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Agüera-González, Sonia. "Cell biology on NKG2D ligands and NK cell recognition." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609348.
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Trundley, Anita Elizabeth. "Aspects of human uterine NK cell biology." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620028.
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Nassiry, Ladan 1962. "Kinetics of Natural Killer (NK) cells in mice having elevated Natural Killer cell activity." Thesis, McGill University, 1986. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=65512.
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Mohan, Bindu. "Role of Siglec-7 in ganglioside recognition and modulating NK cell biology." Thesis, University of Dundee, 2013. https://discovery.dundee.ac.uk/en/studentTheses/93d42a43-7c3c-4d6e-b69a-27cb4673c1db.
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Sialic acid binding Ig-like lectin-7 (Siglec-7), expressed primarily on NK cells, binds preferentially to alpha2,8 linked disialic acids such as present in the ganglioside GD3 that is upregulated in certain cancers. Siglec-7 is classified as an inhibitory receptor as it contains immunoreceptor tyrosine based inhibitory motifs. It has been shown to inhibit NK cytotoxicity in cellular assays thereby implying a role for it in NK cell mediated tumour surveillance. The aim of this project was to study factors affecting ligand recognition by Siglec-7 and its impact on NK cell functions. An investigation into the mechanism by which Siglec-7 mediates inhibitory signals to regulate NK cell biology was also carried out. Recognition of Siglec-7 for GD3 has been reported to be altered in the presence of complex gangliosides. This project was initiated with an aim to examine the role of such cis-interactions between GD3 and other gangliosides such as GM1 in biological systems and thereby its impact on NK cell biology. B16 (78) cell line was genetically modified to over-express both GD3 and GM1. This model system was then analysed using Siglec-7-Fc precomplexes for the recognition of GD3. Siglec-7-Fc binding of B16 (78) cells with high expression of GD3 and GM1 was significantly lower compared to cells having high expression of GD3 and low expression of GM1. However further investigation of these cis-interactions by confocal microscopy revealed that only less than 3% of the cells had patches of co-localization of the two gangliosides. Such lateral segregation of co-expressed GD3 and GM1 was also observed in another cell line model. Next, an investigation into the role of GD3 in modulating NK cell functions via Siglec-7 was carried out. Primary PBMCs and a Siglec-7 deficient NK cell line, NK92, were used for this purpose. The data obtained showed that Siglec-7 could negatively modulate NK cytotoxicity towards targets expressing disialylated ligands such as GD3. Furthermore Siglec-7 was also able to modulate integrin functions on NK cells. LFA-1 mediated adhesion of effectors to ICAM-1-Fc coated plates and the polarization of perforin granules to ICAM-1- Fc coated beads were negatively affected by the expression of Siglec-7 in the NK92 cell line. Biochemical analysis of LFA-1 mediated signalling in NK92 cells showed negative regulation of Src kinase activation, in an Siglec-7 dependent manner. Overall these findings suggest a role for Siglec-7 in modulating NK cell recognition of tumours with aberrant glycosylation patterns. They also form the basis of further investigation into the mechanisms of inhibitory signalling mediated by Siglec-7 and could therefore be of potential clinical relevance in NK cell mediated tumour clearance.
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El-Maghraby, Nermine Mostafa. "Modulation of BLT1 expression in human NK cells by selected cytokines." Mémoire, (Accès réservé UdeS) Droit de reproduction illimitée uniquement pour la création de matériel didactique, 2007. http://savoirs.usherbrooke.ca/handle/11143/3894.
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Meredith, Tobias. "The regulatory effects of CD161 and MAIT cells." Thesis, Federation University Australia, 2020. http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/176644.
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Mucosal associated invariant T (MAIT) cells are connected with the potential regulation of anti-tumour responses, although their role in this regulation is poorly defined. In cancer, the relative frequency of MAIT cells has an impact on patient outcome, although how this impact is mediated is not known. Therefore, we have carefully modulated the frequency of MAIT cells within cultures and assessed the effect this has on the anti-tumour functions of important immune cells such as NK and conventional T cells. We identified that changes in MAIT cell frequency can significantly impact the ability of NK cells to become activated and produce proinflammatory cytokines. Interestingly, changes in MAIT cell frequency do not impact conventional T cell activation, but can alter pro-inflammatory cytokine expression. We also identified trends that suggest alterations in MAIT cell frequency may suppress a broad range of cytokines produced within the PBMC pool. The thesis also examined the potential regulatory impact of the cell surface molecule CD161 on T cells (particularly MAIT cells). Several distinctive characteristics have been identified that provides a broader understanding of the effect ligating and blocking this molecule can have. We have demonstrated that interaction with CD161 can promote activation and affect cytokine and perforin expression by MAIT cells. Conventional T cells are also affected, specifically their cytokine expression and activation. Lastly, we also performed several pilot studies, which identified changes in the expression of some genes of interest (e.g. IL-13, IL-5) and raised the possibility that the products of these genes could also be affected. Taken together, our research indicates that MAIT cell frequency can have significant effects on the anti-tumour roles of other immune cells. Additionally, we have furthered the understanding of which anti-tumour functions CD161 interaction can affect. CD161 has the potential to be used as an immunotherapeutic target in cancer patients, but more knowledge is required to determine the host of potential functions CD161 may affect. We suggest that further study is required, particularly in determining the effect CD161 ligation and blocking can have on cytokine output on a range of cells, including MAIT cells.Doctor of Philosophy
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Jaime-Ramirez, Alena Cristina. "HER2 and Folate Receptor Targeted Therapy is Enhanced by NK Cell-Activating Cytokines." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1364465780.
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Pyzik, Michal. "Immunogenetics of infection: MHC class I molecules and NK cell receptors interplay in the recognition of MCMV-infected cell and infection outcome." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116853.
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Human cytomegalovirus (HCMV) is a herpesvirus found commonly in the world population, causing a severe and potentially fatal disease in neonates and immunocompromised patients. Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in resistance to infection. As infection with mouse CMV (MCMV) shares many pathophysiological aspects with the human disease, the mouse represents an excellent model to study CMV infection. The outcome of MCMV infection depends on the host genetic background and thus varies among the multiple inbred mouse strains. Importantly, mouse NK cells, through the expression of germ line encoded receptors, have the ability to recognize CMV infection, resulting in NK cell activation and the destruction of the infected cells. In each strain NK cells express amongst others, different sets of activating and inhibitory Ly49 receptors, in the presence of strain-specific MHC class I molecules, some of which are natural ligands to Ly49 receptors. Nevertheless, the exact mode of NK cell recognition of infected cell and the impact on the outcome of infection are complex and not fully understood. In order to characterize the molecular mechanisms underlying innate resistance to MCMV, we have initiated a systematic study to identify the possible ligands of Ly49 receptors and the nature of their interaction. We assessed the ability of distinct activating and inhibitory Ly49 receptors to recognize MCMV infection, in the context of diverse MHC class I haplotypes in vitro and in vivo. We show that the cognate interaction between several activating Ly49 receptors and MHC class I molecules depends on the presence of the viral regulator of antigen presentation, gp34/m04. Furthermore, we illustrate that, analogous to activating Ly49 receptors, inhibitory Ly49 receptors can be triggered by MCMV infection. This complex interaction, conditional on the type of MHC class I molecules, results in a spectrum of innate immune control of MCMV spread. Altogether, our results identify the fundamental mechanisms of NK cell receptor function in the recognition and eradication of viral infection. These will provide new grounds to understand and manipulate human NK cells in response to viral infections.Le cytomégalovirus humain (HCMV) est un herpèsvirus omniprésent dans la population mondiale, qui provoque des symptômes graves et potentiellement mortels chez les nouveau-nés et les patients immunodéprimés. Les données cliniques et expérimentales indiquent qu'un sous-ensemble de lymphocytes innés, dites tueuses naturelles (NK), joue un rôle crucial dans la résistance à l'infection. Comme l'infection par le CMV murin (MCMV) partage de nombreux aspects physiopathologiques de la maladie humaine, la souris constitue un excellent modèle pour étudier l'infection par le CMV. La susceptibilité au MCMV varie grandement selon les lignées de souris congéniques et ce, en fonction de leur patrimoine génétique. Plus précisément, chaque lignée de souris exprime une variété de récepteurs activateurs ou inhibiteurs spécifiques aux cellules NK, les récepteurs Ly49, parallèlement à des répertoires de CMH de classe I variés, dont certains sont des ligands naturels des récepteurs Ly49. En effet, les cellules NK, grâce à l'expression de ces récepteurs encodés dans la lignée germinale, ont la capacité de reconnaître une infection au CMV, ce qui entraîne leur activation et la destruction des cellules infectées. Néanmoins, le mode exact de reconnaissance des cellules infectées par les cellules NK et l'impact sur l'issue de l'infection sont complexes et encore mal compris. Afin de caractériser les mécanismes moléculaires qui sous-tendent la résistance innée au MCMV, nous avons entrepris une étude systématique des ligands possibles des récepteurs Ly49 et de la nature de leur interaction. Nous avons évalué la capacité de reconnaître l'infection MCMV de différents récepteurs Ly49 activateurs ou inhibiteurs, dans le contexte de divers haplotypes de CMH de classe I in vitro et in vivo. Nous démontrons que l'interaction spécifique entre plusieurs récepteurs Ly49 activateurs et des molécules du CMH de classe I dépend de la présence de gp34/m04, un régulateur viral de la présentation d'antigène. De plus, nous montrons que, comme les récepteurs Ly49 activateurs, les récepteurs Ly49 inhibiteurs peuvent aussi être stimulés par une infection au MCMV. Cette interaction complexe, qui dépend du type de molécules de CMH de classe I, se traduit par des niveaux variable de contrôle de la propagation du MCMV par le système immunitaire. Nos résultats mettent en évidence des mécanismes fondamentaux de la fonction des récepteurs des cellules NK dans la reconnaissance et l'éradication de l'infection virale, et fournissent de nouvelles avenues pour comprendre et manipuler la réponse des cellules NK humaines aux infections virales.
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Valentin-Torres, Alice M. "Bidirectional Natural Killer Cell and Dendritic Cell Interactions in HIV-1 Pathogenesis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1346268879.
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Blaser, Bradley W. "Interleukin 15 and transplantation biology the interface of innate and adaptive immunity /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1145978587.
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Taylor, Michelle. "NK-T Cell Activation by Alpha Galactosylceramide (a –Gal Cer): A Model for Adjuvant Activation of Innate Immunity." University of Akron / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=akron1367409525.
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Chivero, Ernest Tafara. "Tropism of human pegivirus (formerly known as GB virus C) and host immunomodulation : insights into viral persistence." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1565.
