Academic literature on the topic 'NK differentiation'
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Journal articles on the topic "NK differentiation"
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Kaur, Kawaljit, Angie Perez Celis, and Anahid Jewett. "Natural Killer Cell-Secreted IFN-γ and TNF-α Mediated Differentiation in Lung Stem-like Tumors, Leading to the Susceptibility of the Tumors to Chemotherapeutic Drugs." Cells 14, no. 2 (January 10, 2025): 90. https://doi.org/10.3390/cells14020090.
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We demonstrate that natural killer (NK) cells induce a higher cytotoxicity against lung cancer stem-like cells (hA549) compared to differentiated lung cancer cell lines (H292). The supernatants from split-anergized NK cells (IL-2 and anti-CD16 mAb-treated NK cells) induced differentiation in hA549. Differentiated lung cancer cell line (H292) and NK cells differentiated hA549 expressed reduced NK cell-mediated cytotoxicity but expressed higher sensitivity to chemotherapeutic drugs. This finding validated our previous reports demonstrating that the levels of tumor killing by NK cells and by chemotherapeutic drugs correlate directly and indirectly, respectively, with the stage and levels of tumor differentiation. We also demonstrate the role of IFN-γ and TNF-α in inducing tumor differentiation. NK cells’ supernatants or IFN-γ and TNF-α-induced tumor differentiation was blocked when we used antibodies against IFN-γ and TNF-α. Therefore, IFN-γ and TNF-α released from NK cells play a significant role in differentiating tumors, resulting in increased susceptibility of tumors to chemotherapeutic drugs. We also observed the different effects of MHC-class I antibodies in CSCs vs. differentiated tumors. Treatment with anti-MHC-class I decreased NK cell-mediated cytotoxicity in hA549 tumors, whereas it increased NK cell-mediated cytotoxicity when differentiated tumors were treated with antibodies against MHC-class I.
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Persyn, Eva, Sigrid Wahlen, Laura Kiekens, Sylvie Taveirne, Wouter Van Loocke, Els Van Ammel, Filip Van Nieuwerburgh, et al. "TXNIP Promotes Human NK Cell Development but Is Dispensable for NK Cell Functionality." International Journal of Molecular Sciences 23, no. 19 (September 26, 2022): 11345. http://dx.doi.org/10.3390/ijms231911345.
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The ability of natural killer (NK) cells to kill tumor cells without prior sensitization makes them a rising player in immunotherapy. Increased understanding of the development and functioning of NK cells will improve their clinical utilization. As opposed to murine NK cell development, human NK cell development is still less understood. Here, we studied the role of thioredoxin-interacting protein (TXNIP) in human NK cell differentiation by stable TXNIP knockdown or overexpression in cord blood hematopoietic stem cells, followed by in vitro NK cell differentiation. TXNIP overexpression only had marginal effects, indicating that endogenous TXNIP levels are sufficient in this process. TXNIP knockdown, however, reduced proliferation of early differentiation stages and greatly decreased NK cell numbers. Transcriptome analysis and experimental confirmation showed that reduced protein synthesis upon TXNIP knockdown likely caused this low proliferation. Contrary to its profound effects on the early differentiation stages, TXNIP knockdown led to limited alterations in NK cell phenotype, and it had no effect on NK cell cytotoxicity or cytokine production. Thus, TXNIP promotes human NK cell differentiation by affecting protein synthesis and proliferation of early NK cell differentiation stages, but it is redundant for functional NK cell maturation.
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Vargas, Claudia L., Jennifer Poursine-Laurent, Liping Yang, and Wayne M. Yokoyama. "Development of thymic NK cells from double negative 1 thymocyte precursors." Blood 118, no. 13 (September 29, 2011): 3570–78. http://dx.doi.org/10.1182/blood-2011-06-359679.
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Abstract The differentiation of natural killer (NK) cells and a subpopulation of NK cells which requires an intact thymus, that is, thymic NK cells, is poorly understood. Previous in vitro studies indicate that double negative (CD4−CD8−, DN) thymocytes can develop into cells with NK cell markers, but these cells have not been well characterized. Herein, we generated and characterized NK cells differentiating from thymic DN precursors. Sorted DN1 (CD44+CD25−) CD122−NK1.1− thymocytes from Rag1−/− mice were adoptively transferred into Rag1−/−Ly5.1 congenic mice. After intrathymic injection, donor-derived cells phenotypically resembling thymic NK cells were found. To further study their differentiation, we seeded sorted DN1 CD122−NK1.1− thymocytes on irradiated OP9 bone marrow stromal cells with IL-15, IL-7, Flt3L, and stem cell factor. NK1.1+ cells emerged after 7 days. In vitro differentiated NK cells acquired markers associated with immature bone marrow–derived NK cells, but also expressed CD127, which is typically found on thymic NK cells. Furthermore, we found that in vitro cells generated from thymic precursors secreted cytokines when stimulated and degranulated on target exposure. Together, these data indicate that functional thymic NK cells can develop from a DN1 progenitor cell population.
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Vitale, Chiara. "Plasticity of NK-cell differentiation." Blood 117, no. 13 (March 31, 2011): 3482–83. http://dx.doi.org/10.1182/blood-2011-01-327965.
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Freud, Aharon G., Akihiko Yokohama, Brian Becknell, Melissa T. Lee, Hsiaoyin C. Mao, Amy K. Ferketich, and Michael A. Caligiuri. "Evidence for discrete stages of human natural killer cell differentiation in vivo." Journal of Experimental Medicine 203, no. 4 (April 10, 2006): 1033–43. http://dx.doi.org/10.1084/jem.20052507.
