Dissertations / Theses on the topic 'Killer cells'
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1
El-Sherbiny, Yasser Mohamed. "Natural killer cells and plasma cell neoplasia." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438481.
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Chisholm, S. E. "Natural killer cell recognition of virally infected cells." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597615.
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Natural killer (NK) cells are known to be important for the control of viral infections, particularly infection with large double stranded (ds)DNA viruses such as herpes simplex virus type 1 (HSV-1) and vaccinia virus (VV), but the pathways and interactions important for NK cell recognition of virally infected cells are not well understood. Thus, the aim of this thesis was to study the molecular mechanisms of NK cell recognition of target cells infected with either HSV-1 or VV. Experiments using a set of HSV-1 mutants, deficient in one or more of the immediate early (IE) genes, demonstrated that expression of ICP0 alone was found to be sufficient to render HSV-1 infected target cells susceptible to NK attack, and killing assays demonstrated that the natural cytotoxicity receptors (NCRs) were involved in the NK mediated killing of HSV-1 infected targets. For VV, it was not possible to narrow down exactly which VV gene was sufficient for generating NK cell mediated susceptibility, but the data indicated that the VV gene or genes involved are expressed early, conserved within the poxvirus family, and as such, likely to be essential for the virus. Flow cytometry experiments demonstrated that altered susceptibility of the target cells to NK cell lysis was due to upregulation of ligands for the NCRs, and the importance of the NCRs in NK mediated killing of VV infected targets was confirmed by killing assays. In addition, flow cytometry experiments demonstrated very little down regulation of MHC class I followed infection by either HSV-1 or VV, implying that MHC class I down regulation is not of major importance in NK mediated killing of infected cells.
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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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Damico, Nicole. "Preparing and Cloning a Natural Killer Cell Hybridoma." Youngstown State University / OhioLINK, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1004458025.
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Mahmood, Sajid. "Diverse regulation of natural killer cell functions by dendritic cells." Public Library of Science, 2012. http://hdl.handle.net/1993/23963.
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Natural killer (NK) cells are innate lymphocytes with inherent ability to eliminate infected cells and produce several cytokines/chemokines. They express surface receptors to sense environment and interact with other immune cells including the Dendritic cells (DC). Reciprocally, DCs are also shown to activate NK-cells. NK/DC cross-talk is well-documented, yet the molecular interactions and the diverse NK-cell activities regulated by DC remain unclear.
Several target proteins such as MHC-1, Qa-1 mediate NK-cell target recognition. One such antigen, Ocil/Clr-b functions as a cognate ligand of NKR-P1B/D, NK-inhibitory receptor. In first aim of my study, I documented that deficiency of Ocil/Clr-b expression not only augmented the sensitivity of DC towards NK-cell cytotoxicity but also regulated the development of mature NK-cells. Thus suggesting NKR-P1B/D:Ocil to be another receptor:ligand system, besides Ly49:MHC-1, that regulates NK-cell responsiveness.
Src homology region 2-containing protein tyrosine phosphatase-1 (SHP-1) transmits inhibitory signals of the specific NK-inhibitory receptors, including NKRP-1B/D. SHP-1 silenced NK-cells showed unaffected target recognition towards prototypic target cells in this study. In addition, these cells also displayed an unexpected phenotype of self-killing in-vitro, thus implicated SHP-1 as an important regulator of some other unappreciated NK-cell functions.
The data from my third study suggest that DCs are directly implicated in the induction of NK-cell migration. In summary, using a novel live-cell imaging microfluidic platform and conventional transwell migration assay this project established a clear molecular link between DC-derived soluble factors such as IP-10 and NK cell-chemokine receptor such as CXCR3. Previously, GM-CSF was shown as an inflammatory cytokine, involved in the development of DC as well as in mediating Th-1 immune responses. In this study I found that GM-CSF regulates NK-cell migration negatively.
Lastly, the fourth aim of my thesis highlighted the critical role of immature-DC in the induction of maturation receptors (NK1.1 & Ly49) on differentiating NK-cells. I successfully established a multi-stage in-vitro NK-cell differentiation model and found that differentiating NK-cells required an active engagement with DCs, in addition to the soluble factors.
I believe my PhD project findings would impact the existing knowledge to harness DC-based NK cell therapies in clinical settings.October 2014
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Evans, James Henry. "The interactions of human Natural Killer cells with accessory cells." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/6374.
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Natural Killer (NK) cells are lymphocytes of the innate immune system. However, there is increasing evidence that they can also play important roles in the adaptive immune system; as initiators, through antigen presentation; as effectors, via early release of IFN-y; and as immunoregulators, by eliminating over-activated macrophages. The functions of NK cells in these roles are intimately linked to their interactions with other cells during an immune response, for example recognition of target cells via activating receptors. The activating receptor NKG2D recognises proteins that are not normally expressed at the surface of most cells but are up-regulated during a cellular ‘stress’ response. However, NKG2D ligands can also be induced on human macrophages by TLR stimulation, leading to NK cell-mediated lysis. Here, I clarify that ligation of TLR4 preferentially up-regulates MICA but not MICB, TLR7/8 ligation up-regulated both MICA and MICB, while ligating TLR3, signalling through a MyD88-independent pathway, up-regulated neither. TLR4 stimulation decreased expression of microRNAs, miR-17-5, miR- 20a and miR-93, which target MICA, implicating a novel role for microRNAs in post-transcriptional regulation of NKG2D ligand expression. Moreover, the pathway involved IL-12/TNF- a-mediated autocrine signalling, thus incorporating an intrinsic mechanism for NK cell-mediated elimination of particularly activated macrophages. In addition to this immunoregulatory role, NK cell activity can shape a subsequent adaptive immune response. Subsets of NK cells can have distinct functions. Here, I demonstrate that following culture with IL-2, >25% of human peripheral blood NK cells express HLA-DR, due to an expansion of a small subset of NK cells expressing HLA-DR, in contrast to previous assumptions that HLADR is upregulated on previously negative cells. HLA-DR-expressing NK cells exhibited enhanced degranulation to susceptible target cells and expression of the chemokine receptor CXCR3, which facilitated their enrichment following exposure to CXCL11/I-TAC. Suggestive of an immunological role, stimulation of PBMCs with Mycobacterium bovis BCG triggered dramatic expansion of HLADR- expressing NK cells. In addition, the magnitude of the NK cell IFN-y secretion response in PBMC triggered by BCG was associated with the proportion of HLA-DR-expressing NK cells ex vivo. A direct contribution to the immune response was determined by specifically enriching the HLA-DR-expressing NK cell compartment, which substantially augmented the total NK cell IFN-y secretion response to BCG. Thus, HLA-DR expression marks a distinct subset of NK cells, present at low frequency in peripheral blood but readily expanded by IL-2, that can play a significant role during immune responses.
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El-Jawhari, Jehan Jomaa El-Said. "Tumour-mediated inhibition of natural killer cells." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590426.
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The critical role of immune cells, in particular NK cells and cytotoxic T lymphocytes in recognition and elimination of tumour cells has been clearly demonstrated. However, immune evasion is a central hallmark of cancer; it negatively influences the prognosis and efficiency of therapies. Thus, understanding of this process will help to improve cancer therapy. Genetic alterations such as activation of oncogenes and loss of tumour suppressor genes are highly implicated in carcinogenesis. This study shows that the presence of KRAS oncogene reduced the surface expression of MHC class I on colorectal tumour cells and lead to suppression of CTL response. In contrast, the expression of KRAS oncogene did not affect the susceptibility of colorectal tumour cells to NK. cell killing nor inhibit NK cell functions. This suggests that targeting of the KRAS oncogene in colorectal tumours to improve CTL responses would be of a therapeutic benefit. In contrast, loss of a tumour suppressor gene, VHL in renal tumour cells was associated with reduced inhibitory effects on NK cells. Further investigations into how tumour cells inhibit NK cells were performed via an assessment of the role for an immunosuppressive cytokine, TGF-β Interestingly, the data show that TGF-β participates in colorectal tumour-mediated modification of the surface expression of NK cell receptors as well as suppression of NK cell functions. Supporting in vitro results, malignant ovarian tumour cells (ascitic-derived) had an inhibitory effect on the phenotype and activities of NK cells. Importantly, TGF-β was involved in these suppressive effects. My data strongly support targeting of TGF-β in therapy of colorectal and ovarian cancers to enhance anti-tumour responses ofNK cells.