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Human Pegivirus (HPgV; originally called GB virus C) is an RNA virus within the Pegivirus genus of the Flaviviridae that commonly causes persistent infection. Worldwide, approximately 750 million people are infected with HPgV. No causal association between HPgV and disease has been identified; however, several studies found an association between persistent HPgV infection and prolonged survival of HIV-infected individuals that appears to be related to a reduction in host immune activation. HPgV replicates well in vivo (>10 million genome copies/ml plasma) but grows poorly in vitro and systems to study this virus are limited. Consequently, mechanisms of viral persistence and host immune modulation remain poorly characterized, and the primary permissive cell type(s) has not yet been identified. The overall goals of my thesis were to characterize HPgV tropism, effects of HPgV infection on host immune response and mechanisms of viral persistence.
Previous studies found HPgV RNA in T and B lymphocytes and ex vivo infected lymphocytes produce viral particles. To further characterize HPgV tropism, we quantified HPgV RNA in highly purified CD4+ and CD8+ T cells, including naïve, central memory, and effector memory populations, and in B cells (CD19+), NK cells (CD56+) cells and monocytes (CD14+) obtained from persistently infected humans using real time RT-PCR. Single genome sequencing was performed on virus within individual cell types to estimate genetic diversity among cell populations. HPgV RNA was present in CD4+ and CD8+ T lymphocytes (9 of 9 subjects), B lymphocytes (7 of 9), NK cells and monocytes (both 4 of 5). HPgV RNA levels were higher in naïve (CD45RA+) CD4+ cells than in central memory and effector memory cells (p<0.01). HPgV sequences were highly conserved between patients (0.117 ± 0.02 substitutions per site) and within subjects (0.006 ± 0.003 substitutions per site). The non-synonymous/synonymous substitution ratio was 0.07 suggesting low selective pressure. CFSE-labeled HPgV RNA-positive microvesicles (SEV) from serum delivered CFSE to uninfected monocytes, NK cells, T and B lymphocytes, and HPgV RNA was transferred to peripheral blood mononuclear cells (PBMCs) with evidence of subsequent viral replication. Thus, HPgV RNA-positive SEV may contribute to delivery of HPgV to PBMCs in vivo, explaining the apparent broad tropism of this persistent human RNA virus.
Although HPgV infection reduces NK cell activation in HIV-infected individuals, the mechanism by which this occurs is not characterized. We studied HPgV effects on NK cell non-cytolytic function in HIV-infected people by measuring expression of IL-12 induced interferon gamma (IFNg) and cytolytic function by measuring K562 target-cell induced CD107a and granzyme B. IFNg expression was lower in HIV-HPgV co-infected subjects compared to HIV mono-infected subjects treated with combination antiretroviral therapy (p=0.02). In contrast, cytolytic NK cell functions were not affected by HPgV. Inhibition of IFNg was due to inhibition of tyrosine kinase (Tyk2) by HPgV envelope protein E2. HPgV positive human sera, extracellular vesicles containing E2 protein, recombinant E2 protein and synthetic E2 peptides containing a predicted Tyk2 interacting motif inhibited IL-12-mediated IFNg release by NK cells. Thus HPgV-E2 inhibits NK cell non-cytolytic functions. Inhibition of NK cell-induced proinflammatory/antiviral cytokines may contribute to both HPgV's ability to persist with high viral loads (>10 million genome copies/ml plasma) and reduce immune cell activation. Understanding mechanisms by which HPgV alters immune activation may contribute towards novel immunomodulatory therapies to treat HIV and inflammatory diseases.
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Campbell, Amanda Rose. "The Role of Cellular Crosstalk in Modulating Natural Killer Cell Responses to Immunotherapy for Cancer." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1459507631.
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Lindholm, Cecilia. "Shb and Its Homologues: Signaling in T Lymphocytes and Fibroblasts." Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1813.
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Stimulation of the T cell receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins, leading to activation of the interleukin-2 (IL-2) gene in T lymphocytes. Shb is a ubiquitously expressed adapter protein, with the ability to associate with the T cell receptor and several signaling proteins in T cells, including: the TCR ζ-chain, LAT, PLC-γ1, Vav, SLP-76 and Gads. Jurkat T cells expressing Shb with a mutation in the SH2 domain, exhibited reduced phosphorylation of several proteins and abolished activation of the MAP kinases ERK1, ERK2 and JNK, upon CD3 stimulation. The TCR induced Ca2+ response in these cells was abolished, together with the activation of the IL-2 promoter via the transcription factor NFAT. Consequently, IL-2 production was also perturbed in these cells, compared to normal Jurkat T cells. Shb was also seen to associate with the β and γ chains of the IL-2 receptor, upon IL-2 stimulation, in T and NK cells. This association occurred between the Shb SH2 domain and Tyr-510 of the IL-2R β chain. The proline-rich domains of Shb were found to associate with the tyrosine kinases JAK1 and JAK3, which are important for STAT-mediated proliferation of T and NK cells upon IL-2 stimulation. Shb was also found to be involved in IL-2 mediated regulation of apoptosis. These findings indicate a dual role for Shb in T cells, where Shb is involved in both T cell receptor and IL-2 receptor signaling.
A Shb homologue, Shf was identified, and seen to associate with the PDGF-α-receptor. Shf shares high sequence homology with Shb and a Shd (also of the Shb family) in the SH2 domain and in four motifs containing putative tyrosine phosphorylation sites. When Shf was overexpressed in fibroblasts, these cells displayed significantly lower rates of apoptosis than control cells in the presence of PDGF-AA. These findings suggest a role for the novel adapter Shf in PDGF-receptor signaling and regulation of apoptosis.
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Vasireddi, Mugdha. "Subversion of Natural Killer Cell Defenses Induced by a Deadly Zoonotic Virus." Digital Archive @ GSU, 2009. http://digitalarchive.gsu.edu/biology_diss/65.
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B virus (Macacine herpesvirus 1, Cercopithecine herpesvirus 1, herpes B virus) is an Old World monkey simplex virus endemic in macaques. B virus infection in its natural host, macaque, is very similar to HSV-‐1 infection in humans causing mild or asymptomatic infection. On the other hand, zoonotic infection in humans results in death in the absence of early initiation of antiviral drugs. Viruses evade host immune responses in order to survive and propagate. Most herpes viruses including HSV-‐1 down-‐regulate major histocompatibility complex class I (MHC class I) surface expression on infected cells in order to prevent CD8+ T-‐cell recognition and subsequent cell lysis. MHC class I molecules bind to the inhibitory receptors of NK cells and prevent NK cell activity. Thus, this mechanism protects HSV-‐1 infected cells from CD8+ T-‐cell lysis, making them sensitive to natural killer (NK) cell cytotoxicity. To investigate if B virus pathogenicity is a result of novel immune evasion mechanisms employed by B virus, we determined NK cell regulation during B virus infection. To this end, our experiments demonstrate that B virus does not down-‐ regulate MHC I expression as effectively as HSV-‐1, leading us to hypothesize that B virus in-‐ fected cells are resistant to NK cell activity. We examined the expression of MHC I chain related genes (MICA/ MICB), which are activation ligands to NKG2D receptors on NK cells. Our results show that there is no significant difference in MICA and MICB expression between HSV-‐1 and B virus infected cells. Furthermore, we tested for the up-‐regulation of cytokines and chemokines responsible for NK cell activation and migration. Our results indicate a significant up-‐regulation of IFN-‐α from PBMCs co-‐cultured with HSV-‐1 infected cells, which plays an important role in activating NK cells. NK cells within these PBMCs up-‐regulate perforin release indicative of NK cell activity. PBMCs co-‐cultured with B virus infected cells do not up-‐regulate any cytokines or chemokines responsible for NK cell activity. As a result the NK cells within these PBMCs do not significantly up-‐regulate perforin release. These results demonstrate that B virus employs a novel immune evasion mechanism to subvert NK cell activity.
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Sobolev, Olga Ph D. Massachusetts Institute of Technology. "The role of NK cells in selectin-dependent tumor suppression." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/43227.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008.Includes bibliographical references.
Selectins are a small family of adhesion molecules that are critical for immune cell trafficking. In our laboratory, mice lacking all combinations of selectins have been generated. Previous work from our laboratory has demonstrated that, in the absence of selectins, human tumors transplanted subcutaneously into Rag2'- mice grow significantly larger. This implicates selectins and the innate immune system in tumor immune surveillance. We have extended the xenograft tumor model to immunocompetent C57BL/6 mice. Similarly to previous experiments, we found that many syngeneic tumors grow significantly larger in the triple selectin knockouts (ELP/) than in ELP+' control mice. The difference in tumor growth is most apparent in ELP'- and single L-selectin knockout (L-/) mice. P-selectin also contributes to selectin-dependent tumor suppression, while E-selectin does not appear to be involved. Since selectins are known to play a role in immune cell traffic, we explored recruitment defects in selectin knockout mice, and discovered that natural killer (NK) cell recruitment to tumors in Matrigel is impaired. NK cells in ELP-' and L'/ mice appear otherwise normal and functional. NK cells express L-selectin and selectin ligands, and are known to be tumoricidal. In mice depleted of NK cells, either pharmacologically by TM-P1 antibody injection, or genetically in NK-deficient GrzA-Ly49A transgenic mice, tumor growth is also significantly enhanced.
Tumor growth increase seen in the absence on NK cells is not enhanced further by the absence of both NK cells and selectins, arguing that selectins and NK cells may act in the same pathway to suppress tumor growth. The ability of NK cells to clear tumors in selectin-deficient mice is defective. These results suggest that NK cells act to suppress tumor growth in this system and dependent on selectins to do so. Thus, this work contributes to the understanding of the role of selectins and NK cells in the process of tumor immunosurveillance.
by Olga Sobolev.
Ph.D.
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Jülke, Kerstin. "Role of cytokines for NK cell competence and differentiation." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16216.
