To see the other types of publications on this topic, follow the link: "Inflammation" and "Myeloid derived Suppressor cells".
Dissertations / Theses on the topic '"Inflammation" and "Myeloid derived Suppressor cells"'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic '"Inflammation" and "Myeloid derived Suppressor cells".'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Lotfi-Emran, Sahar. "Transformation of human mast cells by interferon-gamma and the potential role of myeloid derived suppressor cells in mastocytosis." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/4077.
Full textAbstract:
Mast cells respond to a variety of signals, are associated with both increased inflammation and regulation of the immune response, and are able to interact with a variety of hematopoietic and non-hematopoietic cells. The majority of the work that highlights mast cell pleiotropic abilities has been completed in murine models. Though these models have significantly advanced our understanding of what mast cells can do, they cannot inform us as to what mast cells actually do in human beings. The goal of this dissertation is to assess fully mature, primary human mast cell function beyond the well-defined type 1 hypersensitivity function and place mature human mast cells in the context of interactions with other immune cells. The first project addresses the ability of IFNγ, a historically Th1 associated cytokine, to dramatically alter mast cell phenotype. In particular, IFNγ stimulation allows mast cells to act as antigen presenting cells to CD4+ T cells. The second project describes and addresses the T cell suppressive function of myeloid derived suppressor cells in Mastocytosis, a disease of clonal mast cells.
2
Bleve, Augusto. "Decoding of epigenetic and metabolic events driving immune diversion of myeloid cells in cancer." Doctoral thesis, Università del Piemonte Orientale, 2020. http://hdl.handle.net/11579/114772.
Full textAbstract:
Cancers induce ‘emergency’ hematopoiesis and expansion of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), immunosuppressive and tumor-promoting cell populations, correlated with poor prognosis and resistance to chemo-immunotherapies. Molecular characterization of these cells offers new potential therapeutic opportunities. Previously, we showed that nuclear accumulation of p50 NF-kB transcription factor in TAM regulates expression of anti-inflammatory, pro-tumoral genes. Monocytic MDSC share myeloid progenitor and immunosuppressive properties with TAM. Here, we described how p50 NF-kB
mediates the protumor functions of M-MDSC. Indeed, during cancer-related inflammation, chronic production of PGE2 induces nuclear p50 accumulation in M-MDSC, epigenetically reprogramming the response to IFNγ towards an immunosuppressive phenotype. Myeloid-specific deletion of p50 or antagonists of PGE2 receptors restore the antitumor inflammatory response to IFNγ of MMDSC.
Recently, we identified that RORC1/RORγ drives cancer-related myelopoiesis. RORγ is a nuclear receptor co-activated by cholesterol-related molecules (eg. oxysterols). Of note, hypercholesterolemia predisposes to cancer and induces expansion of immature monocytes. Hence, we hypothesized an interplay between cholesterol metabolism and RORγ-driven myelopoiesis. Noteworthy, while tumor bearers (mice and humans) displayed increased levels of LDL-cholesterol, diet-induced hypercholesterolemia promotes metastasis and expansion of immunosuppressive M-MDSC and TAM. RORγ deficiency prevents hypercholesterolemia-induced
myelopoiesis disabling metastasis formation. Collectively, we identified p50 NF-kB as key driver of immunosuppressive M-MDSC in response to tumor-derived PGE2, and we underlined that RORγ induces emergency myelopoiesis remarkably in dyslipidemic conditions. Hence, inhibitors of PGE2/p50 NF-kB and of cholesterol/RORγ axis could be useful in the improvement of anticancer therapy.
3
Haverkamp, Jessica M. "Initiation and regulation of effector T cell responses in the prostate." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/3311.
