Dissertations / Theses on the topic 'Killer immunoglobulin like receptors (KIR)'
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Yindom, Louis Marie. "Human Leukocyte Antigen (HLA) and Killer Immunoglobulin-like Receptors (KIR) in HIV-2 Infection." Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520671.
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Braun, Kali. "Association of killer immunoglobulin-like receptor (KIR) genes with tuberculosis disease in two Canadian cohorts." PLoS ONE, 2013. http://hdl.handle.net/1993/22042.
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In Canada, and more specifically in Canadian-born Aboriginals and foreign born populations, high incidence of tuberculosis (TB) causes significant morbidity and mortality. The presence or absence of specific killer immunoglobulin-like receptor (KIR) genes, individually or in conjunction, may be associated with tuberculosis (active, latent, or uninfected disease status) as well as ethnicity of an individual. It is hypothesized that the differences in KIR profiles, gene frequencies, and/or haplotypes in Canadian-born Aboriginal, Canadian-born non-Aboriginal, and foreign born individuals elicits a differential activation or inhibition profile, resulting in differential cytokine expression and eventually contributes to the outcome of TB infection. In this study we examined the enrichment or depletion of KIR genes in different ethnic populations in Manitoba with special focus on active, latent, and uninfected TB status. In addition, we sought to explore the statistical correlation between TB status and inhibitory/stimulatory KIR haplotypes.
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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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Halfpenny, Iris A. "An investigation into the genetics of the killer immunoglobulin-like receptor (KIR) gene family." Thesis, University of Ulster, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494359.
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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.
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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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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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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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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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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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Kruse, Philip Hermann Verfasser], Lutz [Akademischer Betreuer] Walter, Jürgen [Akademischer Betreuer] [Wienands, and 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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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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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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Twigger, Katie. "The role of killer immunoglobulin-like receptors in HTLV-1 infection." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/25539.
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Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of infected individuals, while the majority are lifelong asymptomatic carriers (ACs). The effectiveness of the CD8+ T-cell response to HTLV-1 is a major determinant of the HTLV-1 proviral load (PVL) and the associated HAM/TSP risk. Host genotype, particularly of HLA class I, strongly influences CD8+ T-cell effectiveness against HTLV-1. Furthermore, possession of the KIR gene 2DL2 was recently shown to enhance protective and detrimental HLA class I-associated immunity to HTLV-1 and HCV (Seich al Basatena et al., 2011). The proposed mechanism explaining this effect is a KIR expression-induced increase in activation thresholds, thus promoting survival. I investigated KIR expression and function on T-cells and NK cells in HTLV-1 infection, focussing on CD8+ T-cells and using new anti-KIR mAbs to analyse 2DL2 expression alongside four other KIRs. This thesis presents evidence supporting the genetic findings and the KIR expression-induced CD8+ T-cell survival hypothesis. AC status was associated with expanded 2DL2+CD8+ T EM cell populations and 2DL2+ and 2DL3+CD8+ T EM cell frequencies were inversely correlated with PVL, consistent with a protective role for 2DL2 (and potentially 2DL3) expression on CD8+ T-cells in HTLV-1 infection. Rather than a generalised reduction in CD8+ T-cell function, specific KIR expression was associated with a shift in effector function profile towards a cytotoxic phenotype without cytokine production. This is consistent with raised activation thresholds and may suggest fine-tuning of CD8+ T-cell effector functions by KIRs, preserving killing without causing inflammation. I further speculate that 2DL2/3 could be a context-dependent modulator of CD8+ T-cell function, optimally tuning responses and contributing to CD8+ T-cell effectiveness. Together with the longevity of 2DL2/3+CD8+ T-cells in vivo, this hypothesis requires further testing, since it may be relevant to other persistent viral infections.
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Speidel, Frieder. "Untersuchungen zur Expression von "Killer-immunoglobulin-like-receptors" und zytotoxischer Aktivität von cytokinstimulierten NK-Zellen /." Tübingen, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253677.
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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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Thielens, Ariane. "Etudes pré-clinique et clinique de l'anticorps immunomodulateur Lirilumab visant à augmenter la réponse anti-tumorale des cellules NK." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM4105.