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Humane NK Zellen können in CD56br und CD56dim NK Zellen unterteilt werden. In dieser Arbeit wurde untersucht, in welchem Zusammenhang die verschiedenen NK Zell Populationen stehen und wie funktional kompetente NK Zellen generiert werden. Des Weiteren wurde die Heterogenität der CD56dim NK Zell Population in Bezug auf Funktionalität und Differenzierungsstadien analysiert. Es konnte gezeigt werden, dass CD56br NK Zellen in CD56dim NK Zellen differenzieren. Währenddessen werden u.a. MHC-I spezifische inhibierende Rezeptoren (KIR) erworben. Diese sind essentiell für die Unterscheidung zwischen “Selbst” und “Nicht-Selbst”, wobei nur NK Zellen, die Selbst-MHC-spezifische KIRs tragen, funktional kompetent sind. In der vor-liegenden Arbeit konnte darüber hinaus gezeigt werden, dass zuvor anerge NK Zellen nach Zytokin-induzierter Expression eines Selbst-MHC-spezifischen KIRs kompetent werden. Ex vivo Analysen humaner Gewebe lassen vermuten, dass diese Prozesse während einer Entzündung in sekundären lymphatischen Organen (SLO) stattfinden könnten. Auch CD56dim NK Zellen selbst sind nicht homogen, hingegen können anhand der Expression von KIRs oder CD62L, welches für die Migration in SLO wichtig ist, weitere Subpopulationen unterschieden werden. Eine umfassende Analyse bezüglich KIR und CD62L Expression führte zur Identifizierung einer zuvor nicht charakterisierten CD56dimCD62L+ NK Zell Population, welche die Fähigkeiten von CD56br, Zytokine zu produzieren und zu proliferieren, mit einem hohen zytotoxischen Potenzial, vereinigt. Weitere ex vivo Untersuchungen des Phänotyps, der Telomerlängen und der Verteilung in Relation zum Alter lassen vermuten, dass die Differenzierung humaner NK Zellen von CD56br über CD56dimCD62L+ zu CD56dimCD62L- verläuft, wobei die Zellen mit fortschreitender Dif-ferenzierung ihre Fähigkeit auf Zytokine zu antworten verlieren und dafür die Fähigkeit er-langen, über aktivierende Rezeptoren stimuliert zu werden.Human NK cells comprise two main subsets, CD56br and CD56dim cells. In this study, an extensive analysis of human NK cell phenotype and functional characteristics has been performed in order to investigate the developmental relation between NK cell subsets, to elucidate how NK cell competence is acquired and to further dissect the heterogeneity of the CD56dim subset with regard to functions and differentiation history of human NK cells. It could be shown that upon cytokine activation, CD56br differentiate into CD56dim NK cells and that this process might take place in inflamed secondary lymphoid organs (SLO). One of the crucial markers acquired during this process is KIR, the main MHC-specific inhibitory receptors responsible for self versus non self recognition. Previously, it has been shown that only cells expressing self-MHC specific KIRs are responsive to activating stimuli. In this study, it was demonstrated that induction of self-MHC specific KIR by cytokines leads to acquisition of functional competence. Ex vivo analysis of human tissues suggests that acquisition of KIR and consequently of cytotoxic competence may occur in inflamed SLO. Finally, it was demonstrated that CD56dim NK cells do not represent a homogenous population. When dissected for CD62L and KIR expression, a new subset of NK cells could be identified, namely CD56dimCD62L+, which uniquely combines properties of CD56br NK cells, particularly high IFN-g production upon cytokine stimulation, proliferation and potential to migrate into SLO, with the capacity of CD56dim to kill, produce cytokines upon activating receptor stimulation and to migrate into inflamed tissues. Ex vivo analysis of the function, phenotype, telomere length and frequencies during ageing of CD56br, CD56dimCD62L+ and CD56dimCD62L- NK cells suggest that CD56dimCD62L+ cells represent an intermediate stage of NK cell maturation between the more immature CD56br and the terminally differentiated CD56dim CD62L- NK cells.
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Gross, Catharina Christiane. "Membrane-Bound Hsp70 an Activating Ligand for NK Cells." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-35788.
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Vogel, Benjamin [Verfasser], and Andreas [Akademischer Betreuer] Burkovski. "Gammaherpesvirus persistence, tropism and human NK cell transformation / Benjamin Vogel. Betreuer: Andreas Burkovski." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2013. http://d-nb.info/1033029858/34.
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Ewen, Eva-Maria [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "Pro-inflammatory cytokines unleash natural killer cell potential for tumor therapy : NK cells want to break free / Eva-Maria Ewen ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1180394402/34.
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Seidel, Diana. "Mechanism and efficacy of a GD2-specific immunotherapy using NK cells." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2015. http://dx.doi.org/10.18452/17151.
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Das Neuroblastom (NB) ist ein solider, extrakranieller Tumor neuroektodermalen Ursprungs, der sich im Kleinkindalter manifestiert. Ein etabliertes Zielantigen für die passive Immuntherapie beim NB ist das Disialogangliosid GD2. Aufgrund der geringen oder fehlenden Expression von MHC Klasse I Molekülen sowie der Tatsache, dass die Lyse von NB-Zellen durch verschiedene Mechanismen der natürlichen Zytotoxizität von NK-Zellen vermittelt werden kann, stellt eine auf NK-Zellen basierende Therapie einen vielversprechenden Ansatz zur Behandlung dieser Erkrankung dar. Auf dieser Grundlage wurde eine NK-Zelllinie generiert, die einen GD2-spezifischen chimären Antigenrezeptor (CAR) exprimiert (NK-92-scFv(ch14.18)-zeta). Die Hauptbestandteile dieses CARs sind ein Einzelkettenantikörper, welcher die variablen Regionen des GD2-spezifischen Antikörpers ch14.18 enthält, und die CD3ζ-Kette als signaltransduzierende Komponente. Im Rahmen dieser Arbeit konnte gezeigt werden, dass NK-92-scFv(ch14.18)-zeta in der Lage sind, auch Chemotherapie-resistente GD2-positive NB-Zelllinien effektiv abzutöten und dass dabei die Interaktion des CARs mit GD2 den Hauptmechanismus darstellt. Die anti-tumorale Wirkung von NK-92-scFv(ch14.18)-zeta in vivo wurde in einem Chemotherapie-resistenten GD2-positiven Xenograft-Mausmodell gezeigt. Die wiederholte Applikation von NK-92-scFv(ch14.18)-zeta in Kombination mit IL-2 resultierte in einem signifikant verlangsamten Tumorwachstum und einem verbesserten Überleben. Die Ergebnisse dieser Arbeit belegen, dass GD2-spezifische NK-92 das Potential für eine zukünftige klinische Anwendung besitzen. Demnach stellt der Einsatz einer solchen GD2-spezifischen NK-Zelllinie, die unter GMP-Bedingungen expandiert werden kann und zu jeder Zeit in einer standardisierten Qualität verfügbar wäre, eine vielversprechende Alternative zur Behandlung von Hochrisikopatienten dar, deren Erkrankung nicht mehr auf die Standardtherapie anspricht.Neuroblastoma (NB) is a solid extracranial childhood malignancy of neuroectodermal origin. The Disialoganglioside GD2 is an established antigen for passive immunotherapy of NB. Cellular therapy of NB with natural killer (NK) cells is especially appealing because MHC class I expression is absent or low in most NB, rendering this tumor sensitive to NK cell recognition. Additionally, natural cytotoxicity of NK cells, mediated by interaction of activating NK cell receptors and their respective ligands on tumor cells, has been shown to play a role in lysis of NB cells. It is therefore tempting to assume that a combination of passive immunotherapy with GD2-specific antibodies and adoptive transfer of NK effector cells would result in an improved NB therapy. To achieve this goal an NK cell line expressing a GD2-specific chimeric antigen receptor (CAR) was engineered: NK-92-scFv(ch14.18)-zeta. This CAR consists of a GD2-specific scFv-fragment, which was generated from ch14.18, and the CD3ζ-chain as intracellular signal-transducing domain. Within this thesis, GD2-specificity of NK-92-scFv(ch14.18)-zeta as well as efficacy towards GD2-expressing NB cell lines, including relapse cell lines that exhibit partial or multidrug resistance were demonstrated. Blocking the interaction between the CAR and GD2 resulted in almost complete abrogation of NK-92-scFv(ch14.18)-zeta-mediated lysis of GD2-positive NB cell lines in vitro, indicating that this interaction is the main mechanism of activation of NK-92-scFv(ch14.18)-zeta. Importantly, repeated application of NK-92-scFv(ch14.18)-zeta in combination with IL-2 significantly decreased tumor growth and prolonged survival of mice in an aggressively growing drug-resistant xenograft NB mouse model. These findings suggest that GD2-specific NK-92 has potential for a future clinical application as NB-specific effector cells that would be ready on demand in a standardized quality.
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Huong, Dang Thi [Verfasser]. "Functional and molecular characterization of T cells and natural killer (NK) cells in rainbow trout (Oncorhynchus mykiss) / Dang Thi Huong." Greifswald : Universitätsbibliothek Greifswald, 2015. http://d-nb.info/1077079761/34.
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Kim, Kwangsin. "The host resistance locus Cmv1Ly49h regulates global gene expression in spleen DX5+ NK cells in response to murine cytomegalovirus infection." Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/27259.
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In mice, the Cmv1/Ly49h locus expressed on Natural Killer (NK) cells determines innate resistance to Murine Cytomegalovirus Virus (MCMV). NK cells provide the first line of defence against infections and tumors through cytokine production or direct cytotoxicity. Acquisition of MCMV resistance in transgenic mice expressing Ly49H, hereafter FVB-Tg (Ly49h), demonstrated the critical role of Ly49H in clearance of the infection, and provided an ideal model to characterize the role of NK cells in host defence.
The scoring of viral titers in the visceral organs of Ly49H transgenic (FVB-Tg (Ly49h)) mice and their MCMV-susceptible counterparts, FVB, indicated a tissue specific effect of Ly49H independent of genetic background in spleen, lung, kidney and thymus. In the liver, the presence of Ly49H was associated with increased numbers of inflammatory foci, suggesting that Ly49H may facilitate localization of NK cells to the vicinity of infected cells.
To identify genes critical to the initial control of virus replication, comparative gene expression analysis of explanted spleen NK cells from FVB-Tg (Ly49h) and FVB mice was carried at 36 hours post-infection. This allows for the onset of Ly49H related mechanisms of host resistance. In contrast to whole spleen samples, RT-PCR from purified NK cells from either mouse strain did not detect MCMV gene expression, indicating that NK cells are not productively infected. Out of 16,000 genes analyzed by microarray, 35 showed greater than 2.5-fold expression difference between resistant and susceptible mice. Genes involved in NK cell proliferation, cytotoxicity and in cell-mediated immunity, such as the early T lymphocyte activation-1 gene (Eta-1 or osteopontin), showed enhanced expression in NK cells from resistant mice.
On the other hand, NK cells from susceptible mice showed increased expression of pro-inflammatory cytokines such as IFN-gamma, MIP2, and TNF-associated receptors, indicating that antiviral cytokines are not sufficient to control viral replication in the absence of Ly49h, and that direct killing of virus-infected cells by NK cells expressing Ly49H is required for successful clearance of MCMV.