Full textAbstract:
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells identified in mice as Gr-1+CD11b+ cells with the ability to inhibit T cell function. MDSC are emerging as important regulators of T cell mediated immune responses. Current paradigm suggests that despite heterogeneity, all Gr-1+CD11b+ cells are suppressive when exposed to inflammatory stimuli. In vitro evaluation shows MDSC from multiple tissue sites have suppressive activity, and in vivo inhibition of MDSCenhances T cell function. However, the relative capacity of MDSC present at localized inflammatory sites or in peripheral tissues to suppress T cell responses in vivo has not been directly evaluated. Using a tissue specific acute inflammatory prostatitis model, we demonstrate that MDSC inhibition of CD8+ T-cell proliferation is restricted to the inflammatory site.Further, MDSC from inflammatory sites possess immediate capacity to inhibit T-cell function, whereas those isolated from peripheral tissues (spleens and liver) were not suppressive without activation of iNOS by exposure to IFN-_.Using two mouse models of prostate cancer, we extend these findings to thetumor micro-environment. During a chronic inflammatory response induced by tumorgrowth, we show Gr-1+CD11b+ cells from the tumor site possess immediate capacity toregulate effector T cell function whereas those from the spleen do not. In both tumormodels and in our prostatitis model, long term culture of activated T cells with splenicGr-1+CD11b+ cells converted precursor cells into functional MDSC during standard in vitro suppression assays. These data highlight the importance of MDSC in the prostate, and demonstrate the function of MDSC during a localized inflammatory response isrestricted to the site of an ongoing immune responseGrowing evidence suggests that prostatitis associated with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is mediated in part by the loss of T cell and B cell tolerance to prostate antigens. Clinical data demonstrates the presence of T cell proliferative responses to prostate auto-antigens in CP/CPPS patients. However, the mechanisms leading to this loss of tolerance are not clearly understood, largely because of a lack of available animal models. We report the development of a new mouse model for the study of chronic prostate inflammation (CPI), the Prostate Ovalbumin Expressing Transgenic-3 (POET-3) model. Adoptive transfer of antigen specific OT-I T cells induces CPI characterized by infiltration of exogenous (OT-I) and endogenous T cells into the prostate persisting as long as 45 days after transfer. In vitro and in vivo data demonstrate inflammation induced loss of T cell tolerance to prostate auto-antigens. Auto-antibody responses to prostate antigens were detected in POET-3 mice after induction of CPI. These data have important therapeutic implications for treatment of CPI.
4
Gerard, Claire. "Développement d’une stratégie thérapeutique immunosuppressive dérivée de cellules myéloïdes dans la maladie du greffon contre l’hôte." Thesis, Bourgogne Franche-Comté, 2020. https://nuxeo.u-bourgogne.fr/nuxeo/site/esupversions/a02d57d7-6368-477d-8e8d-0badac13bda0.
Full textAbstract:
Résumé :Notre équipe a développé une thérapie cellulaire originale dérivant de la lignée monocytaire. Cette sous-population de cellules humaines suppressives d’origine myéloide, appelée Human Monocyte-derived Suppressor Cells (HuMoSC, cellules CD33+), est capable d’inhiber la prolifération des lymphocytes T effecteurs et d’induire des CD4 et CD8 Treg. De plus, les HuMoSC préviennent l’apparition de la maladie du greffon contre l’hôte (GvHD).Dans un premier temps, nous avons montré qu’un environnement inflammatoire ou la présence d’immunosuppresseurs ne diminuaient pas la capacité des HuMoSC à inhiber la prolifération lymphocytaire et à favoriser l’induction de CD4 et CD8 Treg. Enfin, nous avons montré que l’effet graft-versus-leukemia (GvL) est préservé en présence des HuMoSC. Toutes ces données confirment l’intérêt des HuMoSC dans la prévention de la GvHD.Cependant, en raison d’un faible rendement de génération des HuMoSC et d’un problème de disponibilité de billes de tri CD33+ GMP, nous avons aussi modifié notre protocole pour isoler les cellules CD14+, appelées CD14-HuMoSC. Ainsi, dans un second temps, nous nous sommes intéressés aux propriétés des surnageants des HuMoSC et des CD14- HuMoSC. Ces modifications du protocole ont permis d’obtenir un grand nombre de cellules CD14-HuMoSC et de grandes quantités de surnageant produit en conditions GMP. Nous avons montré que les deux surnageants diminuaient l’activation et la prolifération des LT, diminuaient la réponse Th1 au profit de la réponse Th2, favorisaient l’induction des Treg et diminuaient la capacité des cellules dendritiques à induire la prolifération des LT. In vivo, les surnageants préviennent le développement de la GvHD dans un modèle murin de