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Human natural killer (NK) cells originate from CD34(+) hematopoietic progenitor cells, but the discrete stages of NK cell differentiation in vivo have not been elucidated. We identify and functionally characterize, from human lymph nodes and tonsils, four NK cell developmental intermediates spanning the continuum of differentiation from a CD34(+) NK cell progenitor to a functionally mature NK cell. Analyses of each intermediate stage for CD34, CD117, and CD94 cell surface expression, lineage differentiation potentials, capacity for cytokine production and natural cytotoxicity, and ETS-1, GATA-3, and T-BET expression provide evidence for a new model of human NK cell differentiation in secondary lymphoid tissues.
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Grzywacz, Bartosz, Nandini Kataria, Niketa Kataria, Bruce R. Blazar, Jeffrey S. Miller, and Michael R. Verneris. "Natural killer–cell differentiation by myeloid progenitors." Blood 117, no. 13 (March 31, 2011): 3548–58. http://dx.doi.org/10.1182/blood-2010-04-281394.
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Abstract Because lymphoid progenitors can give rise to natural killer (NK) cells, NK ontogeny has been considered to be exclusively lymphoid. Here, we show that rare human CD34+ hematopoietic progenitors develop into NK cells in vitro in the presence of cytokines (interleukin-7, interleukin-15, stem cell factor, and fms-like tyrosine kinase-3 ligand). Adding hydrocortisone and stromal cells greatly increases the frequency of progenitor cells that give rise to NK cells through the recruitment of myeloid precursors, including common myeloid progenitors and granulocytic-monocytic precursors to the NK-cell lineage. WNT signaling was involved in this effect. Cells at more advanced stages of myeloid differentiation (with increasing expression of CD13 and macrophage colony-stimulating factor receptor [M-CSFR]) could also differentiate into NK cells in the presence of cytokines, stroma, and hydrocortisone. NK cells derived from myeloid precursors (CD56−CD117+M-CSFR+) showed more expression of killer immunoglobulin-like receptors, a fraction of killer immunoglobulin–like receptor-positive–expressing cells that lacked NKG2A, a higher cytotoxicity compared with CD56−CD117+M-CSFR− precursor-derived NK cells and thus resemble the CD56dim subset of NK cells. Collectively, these studies show that NK cells can be derived from the myeloid lineage.
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Lee, Jiwon, Suk Hyung Lee, Mira Jeong, and Inpyo Choi. "The effects of tumor necrosis factor-alpha on in vitro differentiation of natural killer cells (138.13)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 138.13. http://dx.doi.org/10.4049/jimmunol.182.supp.138.13.
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Abstract Natural killer (NK) cells are differentiated from hematopoietic stem cells (HSCs) in bone marrow. The differentiation of NK cells is regulated by various factors including soluble growth factors and transcription factors. Here, we demonstrated that tumor necrosis factor-α (TNF-α) is a positive regulator of NK cell differentiation. HSC-derived precursor NK (pNK) cells were further differentiated into mature NK (mNK) cells in the presence of IL-15 in vitro. The potential role of TNF-α on NK cell maturation was evaluated in the presence or absence of IL-15. TNF-α itself induced the expression of NK1.1 and CD122 of mature NK cells and its effects were significantly augmented in the presence of IL-15. IFN-γ production was maximal when NK cells were matured in the combination of IL-15 and TNF-α. Moreover mRNA expression of several transcription factors including T-bet and GATA-3 was increased during TNF-α -mediated in vitro NK cell differentiation. Overall, these data indicate that TNF-α regulates NK differentiation by increasing transcription factors which are crucial for NK maturation.
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Holmes, Tim D., Ram Vinay Pandey, Eric Y. Helm, Heinrich Schlums, Hongya Han, Tessa M. Campbell, Theodore T. Drashansky, et al. "The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation." Science Immunology 6, no. 57 (March 12, 2021): eabc9801. http://dx.doi.org/10.1126/sciimmunol.abc9801.
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Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B-mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.
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Sánchez, M. J., M. O. Muench, M. G. Roncarolo, L. L. Lanier, and J. H. Phillips. "Identification of a common T/natural killer cell progenitor in human fetal thymus." Journal of Experimental Medicine 180, no. 2 (August 1, 1994): 569–76. http://dx.doi.org/10.1084/jem.180.2.569.
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The phenotypic similarities between natural killer (NK) and T cells have led to the hypothesis that these distinctive lymphocyte subsets may be developmentally related and thus may share a common progenitor (Lanier, L. L., H. Spits, and J. H. Phillips, 1992. Immunol. Today. 13:392; Rodewald, H.-R., P. Moingeon, J. L. Lurich, C. Dosiou, P. Lopez, and E. L. Reinherz. 1992. Cell. 69:139). In this report, we have investigated the potential of human CD34+ triple negative thymocytes ([TN] CD3-, CD4-, CD8-) to generate both T cells and NK cells in murine fetal thymic organ cultures (mFTOC) and in vitro clonogenic assays. CD34+ TN thymocytes, the majority of which express prominent cytoplasmic CD3 epsilon (cytoCD3 epsilon) protein, can be divided into high (CD34Bright) and low (CD34Dim) surface expressing populations. CD34Bright TN thymocytes were capable of differentiating into T and NK cells when transferred into mFTOC, and demonstrated high NK cell clonogenic capabilities when cultured in interleukin (IL)-2, IL-7, and stem cell factor (SCF). Likewise, CD34Bright TN thymocyte clones after 5 d in culture were capable of generating NK and T cells when transferred into mFTOC but demonstrated clonogenic NK cell differentiation capabilities when maintained in culture with IL-2. CD34Dim TN thymocytes, however, possessed only T cell differentiation capabilities in mFTOC but were not expandable in clonogenic conditions containing IL-2, IL-7, and SCF. No significant differentiation of other cell lineage was detected in either mFTOC or in clonogenic assays from CD34+ TN thymocytes. These results represent the first definitive evidence of a common T/NK cell progenitor in the human fetal thymus and delineate the point in thymocyte differentiation where T and NK cells diverge.