To characterize the response of NK cells during MCMV clearance further, gene expression patterns were studied in FVB-Tg (Ly49h) during the course of infection. Out of 22690 genes analyzed, the expression of 225 genes was significantly changed at 3 days post-infection, when the effect of Cmv1/Ly49h is strongest and the viral load is highest. At later time points, the number of genes affected and the level of gene expression gradually returned to normal, in parallel with a decrease in viral titer, indicating that altered expression patterns co-varied with viral burden. More than 50% of the genes upregulated were involved in cell proliferation, metabolism, and transcription, while about 15% were involved in NK cell cytotoxic function, indicating that NK cell blastogenesis and direct killing of infected cells are crucial for MCMV-resistance.
Altogether, our results indicate that the differential pattern of expression between resistant and susceptible mice depends on the presence or absence of Ly49h as well as on signals emanating from productively infected cells, such as macrophages and dendritic cells. Genes differentially expressed on MCMV-susceptible NK cells may serve as useful biomarkers for HCMV susceptibility in risk populations, graft recipients in particular.
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Gütgemann, Stephan Alexander [Verfasser], and Walter [Akademischer Betreuer] Nickel. "Molecular basis for the lipid raft recruitment of NK cell receptors and development of a sialic acid-based Siglec-7 inhibitor / Stephan Alexander Gütgemann ; Betreuer: Walter Nickel." Heidelberg : Universitätsbibliothek Heidelberg, 2012. http://d-nb.info/1179785177/34.
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Kannan, Yashaswini. "Functional Characterization Of Human IkappaBzeta In Modulating Inflammatory Responses." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1314564642.
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Nowakowska, Paulina [Verfasser], Beatrix [Akademischer Betreuer] Süß, Adam [Akademischer Betreuer] Bertl, and Torsten [Akademischer Betreuer] Tonn. "Establishment of a good manufacturing practice-compliant procedure for expansion of therapeutic doses of genetically modified, CAR expressing NK-92 cells for the treatment of ErbB2-positive malignancies / Paulina Nowakowska ; Beatrix Süß, Adam Bertl, Torsten Tonn." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2016. http://d-nb.info/1121781799/34.
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Romero, Suarez Silvina. "Migrant or resident? The identification of group 1 innate lymphoid cells in the murine central nervous system." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/20355.
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Angeborene lymphoide Zellen (ILCs) sind sich im Gewebe befindliche Zellen, die eine wichtige Rolle bei der Aufrechterhaltung der Gewebehomöostase spielen. ILCs wurden in verschiedenen Organen untersucht. Ob ILCs im zentralen Nervensystem (ZNS) vorhanden sind und wenn ja, welchen Phänotyp und welche funktionellen Eigenschaften sie in diesem Organ aufweisen, sind Fragen, die bisher unbeantwortet blieben. NK-Zellen sind die seit langem bekannten ILC-Mitglieder, die viele Merkmale mit ILC1s teilen. Im Zusammenhang mit der Autoimmunität wurde gezeigt, dass NK-Zellen eine immunmodulatorische Rollen spielen. Anhand des Tiermodells von Multiple Sklerose, der experimentellen autoimmunen Enzephalomyelitis, zeigte unsere Gruppe, dass reife NK-Zellen auf CX3CR1-abhängige Weise in das ZNS rekrutiert werden. Auf der Grundlage dieser Beobachtungen will ich in meinem PhD Projekt die Chemokinrezeptoren definieren, die die Rekrutierung der unreifen NK-Zellen in das entzündete ZNS vermitteln. Des Weiteren will ich herausfinden, ob die phänotypisch definierten NK-Zellen (CD3-NK1.1 + -Zellen) die im gesunden ZNS vorhanden sind, echte NK-Zellen sind, oder sie zu den ILC1s gezählt werden können.
Die Ergebnisse der vorliegenden Arbeit zeigen, dass die im gesunden ZNS vorhandenen CD3-NK1.1+ -Zellen verschiedene Typ-1-ILC-Subsets umfassen: NK-Zellen, ILC1s, Intermediat-ILC1s und Ex-ILC3s. CXCR3 wurde auf ILC1s und einer Fraktion von unreifen NK-Zellen exprimiert, trug jedoch nicht zur Rekrutierung von NK-Zellen in das ZNS im EAE-Modell bei. Die Expression von CD49a, CD69, CXCR6, DNAM-1high, TRAIL und CD200R und das Fehlen von Eomes unterschieden die ILC1 von den NK-Zellen im ZNS. Zusätzlich ILC1s sezernierten mehr TNF-α als NK-Zellen. ILC1s waren die dominante Typ-1-ILC Subgruppe im Plexus choroideus und im Gehirnparenchym und waren auch in den Meningen vorhanden. Zusammenfassend bietet die vorliegende Arbeit zum ersten Mal eine umfassende Charakterisierung von ILCs des Typs I im ZNS.Innate lymphoid cells (ILCs) are tissue resident cells that play important roles in the maintenance of tissue homeostasis. ILCs have been characterized in diverse organs like the gut and liver. However, whether ILCs are present in the central nervous system (CNS) and if so, what are their phenotype and function in this organ are questions that remain unanswered. NK cells are the longer-known ILC members that share many phenotypical and functional features with ILC1s. Using the animal model of MS, the experimental autoimmune encephalomyelitis (EAE), our group showed that protective mature NK cells are recruited to the CNS on an CX3CR1-dependent manner. Based on that observations, my PhD project aimed to 1) define the chemokine receptors that mediate the recruitment of the immature NK cells into the inflamed CNS and to 2) determine whether the phenotypically defined NK cells (CD3-NK1.1+ cells) that are present in the CNS during steady state constitute bona fide NK cells or constitute also other group 1 ILC subsets. The results of this work indicate that the CD3-NK1.1+ cells present in the healthy CNS comprise diverse group 1 ILC subsets that include conventional NK cells, ILC1s, intermediate-ILC1s and ex-ILC3s. CXCR3 was expressed on ILC1s and a fraction of immature NK cells, but did not contributed to the recruitment of NK cells into the CNS in the EAE model. In addition, the phenotypic and functional characterization of the newly identified CNS-ILC1s is described. The exclusive expression of CD49a, CD69, CXCR6, DNAM-1high, TRAIL and CD200R, and lack of Eomes distinguished the ILC1s from the NK cells in the CNS. IILC1s secreted IFN-γ and more TNF-α than NK cells upon stimulation in the healthy and EAE mice and were the dominant group 1 ILC subset in the choroid plexus and brain parenchyma and were also present in the meninges. In sum, the present work provides for the first time a comprehensive characterization of group 1 ILCs in the CNS.
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Chollat-Namy, Marie. "Effet de l’inactivation du gène suppresseur de tumeur p53 et de sa réactivation pharmacologique sur la réponse cytotoxique anti-tumorale The Pharmalogical Reactivation of p53 Function Improves Breast Tumor Cell Lysis by Granzyme B and NK Cells Through Induction of Autophagy Mutant P53 Gain of Function Stimulates PD-L1 Expression." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL032.
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Le système immunitaire joue un rôle important dans le contrôle et l'éradication du cancer. Des acteurs majeurs de la réponse immune antitumorale sont les cellules tueuses naturelles (ou cellules NK) et les lymphocytes T cytotoxiques (ou CTL), capable de reconnaitre et détruire des cellules tumorales par l’exocytose de perforine et de granzymes contenus dans leur granule cytotoxique. Il a été montré au sein du laboratoire l’implication de la protéine suppresseur de tumeur p53 dans cette voie apoptotique. Or, plus de 50% des tumeurs humaines présentent des mutations inactivatrices de p53 ce qui favorise le développement tumoral. De ce fait, l’inactivation fréquente de p53 dans les tumeurs humaines pourrait leur permettre d’échapper à la destruction par les CTL et les cellules NK.Dans ce contexte, mes travaux de thèse ont montré que la réactivation pharmacologique de la fonction de p53 sauvage dans des cellules tumorales exprimant une p53 mutée augmente leur susceptibilité à la lyse induite par les cellules NK grâce à l’induction d’un processus d’autophagie. De plus, j’ai cherché à déterminer le lien entre les mutations de p53 et l’expression à la surface des cellules tumorales de PD-L1 qui empêche l’activation optimale des cellules cytotoxiques et conduit à leur épuisement. Mes travaux actuels suggèrent que l’expression de p53 mutantes induits une surexpression de PD-L1 à la surface des cellules cancéreuses. Les mécanismes expliquant ce phénomène sont en cours d’étudesImmune system plays an important role in the control and destruction of cancer cells. The major effectors of antitumor immune response are Natural Killer (NK) cells and the cytotoxic T lymphocytes, which recognize et destroy tumor cells by exocytosis of perforin and granzymes contained in cytotoxic granules. It has been previously shown in the laboratory that the tumor suppressor p53 plays an important role in this apoptotic pathway. However more than 50% of human tumors have p53 inactivating mutations which favor tumor development. Consequently, frequent p53 inactivation in human tumor could enable them to escape from destruction by cytotoxic immune cells. In this context, my thesis work has shown that the pharmacological reactivation of wild type p53 function in cancer cells expressing a mutated p53 increased their susceptibility to NK cell-mediated apoptosis cells through the induction of an autophagic process. Moreover, I tried to determine the link between p53 mutations and the expression of the immune checkpoint ligand PD-L1 which prevent efficient activation of cytotoxic cells and promote immune cells exhaustion. My work suggests that the expression of p53 mutants promotes an the expression of PD-L1 at the cancer cell surface. The study of the underlying mechanisms is still in progress
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Cassanelli, Sylvie. "Analyse in situ de l'hétérogénéité d'expression des récepteurs de la progesterone dans les cellules tumorales mammaires." Université Joseph Fourier (Grenoble), 1995. http://www.theses.fr/1995GRE10118.
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La mise en evidence des recepteurs de la progesterone (rp) dans les cellules tumorales mammaires revele a l'echelon cellulaire une heterogeneite d'expression. Les travaux presentes dans cette these ont pour objectif l'etude des origines possibles de cette heterogeneite. Deux lignees tumorales mammaires mcf-7 et t47-d ont ete utilisees ainsi que des empreintes de tumeurs. La quantification par analyse d'images de plusieurs immunomarquages fluorescents (rp-ki-67 ou brdu-adn) a montre que l'expression des rp est, en partie, liee a la cinetique de proliferation des cellules sur les trois modeles etudies ainsi que dans un sous clone de la lignee mcf-7. D'autre part, l'etude de sous populations clonales de la lignee mcf-7 revele l'existence de sous-clones soit rp positifs soit rp negatifs qui indique que l'expression des rp est egalement liee a l'information genetique. Dans un deuxieme temps, nous avons envisage la combinaison de l'immunomarquage des rp et de l'hybridation in situ de leurs arnm mais nous avons rencontre certaines difficultes. De ce fait nous avons synchronise les cellules d'un sous-clone de la lignee mcf-7 et realise les differents marquages cellulaires. Avec l'aide de la technique de rt-pcr (polymerase chain reaction) nous avons etabli un modele d'expression des rp (arnm, proteine) au cours des differentes phases du cycle cellulaire pour le meme sous-clone. Des anomalies numeriques du chromosome 11 (porteur du gene rp) existent dans les cellules tumorales de la lignee t47-d. L'hybridation in situ de ce chromosome et l'immunomarquage des rp sur cellules interphasiques a montre une absence de correlation entre le nombre de chromosomes 11 et la positivite en rp, on l'explique par l'absence de correlation entre le nombre de chromosome 11 et le nombre de copies du gene des rp, detecte par double hybridation des chromosomes 11 et du gene des rp
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Buteyn, Nathaniel J. "Role of Innate Immunity Activators in the Treatment of Acute Myeloid Leukemia." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1574343556916953.