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L’activité anti-tumorale des cellules NK est régulée par des récepteurs de surface activateurs et inhibiteurs qui reconnaissent des ligands exprimés par les cellules cibles. Afin d’augmenter le potentiel cytotoxique des cellules NK face à des cellules cancéreuses autologues, Innate Pharma a développé des Ac bloquant les interactions entre certains récepteurs inhibiteurs de la cellule NK, les KIRs, et leurs ligands, des molécules du CMH de classe I.Dans un premier temps, nous avons mis en place un modèle tumoral d’efficacité des Ac anti-KIR dans des souris transgéniques pour l’expression d’un KIR. Ce modèle nous a permis de démontrer l’efficacité thérapeutique anti-tumorale du blocage des interactions entre les KIRs exprimés par les cellules NK et les molécules HLA exprimées par la tumeur. Ce modèle nous a également permis de tester la combinaison de l’Ac anti-KIR avec un Ac thérapeutique utilisé dans le traitement des lymphomes B non-hodgkiniens, rituximab. Utilisé en combinaison, ces deux Ac augmentent significativement la survie de souris greffées avec une lignée tumorale d’origine B humaine par rapport à chacun des deux traitements seuls.Ces données précliniques nous amènent à proposer une stratégie thérapeutique pour le traitement de tumeurs hématologiques, basée sur la combinaison d’un Ac anti-KIR avec un Ac induisant de l’ADCC afin de potentialiser la réponse anti-tumorale des cellules NKNK cell anti-tumoral activity is regulated by inhibitory and activating receptors interacting with target cell ligands. Innate Pharma has developed anti-KIR Abs (IPH2101 and lirilumab), directed against inhibitory NK cell receptors interacting with HLA molecules, in order to increase NK cell activity against autologous tumor cells.We have set up a preclinical model to assess anti-KIR anti-tumoral efficacy in transgenic mice expressing a KIR receptor. With this model, we have also shown the therapeutic benefit of combining lirilumab with rituximab, a therapeutic Ab mediating ADCC.These results support the rationale of combining anti-KIR Ab with Ab mediating ADCC as a therapeutic strategy for hematological malignancies
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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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Sáez, Borderias Andrea. "Regulation of natural killer and cd4+T cell function by NKG2 C-type lectin-like receptors." Doctoral thesis, Universitat Pompeu Fabra, 2009. http://hdl.handle.net/10803/7133.
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This work is centered on the study of the NKG2 C-type lectin-like receptors on NK and CD4+T cells. We provide evidence supporting that CD4+T cells specific for Human Cytomegalovirus (HCMV) may express different NK cell receptors, and demonstrate that the C-type lectin-like receptor NKG2D is expressed on cytotoxic CD4+T cells with an effector/memory phenotype, enhancing their TCR-dependent proliferation and cytokine production. A second part of the work is centered on the study of the CD94/NKG2 receptors on NK cells. We show that NKG2A can be induced on NKG2C+ NK cells upon activation with rIL-12 or when cocultured with HCMV-infected dendritic cells, and that NKG2A expression inhibits the response of NKG2C+NK clones against HLA-E-expressing targets, providing a potential regulatory feedback mechanism to control cell activation. Altogether, our results support that expression of NKG2 C-type lectin like receptors may be shaped during the course of viral infections, providing mechanisms to finely regulate both NK and CD4+T cell functions.Aquesta tesi es centra en l'estudi dels receptors lectina de tipus C NKG2 en cèl·lules Natural Killer i T CD4+. Demostrem que les cèl·lules T CD4+ específiques pel Cytomegalovirus Humà poden expressar diferents receptors NK, i que el receptor lectina tipus C NKG2D s'expressa en cèl·lules citotòxiques i de memòria, potenciant la proliferació i secreció de citocines depenent del TCR. La segona part d'aquesta tesi es centra en l'estudi de l'expressió dels receptors CD94/NKG2 en cèl·lules NK. Mostrem com l'expressió de CD94/NKG2A s'indueix en cèl·lules CD94/NKG2C+ estimulades amb IL-12 o cultivades amb cèl·lules dendrítiques infectades pel Cytomegalovirus Humà, i que l'expressió de CD94/NKG2A inhibeix la resposta de clons NK CD94/NKG2C+ envers dianes HLA-E+, constituint un possible mecanisme de feedback negatiu per controlar l'activació cel·lular. En resum, els nostres resultats demostren que l'expressió dels receptors lectina tipus C NKG2 pot ser modificada durant les infeccions víriques consitutint un possible mecanisme per regular la resposta tant de cèl·lules NK com T CD4+.
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Hermes, Meike [Verfasser], Lutz [Akademischer Betreuer] Walter, and Torben [Akademischer Betreuer] Lübke. "Characterisation of killer immunoglobulin-like receptors in rhesus macaques (Macaca mulatta) / Meike Hermes. Gutachter: Lutz Walter ; Torben Lübke. Betreuer: Lutz Walter." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2012. http://d-nb.info/1042345627/34.