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Cavazzana-Calvo, M., S. Hacein-Bey, G. de Saint Basile, C. De Coene, F. Selz, F. Le Deist, and A. Fischer. "Role of interleukin-2 (IL-2), IL-7, and IL-15 in natural killer cell differentiation from cord blood hematopoietic progenitor cells and from gamma c transduced severe combined immunodeficiency X1 bone marrow cells." Blood 88, no. 10 (November 15, 1996): 3901–9. http://dx.doi.org/10.1182/blood.v88.10.3901.bloodjournal88103901.
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Natural killer (NK) cells are characterized by their ability to mediate spontaneous cytotoxicity against susceptible tumor cells and infected cells. They differentiate from hematopoietic progenitor cells. Patients with X-linked severe combined immunodeficiency (SCID X1) carry mutations in the gamma c cytokine receptor gene that result in lack of both T and NK cells. To assess the role of interleukin-2 (IL-2), IL-7, and IL-15 cytokines, which share gamma c receptor subunit, in NK cell differentiation, we have studied NK cell differentiation from cord blood CD34 (+) cells in the presence of either stem cell factor (SCF), IL-2, and IL-7 or SCF and IL-15. The former cytokine combination efficiently induced CD34 (+) CD7 (+) cord blood cells to proliferate and mature into NK cells, while the latter was also able to induce NK cell differentiation from more immature CD34 (+) CD7 (-) cord blood cells. NK cells expressed CD56 and efficiently killed K562 target cells. These results show that IL-15 could play an important role in the maturation of NK cell from cord blood progenitors. Following retroviral-mediated gene transfer of gamma c into SCID X1 bone marrow progenitors, it was possible to reproduce a similar pattern of NK cell differentiation in two SCID-X1 patients with SCF + IL-2 + IL-7 and more efficiently in one of them with SCF + IL-15. These results strongly suggest that the gamma c chain transduces major signal(s) involved in NK cell differentiation from hematopoietic progenitor cells and that IL-15 interaction with gamma c is involved in this process at an earlier step than IL-2/IL-7 interactions of gamma c are. It also shows that gene transfer into hematopoietic progenitor cells could potentially restore NK cell differentiation in SCID X1 patients.
Dissertations / Theses on the topic "NK differentiation"
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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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Farren, Timothy william. "The role of the NK cell receptor CD160 in the diagnosis, differentiation and function of chronic B-cell malignancies." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/9011.
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Chronic Lymphocytic Leukaemia (CLL) remains the most abundant leukaemia in those aged over 65 years. It is characterised by the expansion of malignant monoclonal B-lymphocytes that were originally described as being functionally incompetent. Identified by immunophenotypic expression of monoclonal light chain restriction, it falls into the classification of chronic B-cell lymphoproliferative disorders (B-LPD). This thesis aims to demonstrate that CD160, an activating NK cell receptor, is aberrantly expressed in B-LPD and can function as a tumour specific antigen, which has clear translation roles within the clinical environment, aiding in the diagnosis of CLL and monitoring of minimal residual disease (MRD). More so, this study aims to provide an insight into the potential biological roles of CD160 within chronic B-cell malignancies. CD160 is an activating NK cell receptor whose major form is a glycosylphosphatidylinositol (GPI)-anchored cell surface molecule with a single immunoglobulin domain. In-vitro studies on a large cohort of B-LPD patients demonstrated that CD160 was primarily restricted to cases of CLL (98%) and Hairy Cell Leukaemia (HCL, 100%) with only a minor population of other B-LPDs expressing the antigen. More so, within the B-cell lineage, CD160 can be considered a tumour specific antigen (TSA) in that when looking for both transcript and protein, they were absent throughout the normal B-cell hierarchy. Many clinical studies base their entry criteria on clinical and biological prognostication, as this provides insights into the biology of CLL and its response to therapy. Disease eradication has been shown to be prognostic. This study demonstrates the feasibility and clinical importance of MRD detection utilising CD160 as novel marker of residual disease. Subsequently, CD160 analysis by flow cytometry (CD160FCA) demonstrated to be as sensitive and specific as other methodologies, and independent of the type of therapy. Further to this the early detection of MRD was correlated with known biological prognostic risk groups. Patients in CR had significantly different EFS based on their MRD status following treatment using the CD160FCA. For those patients with adverse prognostic markers (including CD38, ZAP-70 and M), the time to detection of MRD or relapsing disease ß2using CD160FCA, was significantly shorter than those with a normal or good prognosis. Within normal NK and T lymphocytes, CD160 has a multifunctional role that upon triggering results in a unique profile of cytokine production via the recruitment of Phosphatidylinositol 3-kinase (PI3K). In CLL cells, CD160 stimulation resulted in the recapitulation of these observations including cell survival, an increase in Bcl-2 family antiapoptotic proteins, and cell cycle progression. This thesis has demonstrated that CD160 is aberrantly expressed in malignant B-cells, it has a clear clinical translation role in terms of diagnosis and MRD monitoring, and multiple biological functions which recapitulate those observed in NK-cells.
