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1
Abalos, Andrew T. « KILLER-CELL IMMUNOGLOBULIN-LIKE RECEPTORS AND HPV PREVALENCE AND INCIDENCE ». Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/145440.
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Introduction: Human papillomavirus (HPV) is the most commonly occurring sexually transmitted infection and is a necessary cause of cervical cancer. The progression from HPV infection to cervical cancer is incompletely understood. Innate immune response to HPV infection has recently been identified as a potential cofactor in this progression. This study examined potential association(s) between killer cell immunoglobulin-like receptors (KIR) and HPV infection. HPV concordance was estimated among heterosexual couples demonstrating the complexity of HPV infection.Methods: HPV concordance was cross-sectionally estimated in 29 heterosexual couples. A polymerase chain reaction based assay for KIR genotyping was developed and validated. 283 women from the Young Women's Health Study and 259 men from the HPV Infection in Men: A Prospective Cohort Study had HPV infection data and samples available for KIR genotyping. Associations between KIR genotype and haplotype with HPV prevalence, incidence and clearance were assessed.Results: Among 29 couples, prevalence for any HPV type was comparable between women 86.2% and men, 75.9%. Partial concordance was observed in 66% of the couples. Forty-one percent (41%) of couples had perfect concordance. A high degree of concordance was observed, however HPV type distributions differed in men and women. In women from the YWHS, KIR2DS5 was significantly associated with oncogenic HPV prevalence (Odds ratio [OR]: 0.56, 95% Confidence Interval [CI]: 0.31-0.99). Any HPV incidence was significantly associated with KIR2DL2 (Hazards Ratio [HR]: 2.11, 95% CI: 1.0-4.44), KIR2DS2 (HR: 2.44, 95% CI: 1.13-5.24), KIR2DS3 (HR: 2.36, 95% CI: 1.16-4.81), and KIR haplotype B (HR: 2.48, 95% CI: 1.02-6.02). Women lacking KIR2DS5 had an increased risk of any HPV acquisition in the presence of KIR2DL2 (HR: 2.95, 95% CI: 1.28-6.86), KIR2DS2 (HR: 3.33, 1.39-7.99), or KIR2DS3 (2.77, 95% CI: 1.24-6.19). In Men, KIR2DS3 was significantly associated with increased probability of any HPV clearance (HR: 1.91, 95% CI: 1.04-3.49).Conclusions: This research contributes to our understanding of HPV infection dynamics through the assessment HPV type concordance in sexual partners. Additionally, through the development of an assay for KIR genotyping, we were able to identify associations with KIR gene positivity and HPV prevalence, incidence, and clearance in men and women.
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Foley, Bree Amanda. « The immunogenetics of natural killer cell alloreactivity ». University of Western Australia. School of Pathology and Laboratory Medicine, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0242.
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[Truncated abstract] Natural killer (NK) cell alloreactivity can be exploited in haploidentical haematopoietic stem cell transplantation (HSCT) to improve graft survival, reduce graft versus host disease and decrease leukaemic relapse. NK cells lyse cells that have reduced expression of class I HLA molecules. In an allogeneic setting, donor NK cells may be activated by the absence of donor (self) class I HLA molecules on recipient cells; the absence of self-epitopes being detected by inhibitory KIR receptors on donor NK cells. The way in which genetic polymorphism of the receptors and ligands affects NK allorecognition of missing self, has not been fully elucidated. HLA-C molecules are divided into two groups, C1 and C2, with KIR2DL1 recognising cells expressing C2 and KIR2DL2 and KIR2DL3 recognising cells expressing C1. Donor NK cells expressing KIR2DL2 or KIR2DL3 can be alloreactive towards a recipient if they lack the C1 epitope and donor NK cells expressing KIR2DL1 can be alloreactive towards a recipient if they lack the C2 epitope. KIR3DL1 recognises the Bw4 epitope present on one-third of HLA-B alleles and certain HLA-A alleles. NK cells from donors expressing KIR3DL1 can be alloreactive towards recipients whose cells lack Bw4. Mismatches of KIR related HLA epitopes does not always results in NK alloreactivity. Therefore it is not possible to reliably predict NK alloreactivity based solely on the donor's HLA type and KIR repertoire and the recipient's HLA type. ... All Bw4-positive HLA-B alleles, with the exception of HLA-B*1301 and B*1302, protected targets from lysis. HLA-A*2402 and HLA-A*3201 unequivocally protected target cells from lysis whereas HLA-A*2501 and HLA-A*2301 provided only weak protection from lysis. KIR3DL1-dependent alloreactive NK clones were identified in donors whose only Bw4 positive allele was HLA-A*2402 but not in donors whose only Bw4 positive HLA allele was HLA-B*1301 or B*1302. Finally this thesis demonstrated that an activating KIR can control NK cell alloreactivity. Donors who are C2 negative and KIR2DS1 positive had NK cells that expressed the activating receptor KIR2DS1 and were capable of lysing cells expressing the C2 epitope. More so, KIR2DS1 dependent NK clones were shown to override inhibitory signals generated by NKG2A interacting with its ligand, HLA-E. The identification of these NK clones has important implications for haploidentical HSCT in that recipient expressing all three NK epitopes, C1, C2 and Bw4 were previously thought to be resistant to alloreactive NK cells controlled by inhibitory receptors. Such patients may be amenable to haploidentical HSCT from C2 negative, KIR2DS1 positive donors. These results will improve the ability to predict NK cell alloreactivity based on a donor's HLA type and KIR repertoire and the recipient?s HLA type.