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Yang, Chin-An. "Characterization of differential Toll-like receptor function in human immune cells and association with susceptibility to recurrent HSV-1 reactivations and gastric cancer." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16268.
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Toll-like Rezeptoren (TLRs) sind essentielle angeborene Rezeptoren, die konservierte Strukturen von Krankheitserregern oder Gefahrsignale, die von beschädigten Zellen freigesetzt werden, erkennen können. Genetische Variationen in TLRs wie Einzel-Nukleotid-Polymorphismus (SNP) können die Funktion von TLRs beeinträchtigen und erste Studien zeigen, dass dies zu einer erhöhten Anfälligkeit gegenüber Virusinfektionen oder einem erhöhten Krebsrisiko führen kann. In dieser Studie haben wir einen Multicolor-Durchflußzytometrie-Test entwickelt, um die TLR-Funktionen in verschiedenen Subpopulationen unseparierter peripherer mononukleärer Blutzellen (PBMCs) simultan analysieren zu können. Wir konnten beobachten, dass das Ausmaß der TLR-Antworten zwischen den Probanden stark variierte, jedoch über einen Zeitraum von einem Monat gut reproduzierbar war. Zunächst untersuchten wir TLR Reaktionen bei Patienten mit rezidivierenden Herpes labilalis (HL). Im Vergleich zu asymptomatischen Personen war eine HL- Anamnese mit einer signifikant verminderten TLR3-IFN-Gamma-Antwort nach Stimulation mit poly(I:C) in NK Zellen assoziiert. Weitere molekulare Untersuchungen zeigten eine mögliche Beteiligung von TLR3 L412F SNP, welcher die oberflächliche TLR3 Expression und die IFN-Gamma-Antworten in NK-Zellen reduzierte. Einige Studien zeigen, dassTLR1 I602S, ein weiterer sehr verbreiteter SNP, in der Lage ist die TNF-Alpah-Antworten von Monozyten gegen den TLR2/1-Agonisten (Pam3Cys) zu verringern. In der hier vorliegenden Arbeit konnten wir zudem nachweisen, dass TLR1 I602S SNP auch die Funktion von NK-Zellen und CD8+ T-Zellen beeinträchtigt. Wir konnten keine Assoziation zwischen TLR2/1-Defizienz und reaktivierendem HL feststellen. Jedoch konnten wir an einer großen Kohorte von über 326 Patienten zeigen, dass der TLR1 SNP sowohl ein Risikofaktor für Magenkarzinomentstehung als auch für die Metastasierung ist. Zusammenfassend weisen unsere Ergebnisse darauf hin, dass genetische Polymorphismen von TLRs die Funktion von NK-Zellen beeinträchtigen und zu einer erhöhten Anfälligkeit für HSV-1 Erkrankung und Magenkarzinom führen können.Toll-like Receptors (TLRs) are essential innate receptors which recognize conserved structures of pathogens, or danger signals released from damaged cells. Alterations of TLR responses might result in severe viral infections or a higher risk of cancer. Therefore, development of clinical assays to evaluate TLR functions could provide personalized information about susceptibility to these diseases. Since TLRs are differentially expressed on different subsets of human peripheral blood mononuclear cells (PBMCs), a multi-color flow cytometry-based assay was developed to detect TLR responses of individual cell types simultaneously. We observed that the magnitude of TLR responses largely varied between human subjects, but was highly reproducible over one month. To evaluate the potential role of differences in natural killer (NK) cell TLR response we studied the association of NK cell TLR function and TLR single nucleotide polymorphisms (SNPs) with susceptibility to recurrent herpes labialis (HL) and gastric cancer. Using our assay, impaired TLR3 response of NK cells was found in people with recurrent HL. In addition, we have identified enhanced levels of homozygous TLR3 L412F SNP in people with recurrent HL, which results in lower surface expression and reduced NK cell response to poly(I:C). TLR1 I602S, another common SNP, has been reported to decrease TNF-Alpha responses of monocytes toward TLR2/1 agonist, Pam3CSK4 (Pam3Cys), stimulation. In our study, we found that TLR1 I602S homozygosity also contributes to impaired IFN-Gamma responses of NK cells and CD8+T cells. Although we did not observe an association of TLR2/1 deficiency with recurrent HL, association of TLR1 I602S with risk for primary as well as metastatic gastric cancer was found in a cohort of 326 patients. To sum up, our results suggest that genetic polymorphisms of TLRs can impair TLR function of NK cells, which contribute to the increased susceptibility to HSV-1 diseases and gastric cancer.
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Plantier, Jean-Luc. "La thrombine dans la physiopathologie vasculaire : une étude structure-fonction." Université Joseph Fourier (Grenoble), 1994. http://www.theses.fr/1994GRE10179.
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La thrombine est une glycoproteine de la famille des proteases a serine. Comparee a celles des autres membres de sa famille, sa structure tertiaire possede une serie de boucles d'insertion particulierement exposees, organisees autour du site actif. Parce que la specificite restreinte de la thrombine pour ses substrats semble faire appel a des interactions a la surface de la molecule, il nous est apparu interessant de determiner quels etaient les roles de ces boucles dans certaines des activites de l'enzyme. Des mutations ponctuelles ont ete realisees dans deux de ces boucles (la boucle b et la boucle ) ainsi que sur la serine du site actif. L'analyse des resultats nous a permis de conclure qu'une thrombine dont le site actif est mutee est denuee de toute activite catalytique. La boucle b est confirmee dans son role de determinant majeur lors de la reconnaissance de tous les substrats testes. En revanche, les mutants que nous avons realises dans la boucle ne modifient que subtilement la poche de specificite primaire et peu les interactions avec les substrats macromoleculaires. En plus de cette etude structurale, nous avons etudier le mecanisme d'augmentation de la permeabilite de l'endothelium induite par la thrombine. La variation de permeabilite depend exclusivement du clivage du recepteur et necessite donc une enzyme catalytiquement active. La reponse des cellules endotheliales depend aussi de l'activation de la proteine kinase c et de phosphorylation sur les tyrosines. Le retour d'une sensibilite a l'enzyme requiere la synthese de nouveaux recepteurs. L'utilisation de nos outils moleculaires nous a permis de montrer que l'activite catalytique de l'enzyme est necessaire pour activer les megacaryocytes et inhiber specifiquement la pousse de leurs progeniteurs, ces deux mecanismes etant medies par le recepteur de la thrombine
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Torki, Moez. "Étude de deux familles multigéniques codant pour des polygalacturonases et des pectine-méthylestérases chez Arabidospsis thaliana." Grenoble 1, 1998. http://www.theses.fr/1998GRE10085.
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La pectine joue un role fondamental dans le maintien de la structure et de l'elasticite de la paroi ainsi que dans la cohesion intercellulaire au cours du developpement des plantes. Plusieurs enzymes, associees a la paroi, interviennent dans les modifications physico-chimiques de la pectine lors de divers processus physiologiques. Parmi ces enzymes, notre interet a porte sur l'etude des polygalacturonases (pg) et des pectine-methylesterases (pme) au niveau moleculaire chez a. Thaliana. Cette etude a ete conduite dans le cadre du sequencage des transcrits chez la plante modele arabidopsis thaliana. Nous avons determine les sequences nucleotidiques completes de quatre adnc codant pour des pg ainsi que celle d'un adnc codant pour une pme similaires a des pga et pme exprimes preferentiellement dans le pollen. Nous avons recherche leurs genes respectifs, analyse leurs sequences peptidiques deduites ainsi que celles d'autres adnc et genes codant pour des pg et pme disponibles dans les banques de donnees et etudie l'expression des deux familles multigeniques des pga et pme dans les differents organes d'a. Thaliana. Les comparaisons des polypeptides deduits de ces genes et l'analyse de leurs relations phylogenetiques moleculaires nous a permis de classer ces genes respectivement en trois et six groupes majeurs pour les pga et pour les pme. Nous avons mis en evidence l'accumulation des transcrits de pga et de pme dans tous les organes d'a. Thaliana examines, avec toutefois une presence beaucoup plus marquee dans les organes constitues de jeunes tissus dont les cellules sont en division et en expansion cellulaire fortement actives (cellules, plantules et jeunes siliques) et dans les organes reproducteurs (boutons floraux et fleurs). L'expression des pga et des pme dans de tels organes, constitues de jeunes tissus en division et en expansion cellulaire active, suggerent leur role fondamental, agissant probablement de concert dans l'elongation du tube pollinique et dans l'expansion cellulaire.
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Huang, Mei Hui, and 黃美惠. "Investigation of the role of GPR56 in human NK cell biology." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/33157544982743383327.
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碩士長庚大學
生物醫學研究所
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Natural killer (NK) cells play an important role in innate immunity. NK cells possess a natural cytotoxic potential against virus-infected cells and tumor cells without priming. NK cells secret cytokines to coordinate innate and adaptive immunity by a variety of germ-line encoded receptors that can be classified into activating, inhibitory, adhesion, cytokine and chemokine receptors. Recently, a specific member of the G protein-coupled receptors, GPR56 has been found to be abundantly expressed in NK cells. However, its function has remained mysterious. GPR56 is involved in cell to cell, cell and matrix interaction in other cell types. GPR56 is able to associate with CD81. We used a stable GPR56 over-expressing NK92 cell line and specific antibody stimuli on fresh peripheral blood NK cells to investigate the biological functions of GPR56 in NK cells. Our data suggests that GPR56 is able to regulate the motility of NK cells, affect cytokine secretion and cytotoxicity when recognizing target cells. Indeed, GPR56 might interact with CD81 to regulate the biological functions of NK cells.
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Colamartino, Aurélien. "Nouvelles approches dans l’immunothérapie de la leucémie aigüe lymphoblastique utilisant les récepteurs chimériques d’antigène." Thesis, 2020. http://hdl.handle.net/1866/24611.