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Huyghe, Matthias. "Approche thérapeutique anticancéreuse par immunothérapie basée sur les cellules NK dérivées de cellules iPS." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL104.
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Les cellules Natural Killer (NK) sont des cellules spécialisées dans l'immunosurveillance, capables de reconnaître et de lyser les cellules transformées ou infectées par des virus. En raison de leurs propriétés biologiques spécifiques, le transfert adoptif de cellules NK pour l'immunothérapie contre le cancer représente une alternative prometteuse à l'utilisation des cellules CAR-T chez certains patients. Les cellules souches pluripotentes induites (iPSC) se sont imposées comme une source attractive pour la génération de cellules NK à des fins thérapeutiques. En effet, les iPSC peuvent être facilement modifiées génétiquement pour produire des cellules NK clonogéniques exprimant des modifications spécifiques.Les cellules NK dérivées d'iPSC modifiées génétiquement ouvrent de nouvelles perspectives pour le développement d'immunothérapies « prêtes à l'emploi ».Dans le cadre du développement de nouvelles stratégies thérapeutiques, j'ai étudié et optimisé des protocoles de différenciation afin d'optimiser les méthodes pré-existantes (Partie 1). J'ai également participé au développement d'une thérapie basée sur l'utilisation des cellules NK dérivées de cellules iPS exprimant un CAR de troisième génération pour traiter les patients atteints de leucémie myéloïde chronique (LMC) réfractaire ou récidivante en phase de crise blastique (Partie 2)Natural Killer (NK) cells are specialized cells involved in immunosurveillance, capable of recognizing and lysing transformed or virus-infected cells. Due to their spécifie biological properties, the adoptive transfer of NK cells for cancer immunotherapy represents a promising alternative to the use of CAR- T cells in certain patients.Induced pluripotent stem cells (iPSCs) hâve emerged as an attractive source for generating NK cells for therapeutic purposes. Indeed, iPSCs can be easily genetically modified to produce clonogenic NK cells expressing spécifie modifications.Genetically modified NK cells derived from iPSCs pave the way for the development of "off-the- shelf" immunothérapies.As part of the development of new therapeutic strategies, I hâve studied and optimized différentiation protocols to enhance existing methods (Part 1). I also participated in the development of a therapy based on the use of NK cells derived from iPS cells expressing a third- generation CAR to treat patients with refractory or relapsed chronic myeloid leukemia (CML) in blast crisis (Part 2)
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Sohlberg, Ebba. "Immune maturation in early childhood and the influence of herpesvirus infections." Doctoral thesis, Stockholms universitet, Institutionen för molekylär biovetenskap, Wenner-Grens institut, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-93034.
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The quality of immune responses develops from birth into adulthood and in the context of the host microbial environment. The aim of this work was to study immune maturation during childhood, and how this process can be affected by the common herpesviruses; Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In paper I we studied monocytes, an important cell type for immunity in the newborn. We showed that the neonatal monocyte subsets exist in similar frequencies as adult subsets, and have a potent capacity for pro-inflammatory cytokine production. In paper II, III and IV we studied the effects of EBV and CMV infections on immune cell function in children. In paper II we found that monocyte-induced NK-cell production of IFN-γ, and plasma IFN-γ levels, were decreased in 2-year old EBV- and/or CMV-seropositive children and mostly so in co-infected children. In paper III we found that in 5-year old children, EBV and CMV co-infection was associated with the highest levels of differentiated NKG2C+ NK cells. CMV+ children had higher plasma IFN-γ and IL-15 levels and higher NK-cell cytotoxic capacity. In vitro PBMC systems showed elevated frequencies of NKG2C+ NK cells in the presence of EBV-infected cells. In paper IV we showed that a child’s age and subsequent capacity for anti-viral cytokine production affects in vitro EBV infection in terms of B-cell proliferation and B-cell acquisition of memory phenotype. PBMC from CMV+ children had lower EBV-induced accumulation of switched memory B cells, which was connected to high prevalence of CD57+CD8+ T cells and IFN-γ production. Taken together, this thesis work shows that monocyte subsets at birth can give potent functional responses and that latency with EBV and CMV has a significant effect on the differentiation process and functional capacity of anti-viral effector cells during childhood. This in turn could affect responses to related or unrelated infections or even to non-invasive antigens such as allergens.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.
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Corbel, Stéphane. "Mise en évidence d'un transport bi-directionnel d'histamine dans les progéniteurs hématopoïétiques murins." Paris 5, 1997. http://www.theses.fr/1997PA055001.