3
Guha, Pokhraj. « Study of the genetic diversity of killer cell immunoglobulin live receptors (KIRs) in some human populations of sub-himalayan region ». Thesis, University of North Bengal, 2017. http://ir.nbu.ac.in/handle/123456789/2586.
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Moesta, Achim Klaus. « Functional specificities of killer cell immunoglobulin-like receptors for MHC-C in humans and chimpanzees / ». May be available electronically:, 2008. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Older, Aguilar Anastazia Magdalena. « Comparison of genomic structure and MHC specificities of killer cell immunoglobulin-like receptors in humans and orangutans / ». May be available electronically:, 2009. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Suck, Garnet, Yeh Ching Linn et Torsten Tonn. « Natural Killer Cells for Therapy of Leukemia ». Karger, 2016. https://tud.qucosa.de/id/qucosa%3A71644.
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Clinical application of natural killer (NK) cells against leukemia is an area of intense investigation. In human leukocyte antigen-mismatched allogeneic hematopoietic stem cell transplantations (HSCT), alloreactive NK cells exert powerful anti-leukemic activity in preventing relapse in the absence of graft-versus-host disease, particularly in acute myeloid leukemia patients. Adoptive transfer of donor NK cells post-HSCT or in non-transplant scenarios may be superior to the currently widely used unmanipulated donor lymphocyte infusion. This concept could be further improved through transfusion of activated NK cells. Significant progress has been made in good manufacturing practice (GMP)-compliant large-scale production of stimulated effectors. However, inherent limitations remain. These include differing yields and compositions of the end-product due to donor variability and inefficient means for cryopreservation. Moreover, the impact of the various novel activation strategies on NK cell biology and in vivo behavior are barely understood. In contrast, reproduction of the thirdparty NK-92 drug from a cryostored GMP-compliant master cell bank is straightforward and efficient. Safety for the application of this highly cytotoxic cell line was demonstrated in first clinical trials. This novel ‘off-theshelf’ product could become a treatment option for a broad patient population. For specific tumor targeting chimeric-antigen-receptor-engineered NK-92 cells have been designed.
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Kruse, Philip Hermann Verfasser], Lutz [Akademischer Betreuer] Walter, Jürgen [Akademischer Betreuer] [Wienands et Wolfgang [Akademischer Betreuer] Engel. « Genetic and functional characterisation of killer cell immunoglobulin like receptors (KIR) of rhesus macaques (Macaca mulatta) / Philip Hermann Kruse. Gutachter : Lutz Walter ; Jürgen Wienands ; Wolfgang Engel. Betreuer : Lutz Walter ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2011. http://d-nb.info/1042640025/34.
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Jiang, Wei. « Killer-cell immunoglobulin-like receptor gene copy number, haplotypes and disease association ». Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607691.
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Sepulveda, Christian Alberto Garcia. « Killer cell Immunoglobulin-like Receptor (KIR) polymorphism : functional implications and clinical relevance ». Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444690/.
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NK cell function is regulated by Killer-cell Immunoglobulin-like Receptors (KIR) some of which recognise class I Major Histocompatibility Complex molecules. KIRs have been shown to exhibit a high degree of functional diversity which is generated at several levels. However, the functional relevance of this diversity remains largely unknown. This thesis describes our approach towards elucidating the functional relevance of KIR diversity. To study this we first compiled all known KIR sequences into a database. We developed bioinformatics tools to facilitate the study of these sequences and have made both the tools and database publicly accessible online. Subsequent efforts were directed towards investigating the structural impact of KIR polymorphism by means of molecular modelling software. The results that were generated by this approach have provided information with regards to the ligand binding properties of most activating KIR proteins. In addition, we have also developed a KIR gene typing system capable of detecting all known KIR genes as well as the alleles of five of the KIR proteins for which a ligand has been described. We have implemented this KIR typing system to three different sample panels: a reference panel of more than 100 B-lymphoblastoid cell lines (BLCL), a family based KIR haplotype segregation study and a cohort of 141 unrelated donor (UD) haematopoietic stem cell transplant pairs. Our investigations have allowed us to generate the largest KIR typing reference panel, to characterise the KIR profile of a Mexican Mestizo population and to investigate the clinical relevance of KIRs in UD-Haematopoietic Stem Cell Transplantation (HSCT). Our results demonstrate that the beneficial effect of NK alloreactivity in the Graft-versus-Host direction as predicted by Ruggeri's algorithm cannot be applied to the UD-HSCT setting. In addition, I describe our findings relating to the clinical role of KIR genes and alleles in the UD-HSCT cohort.
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Maxwell, L. D. « Investigation of the genetics and expression of killer cell immunoglobulin-like receptor genes ». Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426759.
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McGeough, Cathy. « The evaluation of killer cell immunoglobulin-like receptor gene expression profiles in rheumatoid arthritis ». Thesis, University of Ulster, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494371.