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L’immunothérapie a permis des avancées majeures dans la thérapie du cancer. Le traitement par des cellules T modifiées pour exprimer un récepteur chimérique d’antigène (CAR) a changé complètement la vision de la thérapie de la leucémie. L’efficacité de ce traitement sur des cancers résistants, a ouvert la voie à la thérapie cellulaire et génique dans ce contexte. Malgré les premiers résultats très positifs, il s’avère que l’épuisement cellulaire et la perte des cellules T thérapeutiques est un problème majeur pour maintenir l’efficacité de la thérapie CAR et prévenir les rechutes. Les travaux présentés dans cette thèse visent à permettre l’utilisation d’autres types cellulaires pour la thérapie CAR. L’hypothèse de travail est que les cellules NK ou les cellules souches hématopoïétiques (HSC) permettrait de dépasser les limites de la thérapie CAR utilisant les cellules T. Pour permettre l’utilisation des cellules NK, un des problèmes technique est la transduction par les vecteurs viraux. Les travaux présentés ici démontrent que l’utilisation de l’enveloppe BaEV permet une transduction efficace des NK avec un vecteur lentiviral. Par cette méthode nous avons pu générer de grandes quantités de cellules NK transduites avec un CAR, prouvant la possibilité d’utiliser les NK dans la thérapie CAR. L’utilisation des HSC dans la thérapie CAR, permettrait de produire des cellules CAR T en permanence pour renouveler les cellules T épuisées. Cependant, la surexpression d’un récepteur CAR sur toutes les cellules dérivant des HSC pourrait être un problème. Pour permettre l’utilisation des HSC, nous avons développé des promoteurs spécifiques courts restreignant l’expression du transgène à une population précise. Nous avons prouvé la spécificité d’un promoteur T et démontré la possibilité de l’utiliser dans le contexte de la thérapie CAR utilisant les HSC. Ces travaux sont une preuve de concept de l’utilisation d’autres cellules que les cellules T dans la thérapie CAR.Immunotherapy has allowed major advances in cancer therapy. The treatment using modified T cells with a chimeric antigen receptor (CAR) completely changed the vision of leukemia therapy. The efficiency against resistant cancer paved the way to cellular and gene therapy in this context. Despite very positive results at first, the disappearance and exhaustion of therapeutic cells seems to be a major problem to maintain the efficiency of the CAR treatment and prevent relapses. The work of this thesis is to allow the use cell types other than T cells for CAR therapy. The hypothesis is that NK cells or hematopoietic stem cells (HSC) could overcome the limitation of CAR therapy using T cells. To allow the use of CAR NK cells, a major technical issue is the transduction by viral vectors. The work presented here shows the use of BaEV envelope to pseudotype vectors allows an efficient transduction of NK cells. Using this method, we were able to produce large amounts of CAR NK cells, showing the possibility to use NK cells in CAR therapy. The use of HSC in CAR therapy, could allow the permanent replenishment of the pool of CAR T cells once exhausted. Despite that advantage, the overexpression of a CAR receptor on all hematopoietic cells coming from those HSC could be an issue. To allow the use of HSC, we developed short specific promoters restraining the expression of the transgene to a precise population. We prove the specificity of a T cell promoter and demonstrated the possibility to use it in CAR therapy using HSC. This work is a proof of concept of the use of other population than T cells in CAR therapy.
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Deblois, Gabrielle. "Impact de l’IL-15 dans un modèle murin de la sclérose en plaques." Thèse, 2017. http://hdl.handle.net/1866/20535.
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Samarani, Suzanne. "Études sur le rôle d’IL-18 dans l’immunopathogénèse du SIDA." Thèse, 2009. http://hdl.handle.net/1866/3123.
Full textAbstract:
Le virus de l’immunodéficience humaine ou VIH est l’agent qui cause le SIDA. Le VIH donne lieu à une dérégulation dans la production de certaines cytokines qui ont un rôle immunologique très important chez les patients infectés. L’IL-18, autrement nommé facteur inducteur d’IFN-γ, est une cytokine pro-inflammatoire qui affecte le système immunitaire de façon importante. Son activité est régulée par l’"IL-18 Binding Protein" (IL-18BP), une autre cytokine qui se lie avec l’IL-18 et inhibe son activité biologique. Des études ultérieures ont montré des niveaux élevés d’Il-18 chez les patients infectés par le VIH par rapport aux personnes saines. Cependant, aucune étude n’a été réalisée concernant la production d’IL-18BP chez ces patients. Due à sa relevance dans la régulation de l’IL-18, nous avons étudié l’effet de l’infection par le VIH sur l’équilibre entre ces deux facteurs et l’impact de cet équilibre sur l’homéostasie des cellules NK. Nous avons mesuré les taux de l’IL-18 et de l’IL-18BP circulantes dans les sérums des patients infectés par le VIH en les comparants avec le même nombre de personnes saines et séronégatives. Nous avons aussi déterminé le nombre total des différents sous-types de cellules NK et analysé l’activité des cellules NK (Natural Killer). Finalement nous avons cherché à déterminer si l’IL-18 pouvait induire l’apoptose des cellules NK en activant l’expression de Fas ligand. Nos résultats nous démontrent que les patients infectés par le VIH ont trois fois plus d’IL-18 que les donneurs sains. Cependant les niveaux d’IL-18BP sont plus bas chez les patients infectés comparés aux donneurs sains. Alors, le ratio IL-18/IL-18BP est augmenté chez les patients infectés, ce qui entraîne une grande quantité d’IL-18 libre et biologiquement active circulante dans leur organisme. Nos études démontrent que chez ces patients, les concentrations d’IL-18 sont en corrélation négative avec l’activité cytotoxique de leurs cellules NK. Nos études in vitro démontrent que le traitement des cellules NK par l’IL-18 induit de façon fratricide leur apoptose en augmentant l’expression de Fas ligand. Finalement, cette production non coordonnée de ces deux facteurs pourrait contribuer à une immunopathologie induite par l’IL-18 en entraînant une apoptose fratricide des cellules NK qui possèdent un rôle important dans la réponse antivirale. Le dérèglement de l’homéostasie des cellules NK pourrait donc contribuer à la pathogenèse induite par le VIH.HIV-1, the causative agent of AIDS, induces a deregulated production of several immunologically important cytokines in the infected persons. One of these cytokines is IL-18: a powerful proinflammatory cytokine that can regulate both innate and adaptive immune responses. In vivo, its activity is tightly regulated by IL-18 Binding Protein (IL-18BP), another cytokine that specifically binds and neutralizes IL-18 with high affinity. Previous studies have shown that IL-18 concentrations are significantly increased in the circulation of HIV-infected AIDS patients compared to those in healthy people. However, it is not yet clear how the increased levels of this cytokine affect the development of AIDS in HIV infected persons. Furthermore, little is known concerning the production of IL-18 antagonist (IL-18BP) in these patients. These issues were addressed in the studies presented in this thesis. We measured levels of IL-18 and IL-18BP in the sera of HIV-infected patients by using commercial ELISA kits and compared them with the values obtained from a similar number of healthy HIV-seronegative persons. We also determined the absolute and total number of different NK cell subsets and NK cell activity in the peripheral blood mononuclear cells (PBMC) of these individuals. Finally we determined the effects of recombinant human IL-18 as well as of IL-18-rich sera from AIDS patients on cytolytic activity and survival of human NK cells. Our results show that sera from HIV- infected patients contain up to 3 fold higher levels of IL-18 compared to the sera from healthy people. However, levels of IL-18BP were lower in the infected individuals compared to the healthy ones. Consequently, IL-18/IL-18BP ratio is increased in the patients resulting in a further increase in the concentrations of biologically active IL-18 in the circulation of these patients. Our results show that the concentrations of IL-18 correlated inversely with NK cell numbers as well as with their cytolytic activity in the infected persons. These results suggested the involvement of IL-18 in the disappearance of NK cells that prompted us to determine the potential cytocidal effects of this cytokine on human NK cells. The results from our in vitro experiments show that recombinant human IL-18 and IL-18-rich sera from AIDS patients caused apoptosis in a human NK cell line as well as in primary human NK cells. Anti-FasL antagonist antibodies inhibited this cell death. In a series of experiments, we found that IL-18 enhances expression of FasL but does not affect the expression of Fas on human NK cells. In vitro IL-18 also stimulated transcription from human FasL promoter. Furthermore, the cytokine also enhanced susceptibility of NK cells to Fas-mediated death, as it decreased the expression of an anti-apoptotic protein Bcl-XL. Our study shows that enhanced IL-18 bioactivity in HIV-infected patients may contribute to the pathogenesis of AIDS by disrupting NK cell homoeostasis.
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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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Herynek, Štěpán. "Strukturní biologie receptoru NKp44 a jeho ligandu PCNA." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-396717.
Full textAbstract:
Natural killer cells (NK cells) are part of the immune system in human and other mammals. The task of these cells, which belong to the non-specific immunity, is to induce apoptosis in other cells of the body that may represent a threat for the body (i.e., tumour or virally infected cells). NK cells have a variety of surface receptors to recognize their target cells. A number of receptors are well-known today and they may be divided into groups based, e.g., on their structural similarities or on the type of signal which these receptors present to NK cells. Accordingly, we distinguish activation and inhibitory receptors. Inhibitory receptors inhibit NK cell response, while activation receptors elicit this response. During NK cell contact with another cell, the resulting NK cell behaviour is always the result of a certain balance of activation and inhibitory receptor responses. The NKp44 receptor is an immunoglobulin-like receptor. This receptor is very unique among other receptors in many respects, for example because it is associated with both activation and inhibitory motif. The ligand of this receptor is a proliferating cell nuclear antigen (PCNA). PCNA is a clamp protein important, inter alia, during DNA replication, in which it anchors other replisome proteins. This work is focused on...
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Chan, Gordon [Verfasser]. "The role of Vav-1, Vav-2 and Lsc in NK T-cell development and NK cell cytotoxicity / vorgelegt von Gordon Chan." 2002. http://d-nb.info/966206258/34.
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Dvorská, Anna. "Strukturní biologie komplexu potkaních NK buněčných receptorů NKR-P1B a Clrb." Master's thesis, 2014. http://www.nusl.cz/ntk/nusl-338187.
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The Natural Killer (NK) cells have an important role in the nonspecific immunity of the or- ganism. They have the ability to identify and to kill tumor cells and cells infected by a virus without preceding sensitization by antigen. Their function is directed by the amount of sti- mulation and inhibition receptors interacting with ligands on the tumor or infected cell. This thesis focuses on the preparation and the study of the complex of rat NK cellular inhi- bition receptor NKR-P1B ("natural killer cell receptor - protein 1B") and its ligand Clrb ("C-type lectin-related ligand b"). The Clrb initiates the inhibition of NKR-P1B, meaning that if the cell express Clrb, it won't be destroyed. If the cell gets infected by the rat cytome- galovirus, it loses Clrb from its surface and its destruction is therefore no longer prevented. Cells infected with this virus defend themselves from destruction by expression of the viral gene of C-type lectin RCTL, which is a homolog of Clrb. Transient transfection of human embryonic kidney 293 cell line with simple glycosylation (HEK293S GnTI− ) was used for the recombinant preparation of the soluble form of these two receptors of the rat NK cells. The native forms of the receptors - disulfidic homo- dimers - were prepared as the fusion construct with IgG Fc (using...