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L'histamine, un médiateur forme après décarboxylation de l'histidine par une enzyme l'histidine décarboxylase (HDC), est produite par différents types cellulaires du système immunitaire ou nerveux. Sa qualité d'agent immunomodulateur et de neurotransmetteur est clairement démontrée. Son rôle dans les phénomènes de prolifération et différenciation cellulaires est également suggéré par de nombreux faits expérimentaux. L'histamine pourrait aussi être impliquée dans l'hématopoïèse, et quelques arguments sont en faveur de cette possibilité. Ainsi, dans le laboratoire, nous avons montré une production importante d'histamine par les cellules hématopoïétiques en réponse à divers stimuli. Cette histamine endogène est indispensable à la mise en cycle des cellules immatures de la moelle osseuse stimulées par l'il-3. Au cours de cette thèse, nous avons mis en évidence un système bidirectionnel d'entrée et de sortie d'histamine dans les progeniteurs hématopoïétiques. Ce transport est inhibe spécifiquement par les antagonistes des récepteurs h#3 de l'histamine, dont un représentant, le iodoproxyfan, disponible sous sa forme radio marquée, est un ligand typique et efficace. Toutefois, nous avons montré que le mécanisme de captage d'histamine n'implique pas une fixation sur ces récepteurs h#3, et est dépendant des échanges ioniques. Le blocage de la libération d'histamine produite en réponse à l'il-3 par les inhibiteurs du transport bidirectionnel, s'accompagne d'une augmentation du contenu intracellulaire. Cet accroissement du taux d'histamine intracellulaire ne résulte pas d'une accumulation totale de l'histamine non libérée. La production globale d'histamine est en fait atténuée en présence de ces antagonistes et cette diminution s'observe tant au niveau de la protéine HDC, dont l'activité est altérée, qu'au niveau de l'expression du gène, codant cette enzyme, qui est réduite. Nos résultats suggèrent que ces modifications seraient consécutives à l'augmentation de la concentration intracellulaire d'histamine. L'existence d'un rétrocontrôle de la synthèse d'histamine permet d'envisager une nouvelle approche quant aux processus qui régissent la production de cette amine dans différents tissus. De plus, outre l'histamine, les mêmes progeniteurs hématopoïétiques produisent également de l'il-4 et de l'il-6. Des résultats préliminaires montrent qu'une forte concentration intracellulaire en histamine modifie la synthèse de ces cytokines. Ils suggèrent que l'histamine pourrait prendre une part importante dans le contrôle de l'hématopoïèse et de l'immunité dont ces cytokines sont des intermédiaires influents.
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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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Guilbault, Lorie. "Étude génétique et biologique de la différenciation et de la maturation des cellules NK." Thèse, 2016. http://hdl.handle.net/1866/18350.
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Les cellules Natural Killer (NK), un sous-type de lymphocytes, sont cruciales dans l’immunité innée de par leur cytotoxicité directe envers les tumeurs, les cellules infectées et les cellules stressées. Elles contribuent également à l’orchestration de la réponse immunitaire adaptative de par leur capacité à produire des cytokines immunorégulatrices. Pour développer ces fonctions effectrices, les cellules NK requièrent l’intégration d’une multitude de signaux. De là, les cellules NK matures (mNK) sont considérées comme appartenant à quatre sous-types conséquents et concordants avec la polarisation vers la prolifération, la production de cytokines ou les propriétés cytotoxiques. Dans certaines maladies auto-immunes, tel le diabète de type 1 (T1D), un bloc dans leur maturation, et conséquemment des défauts en nombre et en fonctions, peut être observé. Ainsi, afin de découvrir la régulation génétique derrière la proportion et la maturation des cellules NK, des études de liaison génétique ont été produites sur des souris F2 (B10.BR x NOD.H2k) et F2.Rag (B6.Rag1-/- x NOD.Rag1-/-), où le fond génétique NOD est un modèle de T1D. Ces analyses ont révélé des locus potentiellement impliqués dans la régulation de la proportion, des nombres absolus ainsi que dans la maturation fonctionnelle des cellules mNK. Les chromosomes 8, 9 et 17 ont été liés à la proportion des cellules mNK tandis que les chromosomes 2, 4, 7, 10, 11 et 18 ont été liés aux sous-types fonctionnels de ces mêmes cellules. De là, nous avons validé l’influence du locus du chromosome 9 sur la proportion des cellules mNK en générant des souris sous-congéniques avec des insertions de segment génétique B10.BR dans des souris de fond génétique NOD. La proportion et le nombre absolu de cellules mNK ont ensuite été analysés par cytométrie en flux et comparés à ceux de souris contrôles. Pour la maturation fonctionnelle, nous avons retenus certains gènes candidats, et régulateurs associés, liés à un ou plusieurs sous-types de mNK, dont Tbx21, Zeb2, c-Myb, Trp53 et Pmaip1. Par association de voies de signalisation, nous sommes également allés vérifier certaines protéines associées, dont Bim et Eomesodermin. Nous avons alors validé leur implication par l’utilisation de modèles murins knock-out, qPCR, essais de prolifération et d’apoptose. Enfin, nos résultats supportent un rôle pour le locus du chromosome 9 dans la régulation de la proportion de cellules mNK ainsi qu’un rôle pour Trp53, Bim et Pmaip1 dans la maturation fonctionnelle de celles-ci. Nos études révèlent donc de nouveaux gènes candidats potentiels dans la régulation des cellules NK, dont les mécanismes pourront être approfondis dans la perspective de développement de thérapies cellulaires et génétiques dans le combat contre les cancers et les infections chroniques.Natural Killer (NK) cells, a subset of lymphocytes, are crucial in innate immunity due to their direct cytotoxicity towards tumors, viral infected cells and stressed cells. NK cells also contribute to the orchestration of the adaptive response by their ability to produce immunoregulatory cytokines. To develop those effector functions, NK cells require the integration of multiple signals. As of now, mature NK cells (mNK) can be separated into a four-stage model of functional maturation that concords with a polarization either toward proliferation and cytokine production or cytotoxic functional properties. In autoimmune diseases, like type 1 diabetes (T1D), a block in their maturation, and consequently an impaired functionality and diminished numbers, can be observed. Thus, in order to uncover the genetic regulation behind the proportion and functional maturation of NK cells, a linkage analysis was performed by our lab on F2 (B10.BR x NOD.H2k) and F2.Rag (B6.Rag1-/- x NOD.Rag1-/- intercross) mice, where the NOD genetic background is a model of T1D. This analysis revealed loci that were potentially involved in the regulation of mNK cells proportion, absolute numbers or functional maturation. Loci on chromosomes 8, 9 and 17 were linked to the proportion of mNK cells while loci on chromosomes 2, 4, 7, 10, 11 and 18 were linked to different subsets of functional mNK cells. Hence, we validated the influence of the chromosome 9 locus on the proportion of mNK cells by generating congenic sub-strains of mice with insertion of B10.BR genetic segments and NOD genetic background. The proportion and absolute numbers of mNK cells were assessed by flow cytometry and compared to those of wild-type mice. Regarding the functional maturation of mNK cells, we considered potential candidate genes, and their upstream regulators, that were linked to one or more mNK subsets, namely Tbx21, Zeb2, Myb, Trp53 and Pmaip1. From those, we also looked further their associated pathway with proteins such as Bim and Eomesodermin. We proceeded to the in vivo validation of their implication by qPCR, proliferation and apoptosis assays and the use of knock-out mice. Indeed, our results support a role for a locus on chromosome 9 in the regulation of mNK cells proportion and for Trp53, Bim and Pmaip1 in NK cell functional maturation. As such, our study has revealed new candidate genes in NK cell regulation. Further explorations of the mechanisms by which those genes act could lead to the development of cellular and genetic therapies for cancers and chronic infections.