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Takei, Yusuke. « Killer cell immunoglobulin-like receptor 2DL4 is expressed in and suppresses the cell growth of Langerhans cell histiocytosis ». Kyoto University, 2018. http://hdl.handle.net/2433/232094.
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Davidson, Judith Anne. « The influence of killer immunoglobulin-like receptor gene matching in haemopoietic stem cell transplant outcome ». Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498812.
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The aim of this study was to investigate the influence of Killer Immunoglobulin-like Receptor (KIR) gene matching and the relative importance of these genes when identifying potential donors for Haemopoietic Stem Cell Transplantation (HSCT) so that selection may be prioritised where a choice of donors exists. HSCT is used to treat not only haematological malignancies such as leukaemia and lymphoma but also certain solid organ tumours and a small number of immunological disorders.
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Gabriel, Ian. « The role of the killer immunoglobulin-like receptor in haematological malignancies and stem cell transplantation ». Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/24660.
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Natural killer cells (NK) cells are marrow-derived cytotoxic lymphocytes, representing 5-18% of human blood mononuclear cells. NK cells are an important component of the innate immune system in humans playing important roles in both the elimination and control of tumour metastases and leukaemia. NK activity against target cells is determined, by the net balance of the transmitted intracellular signals from both activating (pro-cytotoxic) and inhibitory (anti-cytotoxicity) cell surface receptors. One major class of such receptor is the Killer immunoglobulin-like receptors (KIRs), which were investigated in detail in this study. Using KIR genotype and HLA typing, I found that the KIR2DS1 positive genotype was an independent predictor for failure to achieve complete cytogenetic response (CCyR) and for inferior progression-free survival (PFS) in patients with chronic myeloid leukaemia in first chronic phase disease (CML-CP) treated with tyrosine kinase inhibitors. This was validated in a further 174 CML-CP patients and demonstrated therefore that KIR-HLA immunogenetics is a novel prognostic tool for patients with CML in CP. Following this finding, I hypothesised that as KIR-HLA genotype can predict for outcome in haematological malignancy, then their influence might be greatest at a time of relative NK cell predominance, such as in the immediate post transplant setting. I therefore went on to investigate and demonstrate in the malignancy multiple myeloma (MM), that KIR3DS1 positivity may identify patients at greater risk of progression after an autologous stem cell transplant, and further that there was a significant association of the KIR2DS2/DL2 genotype with acute graft-versus host disease (aGVHD) following allogeneic stem cell transplant. I finally demonstrate that the association of KIR2DS2/DL2 with GvHD is likely due to the demonstration that KIR2DS2/DL2 expressing cells have a significantly greater capacity for the production of IFN-gamma and TNF-alpha, which are directly associated with aGvHD with a relative reduction in IL-2 production which is important for regulatory T-cell development. In conclusion my data show that KIR genotype predicts both the response to targeted therapy in CML, that the role of KIR is also important in disease control during haematopoeitic reconstitution following transplant and that certain KIR molecules associate with increased incidence and severity of aGvHD and this may be mediated by the increased propensity to produce TNF-α, IFN-γ, MIP1-alpha, and MIP1-beta and a reduction in IL-2.
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Chagoury, Odette Louise. « The pattern and functional consequence of Killer Immunoglobulin-like Receptor expression on T cells ». Thesis, University of Birmingham, 2009. http://etheses.bham.ac.uk//id/eprint/398/.
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Killer immunoglobulin-like receptors (KIRs) are a family of proteins expressed on human natural killer cells and a subset of T cells. Several inhibitory KIRs have been shown to recognise MHC class I molecules (predominantly HLA-C), with their engagement preventing target cell lysis. The ligand(s) and function(s) of activating KIRs, however, are less well characterised. Genetic studies of the association of KIRs with disease have identified an association with viral infections and autoimmune disease and this implicates that these proteins are important in human health. This thesis was concerned with an investigation of the factors that determine KIR expression on lymphocytes, and how this might influence the cellular functional response. In my initial work I produced soluble recombinant forms of activating and inhibitory KIRs and studied the biophysical interaction of these proteins with HLA-C molecules. I saw some evidence that KIR2DS2 binds to the HLA-C group 1 allele HLA-Cw*0702, supporting the idea that HLA-C alleles are a true ligand for stimulatory KIRs. I then went on to make a detailed 11 colour flow cytometric analysis of the expression of KIR proteins in healthy individuals. I was able to show that total, and individual, KIR protein expression was correlated and defined a pattern of dominance on lymphoid subsets. I then went on to study the distribution of KIR expression on discrete memory T cell subsets and showed that they were found predominantly on late differentiating CD45RA+ T cells. Interestingly there was also considerable expression on central memory CD8+ T cells although the biological basis for this is unclear. I demonstrated that age and CMV infection have a marked effect on KIR expression and I speculate on the reason for this. Finally I studied KIR expression on CMV-specific T cell clones in order to undertake a functional analysis of the consequence of KIR expression. I observed that KIR expression increased when cells were cultured in vitro but I could not detect any difference in cytokine production or cytotoxicity between KIR+ and KIR- cells. My work has contributed to the literature on KIR biology in relation to lymphoid cells and will have direct relevance to a number of clinical studies.