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Suck, Garnet, Yeh Ching Linn, and Torsten Tonn. "Natural Killer Cells for Therapy of Leukemia." Karger, 2016. https://tud.qucosa.de/id/qucosa%3A71644.
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Clinical application of natural killer (NK) cells against leukemia is an area of intense investigation. In human leukocyte antigen-mismatched allogeneic hematopoietic stem cell transplantations (HSCT), alloreactive NK cells exert powerful anti-leukemic activity in preventing relapse in the absence of graft-versus-host disease, particularly in acute myeloid leukemia patients. Adoptive transfer of donor NK cells post-HSCT or in non-transplant scenarios may be superior to the currently widely used unmanipulated donor lymphocyte infusion. This concept could be further improved through transfusion of activated NK cells. Significant progress has been made in good manufacturing practice (GMP)-compliant large-scale production of stimulated effectors. However, inherent limitations remain. These include differing yields and compositions of the end-product due to donor variability and inefficient means for cryopreservation. Moreover, the impact of the various novel activation strategies on NK cell biology and in vivo behavior are barely understood. In contrast, reproduction of the thirdparty NK-92 drug from a cryostored GMP-compliant master cell bank is straightforward and efficient. Safety for the application of this highly cytotoxic cell line was demonstrated in first clinical trials. This novel ‘off-theshelf’ product could become a treatment option for a broad patient population. For specific tumor targeting chimeric-antigen-receptor-engineered NK-92 cells have been designed.
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Stringaris, Katherine. "Natural killer cells and acute myeloid leukaemia." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/18014.
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Despite successful induction chemotherapy, most patients with acute myeloid leukemia (AML) will relapse. Immune surveillance by T cells or natural killer (NK) cells may play a role in preventing relapse. This thesis examines the potential of NK cells to control AML. Study 1 explored in 248 patients with haematological malignancies from the US National Institutes of Health, the genetic diversity of NK killer immunoglobulin receptor (KIR) genes in patients and their stem cell donors and their impact on outcome after stem cell transplantation (SCT) for haematological malignancy. Individuals with AML receiving SCT from donors inheriting 3 particular B-haplotype KIRs were 4 times less likely to relapse than those with donors without these favourable KIRs. Study 2 explored in samples obtained from 499 patients enrolled on UK MRC/NCRI AML trials, whether KIR genotype affects the risk of developing AML or the outcome of remission induction chemotherapy. While KIRs had no effect on the development or outcome of de novo AML, individuals with more activatory KIRs, in particular 2DS2, developed significantly less secondary AML, suggesting that activatory KIRs can protect against secondary AML. These studies support a role for NK-mediated immune surveillance in AML. Study 3 investigated the phenotype and function of AML NK cells. In 32 prospectively collected samples from AML patients undergoing remission induction chemotherapy at the Hammersmith Hospital, AML patients were found to have reduced NK activatory receptors, increased NK inhibitory receptors, and reduced cytotoxic function towards leukaemia, compared to healthy donors. These abnormalities corresponded with failure to achieve remission and can be induced in normal NK incubated with AML blasts. I conclude that KIR genetics have a limited influence on AML development and outcome but that AML itself can impair NK function, reducing the chance of achieving remission. These findings have implications for NK based immunotherapy for AML.
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Senff, Tina [Verfasser], and Jörg [Akademischer Betreuer] Timm. "The role of Natural Killer cells and Natural Killer T cells in HCV infection / Tina Senff ; Betreuer: Jörg Timm." Duisburg, 2018. http://d-nb.info/1153338009/34.
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Wolf, A. S. "Natural killer cell responses to Plasmodium falciparum-infected red blood cells." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2017. http://researchonline.lshtm.ac.uk/3449324/.
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NK cells are known to respond in vitro to P. falciparum-infected red blood cells (iRBCs), although responses are highly heterogeneous between donors. Although their role during malaria infection is not fully understood, they may play a role in cytokine production during early infection, and furthermore may interact with and kill iRBCs. The work described in this thesis examines the role of NK cell receptors in determining the functional outcomes of NK cell activation by iRBCs, focusing on NK cell responses to exogenous cytokines and the phenotypic and functional profiles of NK cells from malaria naive (LSHTM) and malaria exposed (Ugandan) subjects. In a model of early activation of NK cells by accessory cell-derived cytokines, I have shown a key role for IL-18 in mediating NK cell responses during both primary and secondary immune responses as IL-18 synergises with cytokines from the common gamma chain family. NK cells from LSHTM donors showed low background expression of IFN- and CD25, but responded to iRBCs by secretion of IFN-, which was potentiated by exogenous IL-15. By contrast, NK cells from Ugandan donors showed higher background CD25 expression and signs of in vivo/ex vivo preactivation and enhanced responsiveness to IL-15, but did not make any appreciable response to iRBCs. Potential explanations for these findings are explored and discussed. KIR genotype and KIR expression also varied between LSHTM and Ugandan donors. Specifically, expansions of KIR2DL1+ CD57+ NKG2C+ NK cell populations (possibly driven by human cytomegalovirus (HCMV) infection) were observed in the Ugandan donors. Conversely, percentages of KIR2DL3+ and 2DS4+ NK cells were higher among LSHTM donors, indicating that HLA genotype or allelic KIR polymorphisms may influence KIR expression. Finally, the formation of NK-iRBC conjugates, which may be a precursor to NK cellmediated killing of iRBCs, was observed in cells from nearly all donors, but did not correlate with other functional responses. Analysis of KIR expression and NK cell functional responses indicated that donors expressing inhibitory KIR2DL5 had reduced numbers of conjugates. Further experiments indicated that KIR2DL5 might be specifically upregulated after incubation with iRBCs, and that individuals carrying a normally non-expressed KIR2DL5 gene may be able to express this gene under certain circumstances. This tentatively suggests a role for KIR2DL5 during NK cell responses to malaria infection, and suggests a possible function for a common but frequently non-expressed gene. In summary, my work suggests that NK cell responses are strongly influenced by cytokine receptor and KIR expression, which in turn depend on NK cell maturation status. KIR expression patterns may in part explain differential NK responses to iRBCs between LSHTM and Ugandan donors. I also propose a possible role for KIR2DL5 in malaria infection, and a reason for the low expression of this gene in African populations.
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Walwyn-Brown, Katherine. "Control of Th2 polarisation by dendritic cells and natural killer cells." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/control-of-th2-polarisation-by-dendritic-cells-and-natural-killer-cells(fd15f834-f926-40f1-88ff-217bf1fbf263).html.
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Type 2 (Th2) immune responses are required for immune defence against helminths, but can also have pathogenic effects in allergic conditions. This thesis examined two factors which may influence Th2 immunity at a cellular and molecular level: cross-talk between Natural Killer (NK) cells and dendritic cells (DCs) and the cell surface organisation of DCs. Cross-talk between NK cells and DCs is well-established to impact Th1 responses against tumours and infection; however the influence of this interaction during Th2 inflammation is unknown. To investigate this, human monocyte-derived DCs were stimulated in vitro with different pathogen-associated molecules; LPS or Poly(I:C) which polarise a Th1 response, or soluble egg antigen (SEA) from the helminth worm Schistosoma mansoni, a potent Th2-inducing antigen. These cells were then combined with autologous NK cells. Confocal microscopy showed polarisation of the NK cell microtubule organising centre (MTOC) and accumulation of LFA-1 at contacts between NK cells and immature or Th2-polarising DCs, but not Th1-polarising DCs, indicative of the assembly of an activating immune synapse. NK cells did not lyse DCs treated with LPS or Poly(I:C), but degranulated to and lysed both immature DCs and Th2 polarising DCs. Antibody blockade of NK cell activating receptors NKp30 and DNAM-1 prevented this lysis. Furthermore, depletion of NK cells in mice which were then transferred with Th2 polarising DCs led to an enhanced Th2 recall response. Thus, these data indicate a previously unrecognised role of NK cell cytotoxicity in restricting the pool of DCs involved in Th2 immune responses. Secondly, this thesis investigated the nanoscale organisation of MHC-II on the surface of Th1 and Th2 polarising DCs using ground state depletion super-resolution microscopy. MHC-II was relatively homogenously distributed across the membrane with no significant changes in clustering between immature, Th1 and Th2 polarising DCs. In contrast, imaging CD74, which can mediate internalisation of MHC-II, revealed increased expression and a more homogenous distribution of this receptor on the surface of Th2-polarising DCs compared to Th1-polarising DCs. These data suggest that changes in the clustering of CD74 could modulate MHC-II surface expression during Th2 responses. Overall, the results in this thesis indicate that both molecular and cellular level modulation of DC function contribute to the development of Th2 responses.