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Nogueira, Marta Faro Craveiro. "Thimic Natural Killer cells as mediators of cell competition." Master's thesis, 2020. http://hdl.handle.net/10316/94240.
Full textAbstract:
Dissertação de Mestrado em Investigação Biomédica apresentada à Faculdade de MedicinaAs células Natural Killer (NK) são linfócitos granulares do sistema imune inato cuja função é mediada por recetores expressos na sua superfície celular. A interação entre recetores inibitórios e o complexo principal de histocompatibilidade I (MHC-I), expresso em células saudáveis, impede o desencadear de respostas citotóxicas contra as mesmas. Contudo, em células infetadas ou que sofram transformações, a expressão de MHC-I diminui, despoletando citotoxicidade mediada por células NK. Convencionalmente, a diferenciação destas células ocorre na medula óssea e termina no baço. Não obstante, as células NK estão presentes em diferentes órgãos onde exibem um fenótipo particular. Nomeadamente, células NK tímicas expressam o recetor da interleucina 7 (IL-7) e GATA-3 e desenvolvem-se no timo, contrariamente a células NK convencionais. Apesar de ambas coexistirem no timo, a sua função ainda não foi determinada. Este projeto propõe que as células NK poderão promover a diferenciação de linfócitos T. Especificamente, as células NK poderão estar envolvidas em competição celular, um processo que consiste na eliminação de timócitos menos aptos, e persistência dos mais competentes. A competição celular foi descrita pelo nosso grupo como sendo um processo supressor de tumor, capaz de impedir a acumulação de timócitos menos aptos (com maior tempo de persistência no timo), prevenindo o desenvolvimento de leucemia. Dados preliminares revelam que timócitos “velhos” expressam níveis inferiores de MHC-I relativamente a células competentes. Assim sendo, as células NK poderão reconhecer estas diferenças de MHC-I, eliminando timócitos com menor expressão deste complexo. Os nossos resultados sugerem que a diferenciação das células NK tímicas se assemelha à estabelecida para células NK convencionais. No entanto, as células NK tímicas não apresentam os estadios mais citotóxicos e, relativamente a células convencionais, uma menor percentagem expressa recetores ativadores. Recorrendo a experiências de transplantação de timo, determinámos que as células NK são renovadas em menos de 7 dias e que células recirculantes e residentes exibem cinéticas diferentes. Ainda, estabelecemos um ensaio ex vivo onde confirmámos que células NK do baço e do timo são capazes de eliminar timócitos que não expressem MHC-I. Em suma, os nossos dados revelam que no timo, células NK convencionais recirculantes e células que se desenvolvem especificamente no mesmo coexistem e que estes são, de facto, capazes de desencadear uma resposta citotóxica contra timócitos com ausência de expressão de MHC-I.
Natural killer (NK) cells are granular lymphocytes of the innate immune system whose responses are controlled by cell-surface receptors. Inhibitory receptors bind to class I major histocompatibility complex (MHC-I) on healthy cells and inhibit NK cytotoxicity. When cells are infected or transformed, MHC-I is downregulated, which elicits NK cytotoxicity towards the unhealthy cells. Conventional NK cell differentiation occurs in the bone marrow and terminates in the spleen. Nevertheless, some NK cells are found in other organs and exhibit unique tissue-specific characteristics. One example are thymic NK cells, which develop in the thymus and can be exported. These cells express interleukin 7 receptor (IL-7r) and GATA-3, opposite to their conventional counterparts. Both conventional and thymic derived NK cells can be found in the thymus. However, their function is still to be explored. Here, we hypothesize that NK cells are involved in promoting T lymphocyte differentiation. Specifically, we propose that NK cells play a role in cell competition, a process whereby unfit thymocytes are outcompeted by their fit counterparts. Cell competition in the thymus has been described by our group as a tumor suppressor mechanism that inhibits the accumulation of the unfit thymocytes, thereby preventing leukemia. Preliminary data showed that “old”, unfit thymocytes express lower levels of MHC-I than “young”, fit cells. This supports that differential levels of MHC-I might be measured by NK cells, that eliminate the unfit thymocytes with low MHC-I. We show that thymic NK cells express markers consistent with a differentiation path resembling the one established for conventional NK cells. However, the most cytotoxic stages were absent from thymic NK cells. In addition, the percentage of thymic NK cells expressing activating receptors was lower than for conventional NKs. Thymus transplantation experiments revealed that NK cells have a fast turnover, that was under 7 days for both thymic and conventional NK cells. Nevertheless, circulating and thymus derived NK cells differed in turnover. Finally, we established an ex vivo cytotoxic assay that confirmed that both spleen and thymus NK cells can kill MHC-I deficient thymocytes. These data show that NK cells in the thymus are comprised of two main subsets: one of conventional circulating cells, and the other that originates in the thymus. Furthermore, we characterized NK cells immunophenotypically taking into account differentiation and functional markers. Finally, we could show ex vivo that NK cells from the thymus can indeed mount a cytotoxic response towards thymocytes that lacked MHC-I.