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Silva, Pamela Portela da. « Análise de polimorfismos dos genes KIR e HLA classe I em pacientes com câncer colorretal ». reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/148088.
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O câncer colorretal (CCR) pode ocorrer em qualquer parte do cólon ou do reto e representa o terceiro câncer mais comum no mundo em ambos os sexos. As células Natural Killer (NK) fazem parte do sistema imune inato reconhecendo moléculas de HLA de classe I em células alvo, através de seus receptores de membrana killer cell immunoglobulin-like receptors (KIR). O objetivo deste estudo foi avaliar a associação entre os genes KIR e os ligantes HLA em pacientes com câncer colorretal e controles saudáveis. Examinamos o polimorfismo de 16 genes KIR e seus ligantes HLA em 154 pacientes caucasóides com CCR e 216 controles saudáveis pela técnica de PCR-SSO e PCR-SSP. Quando comparamos os dois grupos, não foram encontradas diferenças significativas para os ligantes HLA e os genes KIR após correção de Bonferroni. Entretanto, o grupo de genótipos Bx (heterozigoto e homozigoto para o haplótipo B) foi mais frequente nos controles, quando comparados com os pacientes. Estes achados sugerem que altos níveis de ativação de sinais KIR aparecem como proteção para o câncer colorretal.Colorectal cancer (CRC) can occur anywhere in the colon or rectum and represents the third most common cancer in the world in both sexes. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA ligands in patients with colorectal cancer and healthy controls. We examined the polymorphism of 16 KIR genes and their HLA ligands in 154 caucasoid CRC patients and 216 healthy controls by PCR-SSO and PCR-SSP. When both groups were compared, no significant differences were found for HLA ligands and KIR genes after Bonferroni correction. However, the Bx group genotypes (heterozygous and homozygous for the haplotype B) were more frequent in controls, when compared with patients. These findings suggest that individuals with Bx genotypes could have some protection to colorectal cancer. These findings suggest that higher levels of activating KIR signals appear as protective to colorectal cancer.
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Silva, Pamela Portela da. « Estudo de polimorfismos dos genes KIR e HLA em pacientes com câncer de próstata ». reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/35890.
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O câncer de próstata é o segundo câncer mais comum entre homens, uma vez que tanto a incidência como a mortalidade aumentam exponencialmente após a idade de 50 anos. As células Natural Killer (NK) fazem parte do sistema imune inato e reconhecem moléculas de HLA de classe I na célula alvo, através de seus receptores de membrana, chamados killer immunoglobulin-like-receptors (KIR). O objetivo desse estudo foi avaliar a associação entre os genes KIR e HLA em pacientes com câncer de próstata e grupo controle. Genotipamos 200 pacientes com diagnóstico de câncer de próstata e 185 pacientes saudáveis para os genes KIR e HLA classe I por PCR-SSP. Quando comparados os grupos, não foram encontradas diferenças significativas para HLA-C do grupo 1 e do grupo 2, HLA-Bw4, HLA-A3 e A11. Nenhuma diferença foi observada na frequência dos genes KIR nos pacientes com câncer de próstata e nos controles. Esses resultados sugerem que não há potencial papel para o sistema dos genes KIR no câncer de próstata.Prostate cancer is the second most common cancer among men, since both incidence and mortality exponentially increases in men over fifty years of age. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA alleles in patients with prostate cancer and healthy controls. Two hundred prostate cancer patients and 185 healthy controls were typed for HLA class I and KIR genes by PCR-SSP. When both groups were compared, no significant differences were found for HLA-C group 1 and group 2, HLA-Bw4, HLA-A3 and A11. No difference was seen either in KIR frequency between patients with prostate cancer and controls. In conclusion, our data suggests no potential role for the KIR gene system in prostate cancer.
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Salim, Patrícia Hartstein. « Estudo do polimorfismo dos genes KIR na esclerose sistêmica ». reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2009. http://hdl.handle.net/10183/15457.