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Jülke, Kerstin [Verfasser]. "Role of cytokines for NK cell competence and differentiation / von Kerstin Jülke." 2010. http://d-nb.info/101054361X/34.
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(10283939), Andrea M. Chambers. "IMMUNOTHERAPY OF SOLID TUMORS WITH IMMUNOMETABOLICALLY-RETARGETED NATURAL KILLER CELLS." Thesis, 2021.
Find full textAbstract:
Cancer is responsible for the second highest cause of death in the United States, and lung cancer accounts for 13% of new cancer diagnoses, with the highest rate of cancer death at 24%. Almost 85% of these cases represent non-small cell lung cancer (NSCLC), which includes lung adenocarcinoma, the most common NSCLC subtype. Traditional cancer treatments often only temporarily stop the spread of the disease, but immunotherapies, which are becoming a standard of care, are much more promising. Natural killer (NK) cells are powerful effectors of innate immunity, and genetically engineered NK cells as immunotherapies have had encouraging clinical responses in the treatment of various cancers. However, more progress is needed for solid tumor treatment, especially for lung adenocarcinoma. The activation of cancer-associated ectoenzymes, CD39 and CD73 catalyze the phosphorylation of ATP to AMP to produce extracellular adenosine (ADO), which is a highly immunosuppressive mechanism contributing to the pathogenesis of solid tumors. Understanding adenosine effects on NK cells will help develop more robust immunotherapeutic treatments to improve cytotoxicity against solid tumors. Here, we established that tumor microenvironment ADO results in impaired metabolic and anti-tumor functions of cytokine-primed NK cells. Specifically, peripheral blood-derived NK cells stimulated with IL-2, IL-15, or a combination of IL-12 and IL-15 showed suppressed anti-tumor immunity due to ADO. This was observed by the downregulation of activation receptor expression, cytotoxicity inhibition, impairment of metabolic activity, and alterations in gene expression. To target ADO-producing CD73 on cancer cells, we redirected NK cells by fusing CD73 ScFv with intracellular and transmembrane regions of NK cell specific signaling components derived from FCyRIIIa (CD16). Engineered NK cells were shown to be cytotoxic against lung adenocarcinoma in vitro and impede tumor growth in a lung adenocarcinoma mouse model in vivo. Engineered cells also had higher levels of degranulation and cytokine release, as well as more infiltration into tumors and longer survival time in mice. In summary, the microenvironment of solid tumors is highly immunosupressive, and redirecting NK cell function using a NK-specific anti-CD73 targeting construct will help to promote anti-tumor immunity and
inhibit cancer growth for a potentially powerful new immunotherapy against solid tumors.
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Dessureault, Mireille. "Effet du sécrétome des cellules sénescentes sur la réponse inflammatoire orchestrée par les macrophages." Thèse, 2016. http://hdl.handle.net/1866/18640.
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L’élimination des cellules sénescentes met en jeu le SASP et les cellules immunitaires de l’immunité innée et adaptative tels que les macrophages (Mφ). Dans le cadre de ce projet, nous rapportons que le SASP a un effet pléiotropique sur l’activité des cellules immunitaires incluant leur recrutement, leur activation et leur différenciation. Nos données montrent que les Mφ humains mis en culture avec le SASP de fibroblastes humains développement un profil inflammatoire spécifique au SASP caractérisé par une sécrétion pro-inflammatoire (M1) (ex : IL- 1β, GM-CSF) et des marqueurs de surface anti-inflammatoires (M2) (cellules CD23+CD206+). Le SASP est aussi capable d’augmenter les capacités d’invasion des Mφ, tel que montré via des essais d’invasion, mais n’a pas d’effet sur la différentiation des monocytes. Nos modèles de co- culture montrent que, quoique les cellules NK sont probablement responsables de l’élimination directe et spécifique des cellules sénescentes, leur activité peut être modulée par d’autres cellules immunitaires tels que les Mφ qui réduisent l’élimination faite par les cellules NK, suggérant un profil M2. Les lymphocytes T CD8+ sont aussi essentiels pour l’élimination des cellules sénescentes puisque leur retrait retarde le processus. De plus, nous démontrons que les cellules T CD4+ mises en culture pendant 48h dans le SASP sécrètent de hauts niveaux d’IL-4, indiquant une polarisation Th2. Somme toute, ces données montrent que le SASP peut moduler l’activité des Mφ tout comme celle d’autres cellules immunitaires impliquées dans l’élimination des cellules sénescentes et peut promouvoir, étonnamment, une réponse immunosuppressive pouvant être importante pendant la réparation tissulaire.Senescent cell clearance brings into play the senescence-associated secretory phenotype (SASP) and immune cells from the innate and adaptive immunity including macrophages (Mφ). In this study, we report that the SASP has a pleiotropic effect on immune cell activity including recruitment, activation and differentiation. We show that human Mφ exposed to the SASP of human fibroblasts develop a SASP-specific inflammatory profile characterized by pro- inflammatory (M1) secretion (e.g. IL-1β, GM-CSF) and anti-inflammatory (M2) surface markers (CD23 and CD206). The SASP also increases Mφ invasion but has no effect on monocyte differentiation. Co-culture models show that while NK cells are likely the direct effectors of senescent cell specific killing, their activity is modulated by other immune cells including Mφ, which reduced NK-mediated killing, suggesting a M2 profile. Alternatively, CD8+ T lymphocytes are essential for senescent cell killing by NK cells. Finally, CD4+ T cells cultured for 48h in the SASP secrete high-levels of IL-4, indicating a Th2 polarization. Overall, our data reveal that the SASP can modulate Mφ and other immune cells involved in senescent cell clearance and surprisingly promote an immunosuppressive response that could be important in tissue repair.
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Groß, Catharina Christiane [Verfasser]. "Membrane-bound Hsp70 an activating ligand for NK cells / Catharina Christiane Groß." 2004. http://d-nb.info/974983829/34.
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Almalte, Zaema. "Innate immunity genes as determinants of resistance/susceptibility to human disease : studies in leukemia patients." Thèse, 2010. http://hdl.handle.net/1866/4471.
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La leucémie lymphoblastique aiguë des cellules Pré-B (B-ALL) reste le type de cancer le
plus souvent diagnostiqué chez les enfants. Des études ont montré que des déterminants
génétiques jouent un rôle important dans la susceptibilité/résistance au développement de
ce cancer. À cet égard, les gènes Killer-cell Immunoglobulin-like Receptor (KIR) sont
d'une importance particulière. Ces gènes sont fortement polymorphiques et codent pour
des récepteurs qui contrôlent l’activité fonctionnelle des cellules Natural Killer (NK).
Notre hypothèse est que les gènes activateurs des KIR s’associent avec la résistance innée
pour développer la B-ALL. Afin d'évaluer cette hypothèse, nous avons entrepris une
étude de cas-contrôles chez des enfants canadiens-français dans laquelle nous avons
utilisé l'ADN génomique de 100 patients atteints de B-ALL ainsi que l’ADN de 245
individus sains. La présence ou l'absence de chaque gène KIR a été détectée par PCR en
utilisant des amorces de séquences spécifiques. Nous avons trouvé que la présence des
gènes KIR activateurs est significativement diminuée chez les enfants leucémiques par
rapport aux témoins. En outre, le nombre de ces gènes a aussi montré une association
significative linéaire avec la résistance au développement d’une B-ALL. Cela suggère des
effets additifs de ces gènes permettant de conférer une protection contre ce cancer. Ces
résultats pourraient être utiles afin de déceler de façon précoce les enfants ayant un risque
de développer cette leucémie. Enfin, des stratégies thérapeutiques basées sur les
récepteurs KIR pourraient être envisagées et s'avérer utiles concernant le traitement de ce
cancer chez les enfants.Investigating genetic determinants that play a role in conferring susceptibility/resistance to the development of acute B cell leukemia (B-ALL) in children is highly desirable. We hypothesized that activating Killer-cell Immunoglobulin-like Receptor (KIR) genes, which are implicated in NK cell activation, may represent one of these determinants. To test this hypothesis, we conducted a case-control study in French-Canadian children in which we used genomic DNA from 100 B-ALL patients and 245 healthy controls. The presence or absence of each KIR gene was detected by PCR using sequence-specific primers. We found that the frequencies of these genes are significantly reduced in B-ALL cases when compared with their healthy counterparts. Furthermore, we found that these genes had an additive effect in reducing risk for developing the cancer. The results may be useful in early identification of children at risk for developing this cancer. Moreover, KIR-based therapies may prove to be useful in treating this cancer.
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Sim, Geok Choo [Verfasser]. "Dysfunctional plasmacytoid dendritic cells but not NK cells in the peripheral blood of stage IV melanoma patients / presented by Geok Choo, Sim." 2011. http://d-nb.info/1010828215/34.
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Cappello, Sabrina. "Exploring molecular patterns and determinants of melanoma cell susceptibility to natural killer cell cytotoxicity." Doctoral thesis, 2020. http://hdl.handle.net/21.11130/00-1735-0000-0005-1420-0.
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Jacques, Alexandre. "Mécanismes de défense immunitaire innée impliqués dans l’hépatite aiguë induite par le virus de l’hépatite murine de type 3." Thèse, 2008. http://hdl.handle.net/1866/2663.