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Liang, Huyi, and 梁湖沂. "Enterovirus 71 directly infects human natural killer cells and induces cell apoptosis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hdl.handle.net/10722/208428.
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Enterovirus 71 (EV71) belongs to the Enterovirus genus of the family Picornaviridae and
is the major causative agent of hand, foot and mouth disease (HFMD). Although clinical
manifestations of HFMD are usually mild and self-limiting, severe HFMD patients suffer
from a diverse array of neurological diseases and sometimes these diseases are fatal.
HFMD usually occurs in young children and gradually becomes a new threaten in Asia.
Unfortunately, effective EV71 vaccine is not available to date and alternative treatments
are still in debate. This is partially due to the lack of understanding of EV71 pathogenesis
and host immune responses against EV71.
Natural killer (NK) cells are key effector cells in host antiviral activities by directly killing
viral-infected cells and producing cytokines and chemokines, especially in early phase of
viral infection. After enteroviruses infection, NK cells were one of the most abundant cell
types in the inflammatory infiltrate, and appeared to limit both enteroviruses replication
and virus-induced disease in experimental mice model. However, role of human NK cells
during EV71 infection, especially the direct interaction between EV71 and human NK
cells, was not studied extensively. Clinical observation manifested that patients with severe
EV71 infection have marked diminished NK cells in peripheral blood. Therefore we
hypothesized that EV71 might directly target human NK cells as one of its immunoevasion
strategies.
Here, we demonstrated for the first time that fresh primary human NK cells were
susceptible to EV71 infection. By flow cytometry and florescence microscope, EV71
capsid protein VP1 was able to be detected in viral-infected NK cells as soon as 6 hours
after infection and peaked at 24 hour after infection. In the same time, EV71 viral RNA
was detected by quantitative RT-PCR and the viral copies increased from 6 hour onwards
to peak at 12 hours after infection. We further demonstrated the infectious entry of EV71
in human NK cells was depended on clathrin-mediated endocytosis. Next, we illustrated
that EV71 infection could trigger NK cells apoptosis as evidenced by increased Annexin
V+, PI+, and activated caspase 3+ cells in EV71-treated NK cells. We further proved that
the cytotoxicity of NK cells was inhibited by EV71 infection and this inhibition might not
be related with down-regulation of NKp46, but may be related to the increased apoptosis.
In conclusion, our data suggested that EV71 might directly target and kill NK cells as a
strategy to evade human innate immunity, which might facilitate virus replication,
transmission and then contribute to viral-related pathogenesis.published_or_final_version
Paediatrics and Adolescent Medicine
Master
Master of Philosophy
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Tabayoyong, William Borj. "Engraftment of embryonic stem cell-derived hematopoietic progenitor cells is regulated by natural killer cells." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1089.
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Embryonic stem (ES) cells possess the remarkable ability to form cells and tissues from all three germ layers, a characteristic known as pluripotency. In particular, the generation of ES cell-derived hematopoietic cells could serve as an alternate source of hematopoietic stem cells for transplantation in place of bone marrow cells, which are limited by donor availability and high immunogenicity. The advantages of ES cell-derived hematopoietic cells over bone marrow cells include a greater proliferative capacity, which alleviates the problems of donor shortage, and low level expression of MHC antigens, which suggests immune privilege. However, it is unclear whether the immune system is capable of recognizing and rejecting ES cell-derived hematopoietic cells following transplantation. The observation that ES cell-derivatives express low levels of MHC class I, the predominant inhibitory ligand for NK cells, led us to hypothesize that ES cell-derived hematopoietic progenitor cells (HPC) are susceptible to NK cell-mediated killing.
To test this hypothesis, we first generated HPCs from murine ES cells ectopically expressing HOXB4, a homeobox transcription factor that confers hematopoietic self-renewal, and confirmed that HPCs expressed low levels of MHC class I antigens. To specifically investigate the role of NK cells in regulating the in vivo engraftment of HPCs, we transplanted NK-replete Rag2-/- or NK-deficient Rag2-/-γc-/- mice with HPCs. We observed permanent HPC engraftment in Rag2-/-γc-/- mice; however, HPC engraftment was significantly reduced in Rag2-/- mice and was eventually eliminated over time. Bone marrow harvested from these animals showed that HPC-derived Lin-c-kit+ and Lin-Sca-1+ progenitor cells, critical progenitor cells for long-term hematopoietic engraftment, were deleted in Rag2-/- but not in Rag2-/-γc-/- mice.
Next, we focused on the mechanism of NK cell activation by HPCs. Increased expression of the cytotoxic proteins Granzyme B and Perforin in the NK cells of HPC-transplanted Rag2-/- mice confirmed in vivo NK cell activation. Phenotypic analysis of HPCs revealed high level expression of H60, a ligand of the NK activating receptor NKG2D, and neutralization of H60 rescued HPCs from NK cell-mediated killing.
Altogether, our results demonstrate that NK cells are a major barrier to the successful engraftment of ES cell-derived hematopoietic cells, underlining an important role of the innate immune system in regulating the long-term engraftment of ES cell derivatives.
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Kurioka, Ayako. "Mucosal associated invariant T cells and CD161 expressing natural killer cells." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:f994e661-d241-4a1c-ac56-b6bea73346ac.
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Mucosal-associated invariant T (MAIT) cells are a population of innate-like lymphocytes within the gut, liver and blood, expressing a semi-invariant T cell receptor (TCR) and high levels of the C-type lectin-like receptor, CD161. These cells recognise a metabolite of the microbial riboflavin synthesis pathway, presented by the highly conserved Major Histocompatibility Complex (MHC) class I-related protein, MR1, and are critical for the control of bacterial infections. The factors regulating the broad effector functions of MAIT cells have not been fully investigated. Utilising a novel flow cytometric killing assay, MAIT cells were shown here to require the induction of a cytotoxic phenotype through bacterial stimulation to efficiently kill target cells. Further in depth phenotypic analysis highlighted a distinct non-cytotoxic subset of CD4+ MAIT cells, with an altered cytokine-producing capacity, enriched within lymphoid tissues. Investigation into the potential role of these cells in psoriatic diseases revealed that MAIT cells within the synovial fluid of psoriatic arthritis patients are potently activated with increased IL-17 production, their frequency correlating with measures of clinical activity. MAIT cells also have an innate-like responsiveness to cytokines, a feature originally attributed to Natural Killer (NK) cells. Microarray analysis and mass cytometry experiments demonstrated that CD161 marks immature NK cells that have retained this ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus (CMV)-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. Thus, CD161 marks cells with innate-effector functions both in T cells and NK cells.
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Hook, C. E. "Interactions between human natural killer cells and Chlamydia trachomatis infected cells." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604208.