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As células Natural Killer (NK) fazem parte da resposta imune inata, sendo a primeira linha de defesa do organismo contra vírus, bactérias, tumores e microorganismos. Estas células induzem a morte da célula-alvo quando não há o reconhecimento das moléculas de antígenos leucocitários humanos (HLA) de classe I, através de seus receptores, chamados Killer cell Immunoglobulin-like Receptor (KIR). Vários estudos demonstram o envolvimento dos genes KIR na patogênese das doenças auto-imunes. Acredita-se que combinações desses genes possam ser favoráveis para o desenvolvimento da esclerose sistêmica (ES). Portanto, o conhecimento destes genes relacionados às células NK poderiam ser úteis para o entendimento da patogênese da ES. O objetivo deste estudo é investigar o polimorfismo dos genes KIR em um grupo de pacientes com ES, incluindo a forma difusa e limitada da doença. A freqüência do receptor inibidor KIR2DL2 foi significantemente menor nos pacientes comparada com a do grupo controle (28,7% versus 65,2%; P<0,001; OR=0,21; IC95% 0,11–0,38). Quando analisamos a combinação do receptor inibidor 2DL2, com a presença do ativador 2DS2 (KI2DS2+/KIR2DL2-), encontramos uma maior freqüência nos pacientes (26,1% versus 1,7%; P<0,001; OR=19,94; IC95% 4,7–175,1). Por outro lado, a presença de ambos KIR2DL2 e KIR2DS2 foi mais freqüente no grupo controle (26,9% versus 57,3%; P<0,001; OR=0,27; 95%CI 0,1–0,4). Nenhuma diferença estatística no polimorfismo dos genes KIR foi encontrada entre a forma difusa e a forma limitada. A combinação KIR2DS2+/KIR2DL2– parece ser um fator de risco para o desenvolvimento da ES enquanto a alta freqüência do gene inibidor KIR2DL2 no grupo controle parece ter uma função protetora. Estes resultados indicam um potencial papel dos genes KIR na patogênese da ES.Natural killer (NK) cells have an important role in the early responses to viral infections. They kill diverse target cells with decreased or absent expression of major histocompatibility complex (MHC) class I molecules through the Killer Cell Immunoglobulin-Like Receptors (KIR). Many studies have reported association of KIR genes with autoimmune diseases. The objective of this study is to investigate possible associations of KIR polymorphisms with systemic sclerosis (SSc), including the limited (lSSc) and diffuse (dSSc) forms of the disease. The frequency of inhibitory KIR2DL2 was significantly decreased among patients with SSc compared with healthy controls (28.7% versus 65.2; P<0.001, odds ratio [OR] 0.21, 95% confidence interval [95% CI] 0.11–0.38). When activatory and inhibitory KIR genes were analyzed in combination, the concomitant presence of KIR2DS2 and absence of KIR2DL2 (KI2DS2+/KIR2DL2-) phenotype was more frequent in SSc patients than in the control group (26.08% versus 1.75%; P<0.001, OR=19.94, 95%CI [4.78–175.10]). On the other hand, the presence of both KIR2DS2 and KIR2DL2 was more frequent in the control group (26.96% versus 57.39%; P=0.000005, OR=0.27, 95%CI [0.15–0.49]). No significant difference in KIR genes polymorphisms was found between lSSc and dSSc disease subsets. The combination of KIR2DS2+/KIR2DL2– may be a risk factor for development of SSc while the higher frequency of the inhibitory KIR2DL2 gene in the control group suggest to a protective effect. These results indicate a potential role of KIR genes in the SSc pathogenesis.
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Ichise, Hiroshi. « NK cell alloreactivity against KIR-ligand-mismatched HLA-haploidentical tissue derived from HLA haplotype-homozygous iPSCs ». Kyoto University, 2017. http://hdl.handle.net/2433/228232.
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Ishida, Yoshihiro. « Killer immunoglobulin-like receptor genotype did not correlate with response to anti-PD-1 antibody treatment in a Japanese cohort ». Kyoto University, 2020. http://hdl.handle.net/2433/253207.
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Jobim, Maria Regina Sampaio Leite. « Estudo do polimorfismo dos genes KIR e HLA em pacientes com câncer de mama e grupo controle ». reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/97026.
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O presente estudo tem como objetivo investigar a frequência dos diversos polimorfismos dos genes KIR (Killer Immunoglobulin-like Receptors) e HLA C1 e C2 em um grupo de pacientes com câncer de mama e comparar com um grupo controle de indivíduos sadios. As células natural killer (NK) são linfócitos que diferem das células T e B e que fazem parte da imunidade natural, reconhecendo as moléculas HLA (Antígenos Leucocitários Humano) de classe I em células infectadas por vírus ou em células tumorais, através de seus receptores de membrana. Os principais receptores das células NK são conhecidos como receptores KIR, sendo codificados por genes localizados no cromossomo 19q13.4 e classificados em grupos funcionais supressores e ativadores. Neste estudo, analisamos 15 genes KIR e alelos do sistema HLA de classe I em 230 pacientes caucasóides e em 278 controles, usando a técnica de PCR com primers específicos (PCR-SSO e PCR-SSP). Nossos resultados demonstraram uma frequência maior do genótipo supressor 2DL2 (P<0,001) em pacientes com câncer de mama, quando comparados ao grupo controle. Os genes HLA-C2 e HLA-BW4 não apresentaram diferenças significantes entre os grupos. Contudo, o gene HLA-C1 foi observado em maior frequência nos pacientes com câncer de mama. Considerando que estes achados sugerem uma potencial associação entre o sistema de genes KIR, HLA classe I e o câncer de mama, estudos adicionais sobre este tema são necessários.We investigated the frequency of various KIR (Killer Immunoglobulin-like Receptors) and HLA C1 and C2 gene polymorphisms in a group of patients with breast cancer and healthy controls. Natural Killer (NK) cells are lymphocytes that differ from T and B cells and are part of the innate immune system, recognizing class I Human Leukocyte Antigens (HLA) molecules on target cells (virus-infected as well as cancer cells), through specific cell surface receptors. KIR comprises the main class of NK receptors, being encoded by genes located in chromosome 19q13.4. They possess both suppressor and activating functional groups. Fifteen KIR genes and class I HLA alleles obtained from 230 Caucasians patients, as well as 278 controls were studied, using PCR techniques with specific primers (PCR-SSO and PCR-SSP). Our results showed a higher frequency of suppressor genotype 2DL2 (P<0,001) in patients with breast cancer as compared to controls. No significant difference between HLA-C2 and HLA-BW4 alleles were observed between the study groups. Notably, a higher frequency of HLA-C1 gene was noted in patients with breast cancer. Our results suggest a potential association between KIR genes, HLA class I and breast cancer, deserving further investigation.