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Suck, Garnet, Yeh Ching Linn, and 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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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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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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Gentle, Nikki Lynne. "The role of killer immunoglobulin-like receptors (KIR) and specific human leukocyte antigen (HLA) class I molecules in control of HIV-1 infection." Thesis, 2015. http://hdl.handle.net/10539/18671.
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A thesis submitted to the Faculty of Health Sciences, University of the
Witwatersrand, in fulfilment of the requirements for the degree of Doctor
of Philosophy
Johannesburg 2015The classical human leukocyte antigen (HLA) class I molecules are important regulators of both the adaptive and innate immune responses to viral infection. Genetic variability within these loci determines the nature of the interaction between both the T cell receptor (TCR) on CD8+ T cells and specific killer immunoglobulin-like receptors (KIR) on the surface of natural killer (NK cell). Both of these interactions have previously been demonstrated to be important in determining the course of HIV-1 disease outcome. We therefore examined patterns of genetic variability within both of these complex gene families in individuals from the Black South African population group, contrasting them with genetic variability observed within the corresponding loci in Caucasian South Africans and demonstrated associations between specific genetic variants within the HLA and KIR gene complexes and HIV-1 control in the Black South African population. Examination of genetic diversity within the KIR gene complex in the Black and Caucasian South African population groups revealed these two population groups differed significantly with respect to their KIR2DS1 and KIR3DS1 gene frequencies, as well as with respect to the full-length (KIR2DS4f) and truncated (KIR2DS4v) forms of KIR2DS4. Like KIR2DS1 and KIR3DS1, KIR2DS4v was most frequently observed in the Caucasian population group, while KIR2DS4f was more frequently observed within the Black population group. These differences could be attributed to the different frequency distributions of specific telomeric KIR haplotype motifs within these two population groups. These findings are of particular importance in the South African context, given the associations of KIR2DS4 and KIR3DS1 with both HIV-1 transmission and disease progression. An insertion-deletion (indel) polymorphism within the 3' untranslated region (UTR) of HLA-C has also been shown to be involved in the regulation of HLA-C expression. Individuals who carry a deletion at this position exhibit increased HLA-C expression, which associates with lower viral set point in HIV-1 infected individuals. This 263 indel (rs67384697) is reported to be in strong linkage disequilibrium (LD) with a single nucleotide polymorphism (SNP) 35 kilobases upstream of HLA-C (-35T/C; rs9264942) in Caucasian individuals, making this SNP a potential marker for both HLA-C expression and HIV-1 disease progression. We therefore examined genetic variation within the UTRs of the HLA-C alleles present in Black and Caucasian South Africans and identified two overlapping haplotypes encompassing the 263 indel and another indel at position 230 in both populations, which we propose may act in concert to regulate levels of HLA-C expression. Concomitant evaluation of variability at the -35 SNP revealed this polymorphism to be an inappropriate marker for either indel in these populations. Recently, individual polymorphic amino acids within the classical HLA class I loci, located predominantly within the peptide binding groove, have been shown to be strongly associated with HIV-1 control. We, therefore, examined patterns of genetic variability within and across the HLA class I loci in Black South African HIV-1 progressors and –controllers. Our findings confirmed those from other populations, demonstrating the importance of HLA-B residues 67, 70, 97 and 116 in determining disease outcome, while also identifying additional residues in HLA-A and -B that may potentially contribute to determining differential disease outcome in this population. Variability at these residues likely impacts the specificity of the peptide bound by the HLA molecule, resulting in differential regulation of both cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses. No significant associations were observed between HIV- 1 control and variability within either the HLA-C peptide binding groove or the 3’ UTR. Finally, we examined the role of genetic variability within the KIR gene complex in regulating HIV-1 control by examining patterns of genetic variability within this locus in Black South African HIV-1 progressors and –controllers. We found loss of control to be significantly associated with specific KIR haplotype motifs lacking KIR2DS4 and KIR3DL1, while maintenance of viral control was found to be associated with possession of KIR haplotypes containing the centromeric cB01 motif. Furthermore, elite controllers were more frequently found to be in possession of cB01 motifs containing KIR2DS5, rather than KIR2DS3. In light of the strong linkage disequilibrium observed across this region, KIR2DS3 and KIR2DS5 are thought act as markers for specific allelic variants of the inhibitory receptors KIR2DL1 and KIR2DL2, which are known to mediate differential inhibition of NK cell function. Collectively, these data represent the first comprehensive description of genetic variability within the KIR gene complex in Black South Africans and provide the valuable insights into the role of these receptors in mediating control of HIV-1 infection through interaction with their HLA class I -encoded ligands.
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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.
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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.
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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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