotype AH8.1 (HLA-A*0101-Cw*0701-B*0801- DRB1*0301-DQB1*0201), were typed for KIR genes. Over all, fourteen different genotypes were identified. The observed frequencies of KIR genes and genotypes composition generally mirror the published frequencies in Caucasians. Non-framework genes with frequency of more than 90 % included KIR2DL1, KIR2DL3, KIR3DL1, KIR2DS4 and KIR2DP1. Except for the KIR2DS4, all activating genes presented frequencies bellow 50 %. KIR2DS5 was the least frequent among activating genes (17 %), whereas KIR2DL5 (37 %) among inhibitory ones. The most frequent (39 %) was AA genotype. 22 individuals (54 %) had a copy of KIR haplotype A and B (AB genotype), whereas 3 (7%) were homozygous for B (BB genotype). Nine of 14 reported genotypes occurred only in one individual. Comparing with published and recorded genotypes (www.allelefrequencies.net), 5 genotypes were reported in less than 20 individuals worldwide and...
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