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Hansi, Navjyot Kaur. « Role of the inhibitory receptor LAIR-1 on NK cells in chronic hepatitis B ». Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/43992.
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There are multiple immune mechanisms identified for persistence of hepatitis B virus (HBV) infection. This thesis considers the vital role that inhibitory receptors play in contributing to impairment of the adaptive immune system in chronic hepatitis B (CHB), and the potential role they play in the innate immune system, focusing on the inhibitory receptor leucocyte-associated immunoglobulin-like receptor (LAIR)-1. The unique aspect of this work is that for the first time LAIR-1 expression has been investigated on natural killer (NK) cells in CHB. Our striking findings of increased LAIR-1 expression on peripheral NK cells in CHB and an inverse correlation between expression and effector function suggest this inhibitory receptor could have a potential role in exhaustion of NK cells in CHB. We therefore additionally explored the expression of LAIR-1 on circulating NK cells from patients with hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease (NAFLD). The particular relevance of LAIR-1 to liver disease is that one of its major ligands is collagen. We demonstrated a downregulation of LAIR-1 expression on intrahepatic NK cells, which we postulate might occur following repetitive engagement with abundant collagen within the liver. In line with this, intrahepatic NK cells with a liver-resident (CXCR6+) phenotype had even lower LAIR-1 expression than liver infiltrating (non-resident, CXCR6-) NK cells. Furthermore, preliminary experiments display attenuation of the cytotoxic degranulation capacity (CD107a) by circulating NK cells from CHB patients upon exposure to plate-bound collagen. We demonstrate differential expression of LAIR-1 on NK cells in viral hepatitis, HCC and NAFLD and between peripheral and intrahepatic NK cells. Preliminary experiments demonstrate a role in inhibiting NK cell function suggesting this as a novel therapeutic target to harness the capacity of NK cells to control chronic infection and cancer.
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Pesce, John Thomas. « Early events leading to the host protective Th2 immune response to an intestinal nematode parasite / ». Download the dissertation in PDF, 2005. http://www.lrc.usuhs.mil/dissertations/pdf/Pesce2005.pdf.
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Martin, Hilmar. « Evaluation von KIR-Liganden Inkompatibilität bei unverwandten Knochenmark-/ Stammzelltransplantationen ». Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2005. http://nbn-resolving.de/urn:nbn:de:swb:14-1124306558415-94790.
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We performed a retrospective study in 185 patients with myelogenous leukemias who had received hematopoietic cells from unrelated donors. The aim of this study was to answer the question wether the benefit of KIR ligand incompatibility seen in haploidentical tranplantations can also be seen using unrelated donors. We could not detect a significant difference in survival between patients with a KIR ligand incompatibility and those with either fully matched or partially mismatched unrelated donors in this patient cohortIn der Therapie von Leukämien ist die Knochenmark- bzw. Stammzelltransplantation eine tragende Säule. Für den Transplantationserfolg ist eine Übereinstimmung der Haupthistokompatibilitätsantige (HLA-Antigene der Klassen I und II) zwischen Spender und Empfänger von zentraler Bedeutung. Diese Notwendigkeit ergibt sich aus der sogenannten MHC-Restriktion in der T-Zellrezeptorerkennung. Ob auch NK-Zellrezeptoren und deren Liganden in der Spenderauswahl berücksichtigt werden sollten, ist bisher unzureichend untersucht. Insbesondere trifft das für die KIR-Rezeptoren zu, die wie die T-Zellrezeptoren ebenfalls HLA-Antigene als Liganden besitzen. Velardi et al. haben 2002 erstmalig gezeigt, daß in der Therapie myeloischer Leukämien die Transplantation von Blutstammzellen verwandter Spender mit KIR-Liganden-Inkompatibilität von klinischem Vorteil ist. Ob KIR-Liganden-Inkompatibilität auch bei Knochenmark-/ Stammzelltransplantationen Unverwandter Bedeutung erlangen könnte, war zu Studienbeginn offen und blieb auch infolge diskrepanter Untersuchungsergebnisse von verschiedenen Arbeitsgruppen im Verlauf der Studie widersprüchlich. Im Rahmen dieser Arbeit wurde diese Fragestellung, die auch Teil einer internationalen Studie war, an 185 Spender-Empfänger-Paaren retrospektiv untersucht. Dabei wurde bei den Paaren einerseits die KIR-Liganden-Kompatibilität auf der Grundlage der HLA-C-Supertypen erschlossen (nach Velardi et al.). Andererseits konnte sie im internationalen Studienprogramm direkt aus dem KIR-Genotyp des Spenders und dem HLA-C-Supertyp des Empfängers ermittelt werden. Die Untersuchungen ergaben folgende Resultate: bei Vorliegen von KIR-Liganden-Inkompatibilität hat die Verwendung von ATG als Bestandteil der GvHD-Prophylaxe keinen Einfluß auf das klinische Ergebnis. Die Vermutungen von Giebel et al. wurden damit nicht gestützt. Die Bestimmung des KIR-Liganden-Status mit Hilfe der Rückschlußmethode allein aus dem HLA-Typ ist unzuverlässig. Für eine exakte Differenzierung ist die gleichzeitige KIR-Genotypisierung erforderlich. KIR-Liganden-Inkompatibilität ist bei unverwandten Knochenmark-/ Stammzelltransplantationen nicht von klinischem Vorteil. Auch ein gezieltes Aussuchen HLA-C-inkompatibler Spender auf der Grundlage einer KIR-Genotypisierung stellt derzeit keine therapeutische Option dar
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Schirrmann, Thomas. « Tumorspezifische Targeting der humanen natürlichen Killerzellinie YT durch Gentransfer chimärer Immunglobulin-T-Zellrezeptoren ». Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/15246.