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Le virus de l’hépatite murine de type 3 (MHV3) est un excellent modèle animal pour l’étude des différents désordres immunologiques lors d’infections virales. L’hépatite aiguë fulminante induite par ce virus chez la souris susceptible C57BL/6 se caractérise par la présence de plusieurs foyers nécrotiques et inflammatoires dans le foie associée à une immunodéficience en lymphocytes B et T, tuant les souris entre 3 et 5 jours post-infection. L’évolution rapide de cette maladie virale suggère un débalancement dans les mécanismes de l’immunité naturelle sous le contrôle des cellules NK et NK-T et un bris de l’équilibre entre la tolérance hépatique et la réponse inflammatoire. Afin d’élucider les rôles respectifs des différents mécanismes de la défense innée impliqués dans le développement de l’hépatite aiguë, des infections in vivo ont été réalisées chez des souris C57BL/6 avec la souche pathogène L2-MHV3 ou avec des variants du virus MHV3. Ces derniers possèdent des tropismes différents pour les cellules endothéliales sinusoïdales hépatiques et les cellules de Kupffer, tels que les virus faiblement atténué 51.6-MHV3, fortement atténué CL12-MHV3 et non pathogène YAC-MHV3. Ces études in vivo ont montré une diminution des cellules NK spléniques et myéloïdes suite à une infection avec le virus MHV3. Cette chute en cellules NK spléniques reflète un recrutement de ces cellules au niveau du foie. Par contre, les cellules NK se sont avérées permissives à la réplication virale entraînant un processus d’apoptose suite à la formation de syncétia induits par le virus. Les niveaux de recrutement et d’apoptose des cellules NK et NK-T dans le foie reflètent la pathogénicité des variants MHV3 durant les trois premiers jours de l’infection virale bien que les cellules NK recrutées au niveau du foie maintiennent leur activité cytotoxique. L’ajout des IL-12 et IL-18, qui sont normalement diminués lors de l’hépatite aiguë, provoque une production synergique d’IFN-g par les cellules NK, résultant d’une interaction entre l’activation de la voie p38 MAPK et la réplication virale. Par ailleurs, le récepteur viral CEACAM1a (carcinoembryonic antigen cell adhesion molecule 1a) serait essentiel à cette synergie, mais exercerait aussi une action inhibitrice dans la production de l’IFN-g. D’autre part, les niveaux de production des cytokines immunosuppressives IL-10, TGF-b et PGE2, impliquées dans la tolérance hépatique et particulièrement produites par les cellules de Kupffer et les cellules endothéliales sinusoïdales, sont en relation inverse avec le degré de pathogénicité des variants du virus MHV3. Finalement, le virus pathogène L2-MHV3 déclenche la production de cytokines inflammatoires par les macrophages, tels que l’IL-6 et le TNF-a. L’induction de ces cytokines par les macrophages serait indépendante de la présence de la molécule CEACAM1a. Cette stimulation est plutôt reliée à la fixation des particules virales sur des récepteurs TLR2, en association avec les régions riches en héparanes sulfates. Tous ces résultats mettent en évidence de nouveaux mécanismes par lesquels le virus MHV3 peut diminuer l’efficacité des mécanismes de l’immunité naturelle sous le contrôle des cellules NK et NK-T intrahépatiques, suite à une stimulation de l’inflammation résultant du bris de la tolérance hépatique.Mouse hepatitis virus type 3 (MHV3) is an excellent model to study immunological disorders related to viral infections. The fulminant acute hepatitis induced in susceptible C57BL/6 mice is characterized by the presence of necrotic and inflammatory foci in the liver associated with B and T cell immunodeficiencies leading to the death of the animals in 3 to 5 days post-infection. The fulminance of this viral infection suggests a deficiency in the natural immunity mechanisms under control of NK and NK-T cells and an imbalance between the hepatic tolerance and the inflammatory responses. To understand the different mechanisms involved in the acute hepatitis, in vivo infections have been done in C57BL/6 mice with either the pathogenic L2-MHV3, or with its attenuated variants: the weak attenuated 51.6-MHV3, the highly attenuated CL12-MHV3 or the non-pathogenic YAC-MHV3 viruses, possessing different tropisms for liver sinusoidal endothelial cells and Kupffer cells. The results demonstrate that splenic and myeloid NK cells are impaired during a MHV3 infection. This impairment is due to a recruitment of these cells in the liver and a virus-induced apoptotic phenomenon. The recruitment and the subsequent apoptosis of NK and NK-T cells during the first three days of infection are in relation with the pathogenicity of the MHV3 variants. In spite of the fact that hepatic recruited NK cells are still cytotoxic, these cells undergo apoptosis due to viral replication via the formation of syncytia. Addition of IL-12 and IL-18, which are impaired during the acute hepatitis, promote a synergistic IFN-g production by NK cells depending of both the p38 MAPK pathway and the viral replication. Moreover, the specific viral receptor CEACAM1a (carcinoembryonic antigen cell adhesion molecule 1a) is essential for this response but also exerts an inhibitory action. Levels of the immunosuppressive cytokines IL-10, TGF-b and PGE2, mainly produced by Kupffer cells and sinusoidal endothelial cells, and implicated in the natural hepatic tolerance, are in inverse correlation with the pathogenicity of the MHV3 variants. Finally, viral infection promotes the secretion of IL-6 and TNF-a by macrophages, triggered by the fixation of viral particules to TLR2 and heparan sulfate receptors rather than the engagement of CEACAM1a receptor and viral replication. In conclusion, our results suggest new mechanisms by which the MHV3 virus disturbs the innate immunity under control of NK and NK-T cells, as well as the cytokines involved in the hepatic tolerance to the detriment of the inflammatory response.
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Richard, Jonathan. "Étude du rôle de la protéine Vpr du VIH-1 dans la modulation de la réponse immunitaire." Thèse, 2013. http://hdl.handle.net/1866/10118.
Full textAbstract:
L’infection par le VIH-1 est caractérisée par une activation chronique du système immunitaire et par une réduction graduelle du nombre de lymphocytes TCD4+, qui contribuent à une détérioration lente du système immunitaire menant à la phase SIDA. Paradoxalement, ce sont majoritairement des lymphocytes T CD4+ non infectés qui sont détruits et la cause de ce phénomène reste encore inconnue. Certaines protéines virales, dont la protéine accessoire Vpr, sont soupçonnées de jouer un rôle dans ce processus. Synthétisée tardivement, Vpr est incorporée à l’intérieur des virions, en plus d’être relâchée sous forme soluble dans le milieu extracellulaire. La principale fonction biologique de Vpr est l’induction d’un arrêt de cycle en phase G2/M, via le recrutement du complexe d’ubiquitine E3 ligase CUL4A-DDB1VprBP et l’activation de la voie de dommage à l’ADN contrôlée par la kinase ATR. Une étude démontre que l’activation des voies de dommages à l’ADN conduit à l’expression de ligands du récepteur activateur NKG2D, exprimés par les cellules NK, déclenchant leurs fonctions cytolytiques. Chose intéressante, plusieurs études suggèrent que le VIH-1 régule positivement l’expression des ligands de NKG2D à la surface des lymphocytes T CD4+ infectés. Cependant, le facteur viral impliqué dans ce processus reste encore indéfini.
Le but de cette thèse était d’évaluer le rôle de Vpr dans la modulation des fonctions cytolytiques des cellules NK et son implication potentielle dans la destruction des lymphocytes T CD4+. Nos travaux ont permis de démontrer que l’expression de Vpr, seule ou dans le contexte de l’infection, est suffisante afin d’augmenter spécifiquement l’expression du ligand de NKG2D, ULBP2, au niveau de lymphocytes T CD4+ primaires. Conséquemment, Vpr augmente ainsi la susceptibilité de ces cellules à une lyse par des cellules NK autologues. Nous démontrons que cette régulation positive d’ULBP2 repose sur la capacité de Vpr de recruter le complexe d’ubiquitine E3 ligase DDB1-CUL4AVprBP et l’activation de la voie de dommage à l’ADN ATR. Plus important encore, nous apportons des preuves que Vpr augmente également l’expression d’ULBP2 au niveau des cellules non infectées lors d’une infection de lymphocytes TCD4+ par le VIH-1. À cet effet, nous montrons que l’acheminement de Vpr au niveau de lymphocytes T CD4+ non infectés via des particules virales défectives est suffisant afin de réguler positivement ULBP2 et d’augmenter leur lyse par des cellules NK autologues. De plus, nous décrivons pour la première fois que Vpr, sous forme soluble, a la capacité d’induire des dommages à l’ADN et de réguler positivement ULBP2 suite à la transduction de différents types cellulaires, incluant des cellules T.
Globalement, nos résultats démontrent que Vpr est un facteur viral clé impliqué dans la régulation positive des ligands de NKG2D induite par le VIH-1. Cette régulation positive d’ULBP2 pourrait alors contribuer à la destruction des lymphocytes T CD4+ infectés et non infectés via l’activation des fonctions cytolytiques des cellules NK. Une meilleure compréhension de la contribution de cette activité de Vpr dans la pathogenèse du VIH-1 a le potentiel de permettre le développement de nouvelles cibles ou stratégies thérapeutiques contre le VIH-1.Chronic immune activation and gradual depletion of CD4+ T cells are hallmarks of HIV-1 infection, which are thought to contribute to the progressive deterioration of the host’s immune response that ultimately leads to AIDS. Paradoxically, the majority of CD4+ T cells that are destroyed are uninfected and causes for this bystander effect of infection on CD4+ T cells remains unclear. Some HIV-1 proteins, including the accessory protein Vpr, are suspected to play a role in this process. Vpr, expressed late during HIV-1 infection, is shown to be incorporated within the budding virions as well as secreted as soluble protein in the extracellular medium from the infected cells. The main biological function of Vpr is the induction of a G2/M cell-cycle arrest through the recruitment of the E3 ubiquitin ligase complex DDB1-CUL4AVprBP and activation of the ATR-mediated DNA damage pathway. One study showed that activation of DNA damage pathways leads to the expression of specific ligands for the activating receptor NKG2D expressed on NK cells, thus triggering NK cell cytolytic function. Interestingly, several evidences suggest that HIV-1 upregulates expression of specific NKG2D ligands on infected CD4+ T cells. However, the viral factor involved in this process remains undefined. The aim of this thesis was to evaluate the role of Vpr in modulating NK cell cytolytic function and its potential involvement in CD4+ T cells depletion. Our work demonstrated that the expression of Vpr, alone or in the context of HIV-1 infection, is sufficient to specifically increase expression of the NKG2D ligand, ULBP2, on primary CD4+ T cells. Consequently, these CD4 T cells become more susceptible to autologuous NK cell-mediated lysis. Our studies have shown that this Vpr-mediated ULBP2 upregulation requires the recruitment of the E3 ubiquitin ligase complex DDB1-CUL4AVprBP and the activation of the ATR-mediated DNA damage pathway. More importantly, we provide evidence that Vpr augments ULBP2 expression on both infected and uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes. In that context, we show that delivery of Vpr into uninfected cells via defective viral particles is sufficient to upregulate ULBP2 and increase their susceptibility to autologuous NK cell-mediated killing. In addition, we describe for the first time that soluble Vpr has the ability to induce DNA damages and upregulate ULBP2 upon transducing target cells, including T cells. Overall, our results show that Vpr is a key HIV-1 factor involved in the upregulation of NKG2D ligands induced by HIV-1. This upregulation of UBP2 might contribute to depletion of infected and uninfected CD4 + T cells through activation of NK cell cytolytic functions. A better understanding of the contribution of this new activity of Vpr in HIV-1 pathogenesis has the potential to enable the development of new therapeutic targets or therapeutic strategies against HIV-1.