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Chlamydia trachomatis (CT) is an obligate intracellular bacteria and is a common cause of ocular and genital infections in human populations. Murine models of CT infection have shown that Natural Killer cells (NK cells) are recruited into the genital tract early after infection, and are an important source of the cytokine IFN-γ. NK cells are part of the innate defences against infection through cytokine production (IFN-γ, TNF-α and GM-CSF) and cytolytic activity. The hypothesis investigated in this thesis was that CT-infection of target cells leads to alterations in the target cell that are recognized by NK cells, activating one or more of their effector functions. Cervical epithelial tumour lines (HeLa and SiHa) were infected with CT and used as targets in cytotoxicity assays, with polyclonal NK cell lines from healthy individuals as the effector cells. It was found that the level of lysis was significantly raised when CT-infected targets were compared to mock-infected controls. UV-inactivated CT did not induce this increase in lysis, and inhibiting CT-protein synthesis also abolished the effect of live infection. Primary human fibroblasts were not lysed significantly following infection. Investigation of the expression NK cell ligands following CT infection revealed reductions in Classical Class I MHC and HLA-E levels on infected cells. This reduction was seen on both the epithelial cell lines and the primary fibroblasts. The different susceptibility to NK cells is likely to be the consequence of expression of different activatory ligands by the different target cells. Cytokine production by the NK cells following exposure to supernatants from CT-infected cells was assessed and it was shown that supernatants from CT-infected HeLa cells could, in conjunction with rhIL-12, induce NK cell IFN-γ production. Supernatants from CT-infected dendritic cells (DCs) were found to induce NK cell IFN-γ production in conjunction with rhIL-18. This thesis provides evidence for interactions between CT-infected cells and Human NK cells; both cell contact-dependent and soluble mediator-dependent interactions have been demonstrated. Thus, mechanisms have been elucidated via which human NK cells could play an important role in the innate defences against CT infection.
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Wehner, Rebekka, Kristin Dietze, Michael Bachmann, and Marc Schmitz. "The Bidirectional Crosstalk between Human Dendritic Cells and Natural Killer Cells." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-137394.
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Dendritic cells (DCs) are professional antigen-presenting cells, which display an extraordinary capacity to induce T-cell responses. Recent findings revealed that DCs also play a crucial role in the activation of natural killer (NK) cells representing important effectors in the innate immune defense against viruses and tumors. Here, we summarize various studies investigating the bidirectional crosstalk between human DCs and NK cells. In this context, it has been reported that DCs efficiently enhance CD69 expression, proliferation, interferon (IFN)-γ secretion and cytotoxic activity of NK cells. Cell membrane-associated molecules as well as soluble factors such as interleukin-12, tumor necrosis factor-α and type I IFNs contributed to DC-mediated NK cell activation. Reciprocally, the ability of human NK cells to enhance the immunostimulatory capacity of DCs was shown. Thus, NK cells promoted the maturation of DCs and markedly augmented their capacity to produce proinflammatory cytokines and to stimulate T-cell responses. The NK cell-mediated effects on DCs were dependent on cell membrane-associated molecules such as NKp30 and soluble factors such as tumor necrosis factor-α and IFN-γ. In conclusion, the reciprocal activating interaction between human DCs and NK cells may play a pivotal role in the immune defense against viruses and tumorsDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Wehner, Rebekka, Kristin Dietze, Michael Bachmann, and Marc Schmitz. "The Bidirectional Crosstalk between Human Dendritic Cells and Natural Killer Cells." Karger, 2011. https://tud.qucosa.de/id/qucosa%3A27732.
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Dendritic cells (DCs) are professional antigen-presenting cells, which display an extraordinary capacity to induce T-cell responses. Recent findings revealed that DCs also play a crucial role in the activation of natural killer (NK) cells representing important effectors in the innate immune defense against viruses and tumors. Here, we summarize various studies investigating the bidirectional crosstalk between human DCs and NK cells. In this context, it has been reported that DCs efficiently enhance CD69 expression, proliferation, interferon (IFN)-γ secretion and cytotoxic activity of NK cells. Cell membrane-associated molecules as well as soluble factors such as interleukin-12, tumor necrosis factor-α and type I IFNs contributed to DC-mediated NK cell activation. Reciprocally, the ability of human NK cells to enhance the immunostimulatory capacity of DCs was shown. Thus, NK cells promoted the maturation of DCs and markedly augmented their capacity to produce proinflammatory cytokines and to stimulate T-cell responses. The NK cell-mediated effects on DCs were dependent on cell membrane-associated molecules such as NKp30 and soluble factors such as tumor necrosis factor-α and IFN-γ. In conclusion, the reciprocal activating interaction between human DCs and NK cells may play a pivotal role in the immune defense against viruses and tumors.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Siu, Lai-ping Lisa. "The molecular pathology of natural killer cell malignancies /." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25205195.
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Parsons, Matthew. "Lessons learned: natural killer cell education as a determinant of the anti-viral functional potential of natural killer cells." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114492.
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A vaccine against the human immunodeficiency virus (HIV) is urgently needed. Recent estimates predict that 34 million people are currently infected with HIV. Attempts to induce potentially protective cytotoxic T-lymphocytes or broadly neutralizing antibodies by vaccination have either proven unsuccessful or failed to elicit the desired immune responses. However, the recent RV144 vaccine trial that provided partial protection against HIV infection appears to have induced antibodies that can utilize cells of the innate immune system, such as natural killer (NK) cells, to mediate antibody-dependent cellular cytotoxicity (ADCC) against HIV-infected cells. This potential mechanism of protection corroborates recent epidemiological and functional studies demonstrating that HIV-exposed seronegative individuals (HESN) and HIV-infected slow progressors (SP) have higher functioning NK cells and carry certain allelic combinations of killer immunoglobulin-like receptors (KIR) and their major histocompatibility complex class I (MHC-I or HLA-I) ligands that confer NK cells with enhanced functionality. Cumulatively, these observations suggest that understanding the conferral of functional potential during NK cell ontogeny could be important for designing anti-HIV vaccine constructs. In particular, data from HESN and SP have demonstrated that allelic combinations of KIR3DL1 and its HLA-Bw4 ligand are associated with protective outcomes in the context of HIV. Although previous work has demonstrated thatinteractions between these receptor ligand combinations during NK cell development confers NK cells with functional potential, the exact mechanism of the protective outcomes in the context of HIV remain unknown. For example, KIR3DL1+ NK cells have been demonstrated to be hypofunctional in the presence of autologous HIV-infected T cells. This suggests that if KIR3DL1+ NK cells are providing protection through mediating function, they require additional activating signals. As previously published data has demonstrated that activation through CD16a by antibody constant regions can overcome KIR-mediated NK cell inhibition and lead to ADCC of allogeneic cells, we hypothesized that ADCC could overcome inhibitory signalling and allow KIR3DL1+ NK cells to respond to autologous anti-HIV ADCC target cells. The data presented in this thesis reaffirms that HIV protective KIR3DL1/HLA-Bw4 allelic combinations confer enhanced functional potential upon NK cells. The results presented demonstrate that KIR3DL1/HLA-Bw4 combinations educate NK cells for enhanced anti-HIV ADCC against autologous target cells, and that this educational advantage is maintained after stimulation with function-conferring cytokines, such as IL-15. Furthermore, allelic combinations of KIR3DL1/HLA-Bw4 that are protective in the context of HIV are shown to confer the highest ADCC functional potential. These data suggest that the education of NK cells by allelic combinations of KIR3DL1/HLA-Bw4 could explain some of the protection observed in individuals with these combined genotypes. However, as we also observed anabrogation of this education-conferred functional advantage in HIV-infected individuals, we propose that the mechanisms of NK cell-mediated protection differ between uninfected HESN and infected SP.Not enough space
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Troke, Angela D. "Investigation of the expression of leukophysin, a novel granule-associated protein, in natural killer cells and lymphokine-activated killer cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0021/MQ57334.pdf.
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Zhu, Yanting. "Cytotoxic dynamics of natural killer cell at the single cell level." HKBU Institutional Repository, 2018. https://repository.hkbu.edu.hk/etd_oa/590.