Texte intégralRésumé :
Die spezifische adoptive Immuntherapie ist ein hoffnungsvoller Ansatz zur Behandlung von Tumoren. Die aufwendige individuelle Bereitstellung primärer Effektorlymphozyten könnte durch den Einsatz etablierter tumorantigenspezifischer Effektorzellinien vermieden werden. In dieser Arbeit wurde untersucht, ob sich ein Tumortargeting der humanen Natürlichen Killer-(NK)-Zellinie YT durch den Gentransfer chimärer Immunglobulin-T-Zellrezeptoren (cIgTCRs) erreichen läßt. Die cIgTCR-Konstrukte wurden aus single-chain-Fv-Fragmenten (scFv), dem IgG1-Fc-Teil und der CD3-Zeta-Signalkette erzeugt. Die scFv-Fragmente wurden aus den humanisierten Antikörpern BW431/26 und HuM195, die spezifisch für das karzinoembryonale Antigen (CEA) bzw. CD33 sind, konstruiert und zeigten als scFv-hFc-Fusionsproteine eine spezifische Bindung an Tumorzellen. Die YT-Zellen wurden mit den cIgTCR-Genkonstrukten über Elektroporation transfiziert und über immunologische Verfahren angereichert. In-vitro-Studien ergaben eine spezifische Lyse von CEA+ Kolonkarzinomzellinien durch die scBW431/26-hFcZeta+ YT-Zellen. Die Zytotoxizität korrelierte mit der Expression des cIgTCR-Antigens auf den Tumorzellen und wurde durch zirkulierendes CEA nicht gehemmt. Die scHuM195-hFcZeta+ YT-Zellen zeigten eine spezifische Lyse der CD33+ myeloischen Leukämiezellinie KG1. Die Bestrahlung wurde zur Wachstumsbegrenzung der YT-Zellen eingesetzt. Die spezifische Zytotoxizität der scBW431/26-hFcZeta+ YT-Zellen gegenüber CEA+ Tumorzellen war einen Tag nach Bestrahlung unverändert. Die Koinjektion von CEA+ Tumorzellen mit bestrahlten scBW431/26-hFcZeta+ YT-Zellen führte zu einer signifikanten Hemmung des Tumorwachstums in NOD/SCID-Mäusen. Die cIgTCR+ YT-Zellen zeigten in vitro eine geringe Sensibilität gegenüber allogenen Blutlymphozyten. Die Ergebnisse zeigen, daß die Zytotoxizität der NK-Zellinie YT tumorantigenspezifisch durch cIgTCR-Gentransfer erweitert wird und ein Potential zur Behandlung minimaler Tumorerkrankungen besteht.The specific adoptive immunotherapy is a promising strategy for cancer treatment. The utilization of established tumor antigen specific effector cell lines could bypass the expendable individual preparation and often limited specificity of primary effector lymphocytes. This study investigated the tumor targeting of the human Natural Killer (NK) cell line YT by gene transfer of chimeric immunoglobulin T cell receptors (cIgTCRs). The cIgTCR constructs were generated of single chain antibody fragments (scFv), the IgG1 Fc part and the CD3 Zeta chain. The scFv fragments were constructed of the humanized antibodies BW431/26 and HuM195 with specificity for the carcinoembryonic antigen (CEA) and CD33, respectively, and showed as scFv-Fc fusion proteins a specific binding to tumor cells. YT cells were transfected with the cIgTCR gene constructs by electroporation and enriched by immunological cell separation. In vitro studies revealed a specific lysis of CEA+ colon carcinoma cell lines by scBW431/26-hFcZeta+ YT cells. The cytotoxicity correlated with the expression of the cIgTCR antigen on the tumor cells and was not inhibited in the presence of soluble CEA. The scHuM195-hFcZeta+ YT cells mediated a specific lysis of the CD33+ myeloic leukemia cell line KG1. The irradiation was used to limit the growth of the YT cell line. The specific cytotoxicity of the scBW431/26-hFcZeta+ YT cells against CEA+ tumor cells was unaltered one day after irradiation. The coinjection of CEA+ tumor cells and irradiated scBW431/26-hFcZeta+ YT cells led to a significant growth inhibition in NOD/SCID mice. The cIgTCR+ YT cells showed a low susceptibility to the cytotoxicity of allogeneic blood lymphocytes in vitro. The results demonstrated that the cytotoxicity of the human NK cell line YT can be specifically extended to tumor antigens by cIgTCR gene transfer. The employment of receptor gene modified YT cells could be a useful tool for the adoptive immunotherapy of minimal tumor diseases.