Outro - Projecto FCT com a referência: PTDC/BIA-BID/30925/2017
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Diaz, Rodriguez Yildian. "La différentiation in vitro des cellules dendritiques plasmacyto des partir de cellules CD34+ de sang de cordon, un outil thérapeutique pour augmenter l'activité́ antitumorale des cellules NK." Thèse, 2017. http://hdl.handle.net/1866/19443.
Full textAbstract:
L’immunothérapie basée dans l’utilisation des cellules NK pour le traitement de différents types de cancers humains est une stratégie très prometteuse. Les cellules dendritiques plasmacytoïdes (pDC) activées permettent de stimuler les cellules NK pour augmenter leurs propriétés anti-tumorales. Les cellules NK activées par les pDC sont capables de développer in vitro et in vivo une forte réponse cytotoxique contre différentes lignées de leucémie lymphoblastiques pre-B. En revanche, les faibles quantités de pDC obtenues à partir du sang périphérique limitent leur l’utilisation en clinique. L’expansion et la différenciation des pDC in vitro à partir des progéniteurs hématopoïétiques CD34, permet d’obtenir des pDC humaines en grande quantité. Récemment il a été démontré que l’utilisation des antagonistes du récepteur de l’aryl hydroxycarbone (AhR) augmente le nombre des pDC générées in vitro. Cependant, la capacité à activer les cellules NK des pDC différenciées in vitro en présence d’antagonistes de l’AhR n’a pas encore été étudiée. Dans cette étude, nous montrons que les pDC obtenues in vitro ont une expression de molécules d’activation et une sécrétion de IFN plus faibles que celles des pDC du sang périphérique, mais que leur capacité à stimuler des cellules NK est similaire. Ces résultats ouvrent donc la voie à l’utilisation des pDC générées in vitro comme agent immuno-therapeutique visant à stimuler les fonctions anti-tumorales des cellules NK.NK cells immunotherapy is a promising treatment for different human cancers. An effective approach to stimulate NK cells has been the use of activated plasmacytoid dendritic cells (pDC). NK cell activated by pDC develops a strong cytotoxic response against pre-B acute lymphoblastic leukemia (ALL) cell lines in vitro and in vivo. However, the use of pDC in the clinic has limitations because of its low frequency. One suitable strategy is the differentiation of CD34+ progenitors using different cytokines and chemokines. Recently, it has been demonstrated that antagonists of aryl hydroxyl receptor (AhR) increase the number of pDC obtained after culture of CD34+ cells. Nevertheless, the ability of these in vitro differentiated pDC to induce NK cells activation has not been well documented. In this study, it was showed that activated in vitro differentiated pDC present different characteristics than adult pDC, like a lower expression of activation markers and IFNalpha secretion, but their capacity to stimulate NK cells was similar to that observed in adult pDC. In addition, NK cells activated by in vitro differentiated pDC showed a strong cytotoxicity against the pre-B ALL cell line REH suggesting its effectiveness to treat ALL patients.
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"Differentiating intercellular interactions that induce cytotoxic activity and cytokine release by NK cells." UNIVERSITY OF MARYLAND, BALTIMORE, 2008. http://pqdtopen.proquest.com/#viewpdf?dispub=3310393.
Full textBooks on the topic "NK differentiation"
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Cerhan, James R., Claire M. Vajdic, and John J. Spinelli. The Non-Hodgkin Lymphomas. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780190238667.003.0040.
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The non-Hodgkin lymphomas (NHL) are a heterogeneous group of over forty lymphoid neoplasms that have undergone a major redefinition over the last twenty-five years, in part due to advances in immunology and genetics as well as implementation of the WHO classification system. NHLs are considered clonal tumors of B-cells, T-cells, or natural killer (NK) cells arrested at various stages of differentiation, regardless of whether they present in the blood (lymphoid leukemia) or lymphoid tissues (lymphoma). In the United States, the age-standardized NHL incidence rate (per 100,000) doubled from 1973 (10.2) to 2004 (21.4) and then stabilized, while five-year relative survival rates improved from 42% in 1973 to 70% in 2004. Established risk factors for NHL or specific NHL subtypes include infectious agents (HTLV-1, HIV, EBV, HHV8, HCV, H. pylori), immune dysregulation (primary immunodeficiency, transplantation, autoimmunity, and immunosuppressive drugs), family history of lymphoma, and common genetic variants identified by genome-wide association studies.
Book chapters on the topic "NK differentiation"
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Huntington, Nicholas D., Jean-Jacques Mention, Christian Vosshenrich, Naoko Satoh-Takayama, and James P. Di Santo. "Dissecting Human NK Cell Development and Differentiation." In Natural Killer Cells, 39–61. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-642-02309-5_2.