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Natural Killer (NK) cell, a crucial player of the human innate immune defense system, detects and kills virus-infected cells and cancer cells. Although the relevant molecular machineries involved in NK cell activation and NK-target cell interactions are largely known, how their collected dynamics regulate fast yet highly selective target cell killing in the complex environment of tissues is poorly understood. In traditional bulk killing assays, heterogeneity and kinetic details of individual NK-target cell interactions are masked, seriously limiting analysis of the underlying dynamic mechanisms. Therefore, the aim of my PhD study is to develop quantitative microscopy assays to elucidate, at the single cell level, real-time killing dynamics of epithelial cancer cells by primary NK cells purified from human blood. Results from my study not only identified the rate-limiting kinetics in NK-cancer cell interaction and mechanistically relevant heterogeneity in the process, but also characterized key molecular events and regulatory components of the NK cell machinery that were associated with the observed cytotoxic dynamics and heterogeneity. NK cells are considered promising candidate for cancer treatment, especially for eliminating residual cancer cells after conventional therapy. The fundamental knowledge acquired from my PhD study, in particular regarding how killing by primary NK cell varies between different target cancer cell types, provides new mechanistic insight that may help to develop this treatment strategy. And the quantitative microscopy assays that I developed are readily extendable to analysis of other cell-cell interaction dynamics, e.g., involved in cytotoxic T cell function.
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Hüber, Christian Markus. "Investigating adaptive immunological features of natural killer cells." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708920.
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Schmidt, Brian P. "The Use of Lactate Dehydrogenase for the Detection of Murine Natural Killer Cell Function." Youngstown State University / OhioLINK, 1999. http://rave.ohiolink.edu/etdc/view?acc_num=ysu999616997.
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Kamel, Fatemah Omar. "Invariant natural killer T cells in multiple sclerosis." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/40281.
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Invariant natural killer T (iNKT) cells are a subpopulation of lymphocytes that express both a CD1d-restricted αβ T cell receptor (TCR) and NK cell markers. iNKT cell perturbations are implicated in a wide variety of autoimmune diseases including Multiple Sclerosis (MS). Our results confirmed a significant reduction in the percentage of iNKT cells in MS patients with respect to healthy donors. In order to understand the immunological significance of iNKT cell reduction in MS, we aimed to define iNKT subsets in a cohort of MS patients of different disease types, Clinically Isolated Syndrome patients (CIS) and patients on different treatments by means of multiparameter flow cytometry and TCR analysis. TCR analysis showed that Vα24 CDR3 region is highly conserved between healthy controls and MS patients, while TCR Vβ11 CDR3 region in iNKT cells of MS patients appeared constrained relative to the pool of cells in healthy controls. As activation, differentiation and maturation processes can be involved in the reduced frequency of iNKT cells, we investigated the role of CD25, CD62L, CD69, CD161 and CD195. Initial observation suggested that co-expression of CD25 and CD161 on iNKT cells is significantly higher in MS patients compared to healthy controls, while CD161 alone is decreased, suggesting that a subpopulation of iNKT cells might be acting as 'regulatory subsets' in MS. Because many genetic studies have shown that specific killer cell immunoglobulinlike receptor (KIR) family have a strong association with MS, we evaluated the expression of KIR2DL1/S1, KIR2DL2/L3 and KIR3DL1 on iNKT cells. Our results showed that expression of KIR2DL1/S1 and KIR3DL1 is lower in progressive MS patients compared to healthy controls. RRMS untreated patients have lower expression of both KIR2DL2/L3 and KIR3DL1 than patient treated with Natalizumab, while the contrary is true when looking at expression of KIR2DL1/S1. All together our data showed that perturbation of iNKT cells is associated with expression of specific surface receptors, thus defining subsets of iNKT cells that might be related to progression of disease or used as disease markers.
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Kamya, Nabukenya. "Natural killer cells in HIV infected slow progressors." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104518.
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Acquired immunodeficiency syndrome AIDS-related illnesses are a leading cause of infectious disease mortality worldwide. The development of a safe and effective prophylactic HIV vaccine is an imperative global public health priority fraught with significant obstacles because the answers to fundamental immunological questions remain unknown. One such gap in knowledge includes the identification of the elusive correlates of immune protection against HIV.Untreated HIV infection is characterized by severe dysregulation of the antiviral immune response that begins during the earliest stages of infection. A rare subset of HIV infected individuals demonstrate sustained ability to control HIV replication and/or maintain stable CD4+ cell counts without therapy. Determining the genetic and immunological bases underlying their benign disease course will aid in the development of novel anti-viral strategies and suggest ways the immune system can be manipulated in a vaccination setting to support the development of protective immunity. Epidemiological studies suggest that licensed NK cells may play a significant role in disease progression by associating the co-carriage of certain KIR/HLA combined genotypes with favorable disease outcomes. The projects described in this thesis provide a functional basis in support of these epidemiological data and contribute to our understanding of how interactions between protective HLA alleles and NK cell receptors may enhance the control of viremia by NK cells. In chapter II, I investigate whether T-cell immune activation levels account for the heterogeneity in longitudinal changes in the rates of CD4 counts among HIV-infected elite controllers (EC) with undetectable viral load (VL) and demonstrate that EC with protective HLA or KIR/HLA combined genotypes exhibit elevated immune activation levels which may be indicative of beneficial antiviral immune responses. Chapters III and IV explore novel mechanisms through which licensed NK cells can influence HIV disease progression by demonstrating that KIR/HLA receptor-ligand combinations affect the NK cell functional potential of HIV infected slow progressors (SP). As mediators of the innate and adaptive immune response, understanding the mechanisms that may underlie the development of protective immunity by NK cells is key. The work presented in this thesis contributes to our understanding of how protective HLA alleles interact with NK cells to influence HIV pathogenesis and provide insights as to the type of immunity an HIV vaccine should recapitulate.Les maladies liées au syndrome de l'immunodéficience acquise (SIDA) sont principalement responsables de la mortalité par maladies infectieuses dans le monde. La mise au point d'un vaccin préventif sécuritaire et efficace contre le VIH reste un problème urgent et prioritaire détenant des obstacles majeurs pour la santé publique mondiale, car on ignore les réponses aux questions fondamentales sur l'immunologie. Un tel fossé dans la science inclut la détermination des corrélats indéfinissables quant à la protection immunitaire contre le VIH.Une rare cohorte d'individus infectés par le VIH démontre une capacité continue de limiter la réplication du VIH et/ou de maintenir un taux stable de cellules CD4+ sans traitement. Déterminer les bases génétiques et immunologiques qui sous-tendent la progression de leur maladie bénigne favorisera la création de stratégies antivirales inédites et évoquera des façons dont le système immunitaire peut être manipulé dans un contexte de vaccination dans le but d'appuyer le renforcement d'une immunité protectrice.Une infection par le VIH non traitée se caractérise par une dérégulation sévère de la réponse immunitaire antivirale qui débute pendant les premières phases de l'infection. Les études épidémiologiques avancent que les cellules NK sont susceptibles de jouer un rôle important dans la progression de la maladie en associant l'expression de certaines combinaisons des génotypes KIR/HLA avec des résultats favorables de la maladie. Les projets décrits dans cette thèse fournissent une base utile en faveur des données épidémiologiques et contribuent à notre compréhension de la manière dont les interactions entre les allèles HLA et les récepteurs des cellules NK sont susceptibles d'améliorer le contrôle de virémie par les cellules NK.Dans le chapitre II, j'examine si les niveaux d'activation immunitaire des cellules T expliquent l'hétérogénéité dans les changements longitudinaux des taux des lymphocytes CD4 parmi les « contrôleurs élite » (EC) ayant une charge virale indétectable et je démontre que ces derniers, qui possèdent des gènes HLA protecteurs ou une association des génotypes KIR/HLA, montrent des niveaux d'activation immunitaire élevés, ce qui indiqueraient que des réponses immunes antivirales sont bénéfiques. Les chapitres III et IV fournissent à l'appui de cellules NK la progression lente de la maladie et démontrent que les combinaisons des récepteurs-ligands KIR/HLA influencent le potentiel fonctionnel des patients infectés du VIH à progression lente. En tant que médiateurs des réponses immunitaires innées et adaptives, comprendre les mécanismes qui sous-tendent la progression de l'immunité protectrice des cellules NK est la clé. Le travail présenté dans cette thèse contribue à notre compréhension de la manière dont les allèles HLA interagissent avec les cellules NK pour influencer la pathogénèse du VIH et donnent un aperçu quant au type d'immunité qu'un vaccin contre le VIH devrait récapituler.