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Hermes, Meike. « Characterisation of killer immunoglobulin-like receptors in rhesus macaques (Macaca mulatta) ». Doctoral thesis, 2012. http://hdl.handle.net/11858/00-1735-0000-000D-F0C1-A.
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Kruse, Philip Hermann. « Genetic and functional characterisation of killer cell immunoglobulin like receptors (KIR) of rhesus macaques (Macaca mulatta) ». Doctoral thesis, 2010. http://hdl.handle.net/11858/00-1735-0000-0006-ADED-9.
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Hardie, Rae-Anne Michelle. « Sequence-based genotyping of killer cell immunoglobulin-like receptors and their associations with HIV-1 resistance and disease progression ». 2009. http://hdl.handle.net/1993/21431.
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Albrecht, Christina. « Association of killer immunoglobulin-like receptor genes with viral loads in experimental SIV infection of rhesus macaques (Macaca mulatta) ». Doctoral thesis, 2012. http://hdl.handle.net/11858/00-1735-0000-000D-EF91-8.
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Jesus, Kátia Ribeiro de. « Immunology and genetics in nonhuman primates : Study of KIR3DL02 interaction with MHC-class-I ligands of rhesus macaques ». Master's thesis, 2018. http://hdl.handle.net/10316/82073.
Texte intégralRésumé :
Dissertação de Mestrado em Investigação Biomédica apresentada à Faculdade de MedicinaCélulas natural killer (NK) são linfócitos capazes de matar células alvo infectadas ou transformadas por vírus. A ativação da lise de células alvo pelas células NK é mediada pelos receptores presentes nestas células. Um grupo importante de receptores são os receptores tipo imunoglobulina das células killer (KIR), sabe-se que estes ligam a membros da família polimórfica de moléculas MHC-classe-I. O macaco rhesus foi considerado um modelo animal primata não-humano de grande importância para doenças infeciosas nos humanos. Durante infecção experimental com o vírus da imunodeficiência símia (SIV), foi estabelecida uma conexão entre a presença de certos KIR e alelos MHC-classe-I com maiores ou mais baixos níveis virais, e consequentemente com uma mais rápida ou mais lenta progressão da doença. Curiosamente, foi demonstrado que a expressão de KIR3DL02 está associada com níveis virais mais baixos em animais em ensaios experimentais de infecção. Contudo, as especificações da interação entre KIR3DL02 e ligandos de MHC-classe-I são desconhecidas. O objetivo do presente trabalho, foi, por um lado, estudar a interação entre KIR3DL02 e certos alelos de Mamu, através do uso de proteínas recombinantes de KIR-Fc multimerizadas para marcar células que expressam Mamu. Para além disto, de modo a expandir o espectro de futuros estudos de interação, novos alelos de Mamu foram amplificados de cDNA de macaco rhesus e clonados em vectores de expressão de mamíferos. O trabalho aqui descrito permitiu a otimização dos estudos de ligação com o uso de proteínas KIR-Fc de fusão e células K-562 transfectadas com Mamu AcGFP. Identificação de potenciais ligandos para KIR3DL02 assim como construção de novos vectores de expressão de Mamu foram conseguidos com sucesso. Contudo, é necessária a realização de mais estudos para averiguar os resultados aqui descritos e para estudar a interação entre KIR3DL02 e os novos alelos de Mamu amplificados, com especial interesse no alelo Mamu B*008 por estar associado a um efeito protetivo.
Natural killer (NK) cells are lymphocytes that are able to kill virus infected or transformed target cells. The activation of the NK cell mediated target cell lysis is achieved by the action of NK cell receptors. An important group of receptors are the killer cell Ig-like receptors (KIR), which are known to bind members of the polymorphic family of MHC-class-I molecules. The rhesus macaque has been considered of great importance as a nonhuman primate model of human infectious diseases. During experimental simian immunodeficiency virus (SIV) infection, a connection has been established between the presence of certain KIR and MHC-class-I alleles with higher or lower viral load, and consequently to faster or slower progression of the disease. Interestingly, the expression of KIR3DL02 transcripts was shown to be associated with low viral loads and elite controller animals. However, the specificity of interaction between KIR3DL02 and MHC-class-I ligands is unknown. The aim of the present work was, for one, study the interaction between KIR3DL02 and certain Mamu alleles using multimerized KIR-Fc recombinant proteins to stain Mamu expressing cells. Additionally, in order to widen the spectrum of future interaction studies, new Mamu alleles were amplified from cDNA of rhesus macaque and cloned into a mammalian expression vector. The present work allowed the optimization of binding assays using KIR-Fc fusion proteins with K-562 Mamu AcGFP transfected cells. Identification of potential KIR3DL02 ligands as well as production of new Mamu mammalian expression constructs was accomplished. However, further studies need to be conducted to verify results here described and to study interaction between KIR3DL02 and new Mamu alleles amplified. Herein, in special, the known protective Mamu B*008 allele.