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Male, Victoria, and Hugh J. M. Brady. "Transcriptional Control of NK Cell Differentiation and Function." In Transcriptional Control of Lineage Differentiation in Immune Cells, 173–87. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/82_2014_376.
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Wałajtys-Rode, Elżbieta, and Jolanta M. Dzik. "Monocyte/Macrophage: NK Cell Cooperation—Old Tools for New Functions." In Results and Problems in Cell Differentiation, 73–145. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-54090-0_5.
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Sakuishi, Kaori, Sachiko Miyake, and Takashi Yamamura. "Role of NK Cells and Invariant NKT Cells in Multiple Sclerosis." In Results and Problems in Cell Differentiation, 127–47. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/400_2009_11.
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Sivakumar, P. V., I. Puzanov, N. S. Williams, M. Bennett, and V. Kumar. "Ontogeny and Differentiation of Murine Natural Killer Cells and Their Receptors." In Specificity, Function, and Development of NK Cells, 161–90. Berlin, Heidelberg: Springer Berlin Heidelberg, 1998. http://dx.doi.org/10.1007/978-3-642-46859-9_11.
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Keever, C. A., M. V. Gazzola, K. Pekle, J. H. Bourhis, and A. Gillio. "Regulatory Effect of Recombinant Cytokines on NK Cell Differentiation from Early Marrow Precursors." In Cytokines in Hemopoiesis, Oncology, and AIDS, 227–36. Berlin, Heidelberg: Springer Berlin Heidelberg, 1990. http://dx.doi.org/10.1007/978-3-642-75510-1_32.
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Riccardi, Carlo, Graziella Migliorati, Antonio Giampietri, Lorenza Cannarile, Emira Ayroldi, and Luigi Frati. "In vivo treatment with recombinant interleukin-2 (IL-2) stimulates the differentiation of natural killer (NK) precursor cells." In The Role of Pharmacology in Pediatric Oncology, 303–7. Dordrecht: Springer Netherlands, 1987. http://dx.doi.org/10.1007/978-94-009-4267-7_24.
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Lowe, Emily, Laurel C. Truscott, and Satiro N. De Oliveira. "In Vitro Generation of Human NK Cells Expressing Chimeric Antigen Receptor Through Differentiation of Gene-Modified Hematopoietic Stem Cells." In Natural Killer Cells, 241–51. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-3684-7_20.
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Tonini, Gian Paolo. "Antineoplastic drugs modulating c-myc expression in K562, induce erythroid differentiation and modify, with IFN, susceptibility to NK cell mediated lysis." In The Role of Pharmacology in Pediatric Oncology, 295–301. Dordrecht: Springer Netherlands, 1987. http://dx.doi.org/10.1007/978-94-009-4267-7_23.
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"Fibronectin Expression by Endogenous and Activated NK Cells." In Lymphocyte Activation and Differentiation, 489–92. De Gruyter, 1988. http://dx.doi.org/10.1515/9783110850253-072.
Full textConference papers on the topic "NK differentiation"
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Giraud, J., D. Chalopin, E. Ramel, M. Derieppe, T. Boyer, N. Larmonier, O. Adotevi, et al. "P02.07 Innate immunity atlas of hepatocellular carcinoma unravels the differentiation hierarchy of myeloid NK cells and MDSCs." In iTOC9 – 9th Immunotherapy of Cancer Conference, September 22–24, 2022 – Munich, Germany. BMJ Publishing Group Ltd, 2022. http://dx.doi.org/10.1136/jitc-2022-itoc9.26.
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Zhang, Sen, Hongbing Pu, Boqian Wang, Shenren Xu, Yong Zhang, Xiuquan Huang, and Dingxi Wang. "Implementation of a Newton−Krylov Algorithm in the Open-source Solver of PHengLEI." In GPPS Hong Kong24. GPPS, 2023. http://dx.doi.org/10.33737/gpps23-tc-124.
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This paper presents the implementation of a Newton–Krylov (NK) algorithm in the open-source solver of Platform for Hybrid ENGineering simulation of flows (PHengLEI). The linearized equation system is solved using the Generalized Minimal Residual Method (GMRES). The elements of the exact Jacobian matrix are first computed using the automatic differentiation tool of Sacado and then manually assembled. In this work, two solution strategies are investigated for the solution of the RANS equations and the turbulence model equation: a decoupled approach and a coupled approach. The decoupled approach solves the RANS equations and the turbulence model equation sequentially while the coupled approach solves the RANS equations and the turbulence model equation simultaneously. The NACA0012 airfoil is used as the test vehicle to examine the two solution strategies. Results from the Lower-Upper Symmetric-Gauss-Seidel method are also presented as references.
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Good, Charly R., Shunichiro Kuramitsu, Parisa Samareh, Greg Donahue, Kenichi Ishiyama, Yujie Ma, Nils Wellhausen, et al. "Abstract 60: Induction of T cell dysfunction and NK-like T cell differentiation in vitro and in patients after CAR T cell treatment." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-60.
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Kennedy, Philippa R., Quinlan M. Kile, Rhett L. Waller, Laura Bendzick, Carly Selleck, Peter Hinderlie, Marissa Kaufman, et al. "365 Oxygen levels found in bone marrow (5%) provide an optimal niche for the differentiation of induced-pluripotent stem cell-derived NK cells for the treatment of AML." In SITC 38th Annual Meeting (SITC 2023) Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/jitc-2023-sitc2023.0365.
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