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Norgate, Zoe. "Gene expression in rat uterine natural killer cells." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614884.
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Wantoch, Michelle Hannah. "Activation of natural killer cells by oncolytic viruses." Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/21629/.
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Campbell, Tessa Mollie. "On interactions between alphaherpesviruses and natural killer cells." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20929.
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Natural killer (NK) cells are a critical component of the innate immune response to viral infection. NK cells are responsible for the early control of virus spread, cytolytically killing infected cells, as well as secreting proinflammatory cytokines to enhance immune responses. In patients with deficiencies in NK cell function, there is an extreme susceptibility to infection with herpesviruses, in particular, varicella zoster virus (VZV) and herpes simplex virus type 1 (HSV-1). These two medically important human alphaherpesviruses cause widespread disease in human hosts, with VZV being the causative agent of varicella (chickenpox) and herpes zoster (shingles), while HSV-1 causes recurrent orolabial lesions (cold sores). Both viruses have the potential to cause severe complications, such as encephalitis and debilitating nerve pain. The vital role that NK cells play in controlling VZV and HSV-1 infections denotes an intricate struggle for dominance between virus and NK cell antiviral immunity; however, research in this area has remained surprisingly limited. This thesis explored the interactions between human NK cells and alphaherpesviruses, examining NK cell recognition of infected cells, as well as investigating viral infection of NK cells and manipulation of their function. Investigation into alphaherpesvirus interactions with NK cells first focused on examining whether VZV and HSV-1 modulated the surface of infected cells to potentially regulate NK cell recognition. In vitro co-culture of NK cells with VZV infected cells revealed that NK cells did not display enhanced activation in response to the infection, suggesting that specific viral mechanisms to limit NK cell detection may be at play. Delving into this, the expression of four specific ligands (MICA, ULBP1–3) recognised by the activating NK cell receptor, NKG2D, were examined during viral infection. Comparing VZV and HSV-1, differential patterns of regulation were found between the two viruses, as well as between distinct NKG2D ligands. Given that VZV appeared to be evading NK cell recognition, the research focus then turned to investigating how VZV directly interacted with NK cells. VZV is established as a lymphotropic virus, using the infection of immune cells to disseminate virus around the body, however it has so far remained unknown whether NK cells are permissive to VZV infection. Examination of human peripheral blood NK cells revealed that VZV productively infected NK cells, facilitating transmission of infectious virus to other cells in culture. VZV preferentially infected mature NK cell populations, as well as modulating cell-surface expression of maturityassociated markers. Notably, VZV infection of NK cells led to upregulated expression of chemokine receptors implicated in trafficking to the skin, suggesting that NK cells may play a key role in VZV pathogenesis. As NK cells were permissive to productive VZV infection, the effect of VZV on NK cell function was then investigated. Assessing cytolytic function, it was found that co-culture with VZV lead to potent inhibition of NK cell responsiveness to target cell stimulation. Remarkably, not only were VZV infected NK cells impaired, but also NK cells exposed to virus were inhibited without needing to progress to full productive infection. HSV-1 had a similar capacity to paralyse NK cell cytolytic function, identifying a powerful immune evasion strategy shared by both alphaherpesviruses. In contrast, when NK cell cytokine responses were investigated, differential targeting of cytokine production was demonstrated between VZV and HSV-1. Overall, this thesis illuminates the complex interactions that occur between viral infection and the immune response. The findings presented in this thesis enhance our understanding of how viruses like VZV and HSV-1 are able to evade the immune system to establish lifelong infections, as well as furthering our understanding of how viruses can shape and manipulate the immune response.
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Belfrage, Hans. "Activation of murine cytotoxic cells with interleukin-2 and the bacterial superantigen staphylococcal enterotoxin A." Lund : Dept. of Cell & Molecular Biology, Section of Tumor Immunology, the Wallenberg Laboratory, 1996. http://catalog.hathitrust.org/api/volumes/oclc/38037867.html.
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Assarsson, Erika. "Acquisition and function of NK cell-associated molecules on T cells /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-487-9/.
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黃傑煇 and Kit-fai Wong. "CD56-positive: natural killer cell lymphoma/leukaemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B3198177X.
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Wong, Kit-fai. "CD56-positive natural killer cell lymphoma/leukaemia /." Hong Kong : University of Hong Kong, 2001. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23736197.
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Magri, Giuliana. "Characterization of natural Killer cell response to human cytomegalovirus infected dentrilic cells." Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/38527.
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S'ha establert un sistema experimental autòleg per a poder estudiar la resposta de les cèl.lules Natural Killer (NK) contra les cèl.lules dendrítiques derivades de monòcits (moDC), infectades pel Cytomegalovirus humà (HCMV). Els nostres resultats mostren que les cèl.lules NK responen contra les moDC infectades per HCMV, que presenten una expressió de les molècules MHC de classe I a superficie reduïda. Específicament, demostrem que la infecció per HCMV disminueix l'expressió en superficie d'HLA-E en les moDC, alliberant així la inhibició de les cèl.lules NK NKG2A+. Mostrem que els NKR anomenats NKp46 i DNAM-1 tenen un paper dominant en el reconeixement de les moDC infectades per HCMV i evidenciem la importància de la dinàmica dels mecanismes d'immunoevassió en la susceptibilitat a la resposta NK. Finalment, trobem que els interferons de tipus I i la IL-12 secretats en resposta a la infecció per HCMV, a més de participar en l'activació de la cèl.lula NK i en la secreció d'IFN-, inhibeixen l'expressió i la funció de NKG2D en les cèl.lules NK, com un mecanisme de regulació potencial per prevenir la reactivitat NK contra cèl.lules veïnes sanes.Suitable experimental conditions have been established to dissect the role of NK cell receptors (NKR) and cytokines in the NK cell response against autologous human cytomegalovirus (HCMV) infected monocyte derived dendritic cells (moDC). Our results reveal that NK cells are capable of responding to HCMV infected moDC that have down-regulated surface MHC class I molecules. In particular, we prove that HCMV infection decreases surface HLA-E expression on moDC, thus releasing NKG2A+ NK cells from inhibition. We show that NKp46 and DNAM-1 NKR play a dominant role in the recognition of HCMV infected moDC and we provide evidences stressing the importance of the dynamics of viral immune evasion mechanisms in NK cell susceptibility. Finally, we find that type I interferons and IL-12 secreted in response to HCMV infection, beyond their participation in NK cell activation and IFN- secretion, transiently inhibit the expression and function of NKG2D in NK cells, thus providing a potential regulatory feedback mechanism to prevent NK cell reactivity against bystander healthy cells.
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Magri, Giuliana. "Characterization of natural Killer cell response to human entomegalovirus infected dentrilic cells." Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/38527.
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S'ha establert un sistema experimental autòleg per a poder estudiar la resposta de les cèl.lules Natural Killer (NK) contra les cèl.lules dendrítiques derivades de monòcits (moDC), infectades pel Cytomegalovirus humà (HCMV). Els nostres resultats mostren que les cèl.lules NK responen contra les moDC infectades per HCMV, que presenten una expressió de les molècules MHC de classe I a superficie reduïda. Específicament, demostrem que la infecció per HCMV disminueix l'expressió en superficie d'HLA-E en les moDC, alliberant així la inhibició de les cèl.lules NK NKG2A+. Mostrem que els NKR anomenats NKp46 i DNAM-1 tenen un paper dominant en el reconeixement de les moDC infectades per HCMV i evidenciem la importància de la dinàmica dels mecanismes d'immunoevassió en la susceptibilitat a la resposta NK. Finalment, trobem que els interferons de tipus I i la IL-12 secretats en resposta a la infecció per HCMV, a més de participar en l'activació de la cèl.lula NK i en la secreció d'IFN-, inhibeixen l'expressió i la funció de NKG2D en les cèl.lules NK, com un mecanisme de regulació potencial per prevenir la reactivitat NK contra cèl.lules veïnes sanes.Suitable experimental conditions have been established to dissect the role of NK cell receptors (NKR) and cytokines in the NK cell response against autologous human cytomegalovirus (HCMV) infected monocyte derived dendritic cells (moDC). Our results reveal that NK cells are capable of responding to HCMV infected moDC that have down-regulated surface MHC class I molecules. In particular, we prove that HCMV infection decreases surface HLA-E expression on moDC, thus releasing NKG2A+ NK cells from inhibition. We show that NKp46 and DNAM-1 NKR play a dominant role in the recognition of HCMV infected moDC and we provide evidences stressing the importance of the dynamics of viral immune evasion mechanisms in NK cell susceptibility. Finally, we find that type I interferons and IL-12 secreted in response to HCMV infection, beyond their participation in NK cell activation and IFN- secretion, transiently inhibit the expression and function of NKG2D in NK cells, thus providing a potential regulatory feedback mechanism to prevent NK cell reactivity against bystander healthy cells.
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Bowles, Paul Anthony. "Natural killer cell recognition and killing of virally-transformed and cancer cells." Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550269.
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Natural Killer (NK) cells are important in the elimination of virally-infected and cancer cells. NK cell recognise changes in surface molecules on cells, which can cause an NK cell to kill the target cell by either ligation of death receptors or perforin-mediated release of granzymes. Granzymes are serine proteases that cleave numerous cellular proteins that are important in co-ordinating cell death in the target cell. Induction of apoptosis involves dysregulation of cellular machinery including disruption of mitochondrial membrane potential, nuclear fragmentation and cell membrane permeability. Here I have analysed the differences in NK cell susceptibility of human cells transformed with either the adenovirus species A (Ad12) or adenovirus species C (AdS) El regions, as well as looking at the mechanisms of how a cancer cell could become resistant to NK cell-mediated killing.
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Pfeifer, Caroline [Verfasser], and Marcus [Akademischer Betreuer] Altfeld. "Association between Natural Killer Cell Education and Cellular Glucose Metabolism in Human Natural Killer Cells / Caroline Pfeifer ; Betreuer: Marcus Altfeld." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2019. http://d-nb.info/1179362616/34.
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Li, Peng. "Reprogramming of T cells to natural killer-like cells upon BCL11B deletion." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609198.
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Kieckbusch, Jens. "How do natural killer cells contribute to reproductive success?" Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708449.
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Parihar, Robin. "Characterization of the natural killer cell cytokine response to antibody-coated tumor cells." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1091216058.
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Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages; contains xx, 230 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 Aug. 3.
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邵麗平 and Lai-ping Lisa Siu. "The molecular pathology of natural killer cell malignancies." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31243605.
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Alici, Evren. "Therapeutic potential of natural killer cells in multiple myeloma /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-998-X/.
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Alheim, Mats. "Inhibitory receptors of natural killer cells : specificity and regulation /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19981009alhe.
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Lee, I.-Fang. "The role of natural killer cells in autoimmune diabetes." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/29156.
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Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing β-cells with consequent hyperglycemia and serious chronic complications. Both innate and adaptive immune responses are involved in the pathogenesis of this disease. Studies in animal models and in patients with T1D have shown that natural killer (NK) cells are involved both in disease progression and in disease protection, thus suggesting that NK cells can represent a potential therapeutic target in this disease, once the contribution of NK cells to islet immunity has been fully elucidated. Using the model of complete Freund’s adjuvant (CFA) injection, which has been reported to efficiently prevent diabetes in non-obese diabetic (NOD) mice, the role of NK cells in diabetes was investigated. Results showed that CFA immunization of NOD mice markedly increased frequency and function of NK cells. Notably, the adoptive transfer of diabetes into NOD/SCID recipients clearly implied that IFNγ secreted from NK cells mediated the protection effect of CFA, suggesting that the NK cell is a critical mediator for diabetes protection. Furthermore, investigation of the mechanism by which CFA activates NK cells found that this activation was through a CD1d-dependent but MyD88-independent pathway. These experiments also showed an up-regulation of NKG2D expression of NK cells and this might possibly be through decreased surface expression of NKG2D ligand.
Similar to the NOD mouse, in which NK cells exhibit numeric and functional abnormalities, experiments in peripheral blood mononuclear cells (PBMCs) from patients with T1D also demonstrated that NK cells from T1D patients are present at reduced frequencies and show diminished responsiveness to the cytokines IL-2 and IL-15. Interestingly, cell surface analysis reveals that NKG2D ligands are also expressed on human NK cells and that unlike in non-diabetic controls, T1D NK cells fail to down-regulate NKG2D ligands upon activation by cytokines. Furthermore, NK cells from patients exhibit decreased NKG2D-dependent cytotoxicity and cytokine secretion, as well as reduced NKG2D-mediated signaling pathways. Collectively, these results suggest that NK cell dysfunction and aberrant NKG2D signaling may contribute to the pathogenesis of T1D.
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Fraser, Rupsha. "The role of decidual natural killer cells in pregnancy." Thesis, St George's, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558353.
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During pregnancy, maternal uterine spiral arteries are remodelled from minimal flow, high resistance vessels into large diameter, low resistance, high flow vessels. This change is crucial for delivery of adequate blood supply to the developing fetus, and is impaired in pregnancies complicated by pre-eclampsia. In early pregnancy, fetal trophoblasts invade into the decidua and remodel the spiral arteries. However, decidual natural killer (dNK) cells accumulate around spiral arteries and are present ahead of trophoblast invasion. Their presence is continuous during trophoblast invasion and spiral artery remodelling. A functional role for dNK in remodelling has not yet been defined. Measurement of uterine artery resistance indices (RI), by Doppler ultrasound at 9-14 weeks of gestation, was used to identify pregnancies with <1 % risk (normal RI) of developing pre-eClampsia or a >21 % risk (high RI). Following surgical termination of pregnancy, CD56+ dNK cells were isolated and comparisons made between cells from normal and high RI pregnancies. dNK cell-secreted factors and receptor expression were characterised by proteome profiler arrays, multiplex assays, flow cytometry and western blot analysis. Differences between the two groups were detected in several factors, including angiogenin, endostatin, hepatocyte growth factor (HGF), placental growth factor (PIG F), the soluble interleukin-2 receptor (sIL-2R), active matrix metalloproteinases (MMPs), tumour necrosis factor (TNF)-α, Fas ligand (FasL) and TNF-related apoptosis inducing ligand (TRAIL). dNK effects on trophoblasts and vascular cells were investigated by eo- culture studies to model the interactions at the maternal-fetal interface. Normal RI dNK solube factors were able to promote trophoblast motility (an important component of invasion), to a greater extent than high RI dNK, and a function for dNK-secreted HGF in promoting trophoblast motility was determined. Normal RI dNK caused destabilisation of endothelial cell tube-like structures, partly through TNF-α, whereas this effect was not seen with high RI dNK. Normal RI dNK cells also induced vascular cell apoptosis partly via FasL, while high RI dNK cells did not. These studies demonstrate a functional role for dNK in regulating trophoblast motility and vascular cell remodelling, events of importance in a successful pregnancy. The ability of dNK to regulate these events in pregnancies at higher risk of pre-eclampsia is impaired, which may contribute to the poor remodelling seen in these pregnancies.
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Olofsson, Karl, and Gustav Stenbom. "Directed Migration of Natural Killer Cells by Microcontact Printing." Thesis, KTH, Tillämpad fysik, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-145736.
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NK cells are large granular lymphocytes that patrol the body for defect or virally infected cells. The migration of natural killer (NK) cells is critical for the detection and elimination of aberrant cells such as tumor- and virally infected cells. If a NK cell stumbles upon a target, i.e. an aberrant or stressed cell, the NK cell has the ability to kill the target cell. Limitations in the efficiency of NK cells, such as limited migration speed, and the finite number of target cells that can be killed by one NK cell, leaves the immune system vulnerable to diseases. However it has been shown that NK cell populations are heterogeneous, and from one host to another the overall efficiency of NK cells may vary. If the most efficient NK cells could be isolated from a cell population and cultivated, great numbers of high performing NK cells could then possibly be reintroduced to a body and be used to fight maladies such as cancer and HIV. In an attempt to bring us closer to these possibilities, and further examine the characteristics of NK cells, a high quality master was manufactured and used for microcontact printing. This project has focused on how NK cell migration is affected by cell structure and whether NK cells can be directed along a pattern to provide a situation where NK cell migration speed can be measured rigorously. This was done by using microcontact printing to create micro patterns of proteins that mimics the geometry of the NK cells migrating phenotype. This report will give a description of the master fabrication process and it will be shown that NK cells can be influenced to move straighter by interacting with a microcontact printed pattern of proteins. Furthermore our results will conclude that NK cell migration speed is not affected significantly by the microcontact printed proteins.
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Artavanis-Tsakonas, Katerina. "Activation of human natural killer cells by Plasmodium falciparum." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2003. http://researchonline.lshtm.ac.uk/1520136/.
Full textAbstract:
The purpose of work described in this thesis was to (i) determine the contribution of innate immune responses to the early pro-inflammatory cytokine response to Plasmodium falciparum, (ii) describe the kinetics and cellular sources ofIFN-y production by human PBMC in response to activation by intact, infected erythrocytes (iRBC) or freeze-thawed schizont lysate (PfSL) and (iii) determine the activation requirements for innate immune cells responding to P. falciparum. Infected erythrocytes induce a more rapid and intense IFN-y response from malaria naive PBMC than does PfSL, correlating with rapid iRBC activation of CD3-CD56+ natural killer (NK) cells to produce IFN-y. There is marked heterogeneity between donors in the magnitude of the NK-IFN-y response not correlating with mitogen or cytokine-induced NK activation or prior malaria exposure. The NK-IFN-y response is highly IL-I2 dependent, partly IL-I8 dependent and highly dependent on direct contact between the NK cell and the parasitized erythrocyte. Exogenous rIL-I2 or rIL-I8 did not augment NK-IFN-y responses indicating that IL-I2 and IL-18 production is not the limiting factor explaining differences in NK cell reactivity between live and dead parasites or between donors. The possibility that donor heterogeneity is due to genetic variation in killer immunoglobulin- like receptors (KIR) and/or differential expression of C-type lectin receptors was also investigated. A significant up-regulation ofCD94 and NKG2A was observed in IFN-y+ NK cells of responding donors, suggesting that the inhibitory CD94:NKG2A heterodimer may serve a regulatory function on P. falciparum activated NK cells. Collectively, these data indicate that NK cells may represent an important early source oflFN-y, a cytokine implicated in induction of various anti-parasitic effector mechanisms. The heterogeneity of this early IFN-y response between donors suggests variation in their ability to mount a rapid pro-inflammatory cytokine response to malaria that may, in turn, influence their innate susceptibility to malaria infection, malaria-related morbidity or death from malaria.
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Sekine, Takuya. "Role of natural killer cells in cord blood transplantation." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/31584.
Full textAbstract:
Cord blood transplantation (CBT) for high-risk hematologic cancers is limited by the low numbers of immune cells in a single CB unit, leading to diminished graft-versus-leukemia effect. Although natural killer (NK) cells can mediate potent graft-versus-leukemia effect, and are the first reconstituting lymphocytes after transplantation, the receptor-ligand interactions mediating their cytotoxicity are not well understood. I first studied killer-cell immunoglobulin-like receptor (KIR) and HLA genotypes, NK phenotype and function for 110 CBT recipients to identify specific patterns of KIR-HLA interaction that might predict for CBT effectiveness. I found that the donor genotype of HLA-C1-KIR2DL2/3 combined with KIR2DS2/3 to be an important predictor of disease control after CBT in patients with an HLA-C1/C1 or HLA-C1/C2 background. These findings suggest means to improve the clinical efficacy of NK cells in HLA-defined patient subgroups, especially those with HLA-C2 homozygosity. I then extended my studies to investigate the role of NK cells in the control of CMV reactivation, as cord blood grafts are known to be more susceptible to latent virus infection from lack of transfer of adaptive subsets unlike other graft sources. I found that CB grafts expressing a NKG2C deletion allele possessed higher risk of CMV reactivation post CBT, with the risk significantly reduced with the presence of the wild type allele. Results collectively suggested that the susceptibility of CBT recipients to CMV reactivation is determined by the NKG2C content of the infused CB units. Based on the current understanding of NK licensing/education, the most critical developmental process required for functional competence, I attempted to identify markers that distinguish between 'licensed/educated' and 'unlicensed/hyporesponsive' NK cells. I discovered differential adhesive properties between the two functionally distinct subsets, and also report the possible contribution of the adaptor protein CrkL in NK licensing/education.
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Martelli, Serena. "Maturation and function of natural killer cells during aging." Thesis, University of Southampton, 2017. https://eprints.soton.ac.uk/422259/.
Full textAbstract:
Current population aging is without parallel in human history and it brings significant socio-economic and political challenges with it. The immune system is profoundly affected during aging, a process termed immunosenescence. A hallmark of aging is the increased susceptibility to infections and cancer. Since Natural Killer (NK) cells play a critical role in immune-surveillance against virally-infected and transformed cells, a clearer understanding of the key players in NK cell maturation might help to better design innovative therapeutic strategies relevant to aging and other conditions of persistent immune activation, such as chronic infections and cancer. The aim of this thesis is to detail the age-associated alterations in human and murine NK cell subset repartition, maturation, phenotype, transcriptional regulation and effector functions. We compared the phenotype and function of human NK cell subtypes using three models of persistent immune activation: aging, cytomegalovirus (CMV) infection and hepato-cellular carcinoma (HCC). This study established that CD57, NKG2C and TIM-3 were hallmarks of NK cell immunosenescence and that acquisition of these markers correlated with CMV and inflammation status of the donors. Mature NK cells gained poly-functionality but lost cytotoxicity potential in older donors and their functionality was, at least partially, regulated by the TIM-3/Ceacam-1 pathway. Also, work demonstrated that HCC progression was associated with tumor infiltration of exhausted and cytotoxic-deficient NK cells expressing CD57, TIM-3 and Ceacam-1. Clinical stages of HCC could be segregated according to co-expression of Ceacam-1 and TIM-3. Moreover, we sought to expand the knowledge on how aging impacts NK cell differentiation and function in murine models, such as C57BL/6 wild-type mice and Timp-3 KO mice. We demonstrated that, in aged C57BL/6 wild-type mice and aged Timp-3 KO mice, NK cells are reduced in frequency and numbers and exhibit an altered phenotype in the blood and spleen. Investigating the expression of a variety of cell surface markers associated with the maturation process, we showed that aging is characterized by an accumulation of immature NK cells coupled with a reduction in the late differentiated subset. This phenotypic immaturity reflected a relevant functional immaturity. Our results showed that cytokine secretion, cytotoxicity and gene expression of NK cells are modulated by the aging process along a maturation pathway defined by CD11b and CD27 and, in some cases, LY49H and KLRG1. In particular, NK and T cells from older Timp-3 KO mice experienced the same qualitative age-related changes as the lymphocytes from the wild-type counterparts; however, the kinetic of these changes was accelerated in old Timp-3 KO animals, resulting in earlier NK and T cell immunosenescence. These data offer new insights into TIMP-3 biological role in adaptive and innate immunity, especially its importance during the aging process. This project deepened our understanding of human and murine NK cell differentiation and functionality during aging, leading to novel insights into age-related dysfunctions in NK cell responses and innate immunosenescence. Our findings could support the identification of new immunological targets for checkpoint blockade therapies in order to rescue early innate defense upon aging, chronic infections and cancer.
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Pannunzio, Pardo. "Transferrin and its role in human natural killer cell binding of target cells." Thesis, McGill University, 1988. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61734.
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