GvHD xénogénique. Enfin, pour montrer que ces deux surnageants seront efficace chez les patients, nous avons montré qu’un environnement inflammatoire ou que la présence d’immunosuppresseurs n’altéraient pas l’effet immunosuppressif des surnageants. Ces résultats confirment leur intérêt thérapeutique. L’étude proteomique de ces deux surnageants a permis d’identifier des protéines immunosuppressives qui pourraient être responsables de leurs capacités immunosuppressives.En conclusion, les HuMoSC et les surnageants des cellules dérivées des HuMoSC représentent un arsenal thérapeutique prometteur dans la prévention de la GvHD mais aussi dans les maladies inflammatoires<br>Abstract :Our team has developed an original cell therapy derived from monocytes. This sub-population of human suppressor cells of myeloid origin, called Human Monocyte-Derived Suppressor Cells (HuMoSC, CD33+ cells) is able to inhibit effector T cell proliferation and to induce CD4 and CD8 Treg. It has been demonstrated that HuMoSC prevent from graft-versus-host disease (GvHD).In a first time, we showed that an inflammatory environment or the presence of immunosuppressive drugs did not decrease HuMoSC abilities to inhibit T cell proliferation and to promote CD4 and CD8 Treg induction. Finally, we showed that graft-versus-leukemia (GvL) effect is preserved in presence of HuMoSC. Taken together, those data confirm the interest of HuMoSC in GvHD prevention.Nevertheless, due to a low yield of HuMoSC generation with this protocol and problem with avaibility of CD33 GMP beads, we also modified our protocol to isolate CD14+ cells, called CD14-HuMoSC. This is why in a second time, we took interest in HuMoSC and CD14-HuMoSC supernatant properties. These protocol modifications allow us to obtain large number of CD14-HuMoSC cells and large quantities of supernatant produced under GMP conditions. We showed that both supernatants decrease T cell activation and proliferation, decrease Th1 response in favor of Th2 response, promote Treg induction and decrease capacity of dendritic cells to induce T cell proliferation. In vivo, supernatants prevent from GvHD in a murine model of xenogenic GvHD. Finally, in order to assess that these supernatants will be efficient in patient, we showed that an inflammatory environment or presence of immunosuppressive drugs did not alter both supernatant immunosuppressive effects. These results confirm their therapeutic interest. Proteomic analysis allowed us to identify immunosuppressive proteins which could be responsible for supernatants immunosuppressive capacities.In conclusion, HuMoSC and supernatant derived from HuMoSC represent a promising therapeutic arsenal for GvHD prevention but also in inflammatory diseases
5
Pyzer, Athalia Rachel. "Myeloid-derived suppressor cells in acute myeloid leukaemia." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/36704.
Full textAbstract:
The tumour microenvironment consists of an immunosuppressive niche created by the complex interactions between cancer cells and surrounding stromal cells. A critical component of this environment are myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells arrested at different stages of differentiation and expanded in response to a variety of tumour factors. MDSCs exert diverse effects in modulating the interactions between immune effector cells and malignant cells. An increased presence of MDSCs is associated with tumour progression, poorer outcomes, and decreased effectiveness of immunotherapeutic strategies. In this project, we sought to quantify and characterise MDSC populations in patients with Acute Myeloid Leukaemia (AML) and delineate the mechanisms underlying their expansion. We have demonstrated that immune suppressive MDSCs are expanded in the peripheral blood and bone marrow of patients with AML. Furthermore, AML cells secrete extra-cellular vesicles (EVs) that skew the tumour microenvironment from antigen-presentation to a tumour tolerogenic environment, through the expansion of MDSCs. We then demonstrated that MDSC expansion is dependent on tumour and EV expression of the oncoproteins MUC1 and c-Myc. Furthermore, we determined that MUC1 signalling promotes c-MYC expression in a microRNA (miRNA) dependent mechanism. This observation lead us to elucidate the critical role of MUC1 in suppressing microRNA-genesis in AML, via the down-regulation of the DICER protein, a key component of miRNA processing machinery. Finally, exploiting this critical pathway, we showed that MDSCs can be targeted by MUC1 inhibition or by the use of a novel hypomethylating agent SGI-110.
6
Mundy-Bosse, Bethany L. "Myeloid-Derived Suppressor Cells in Tumor Immunology." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1311261626.
Full text
7
Dhakal, Santosh. "CHARACTERIZATION OF PORCINE MYELOID DERIVED SUPPRESSOR CELLS." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1437055804.
Full text
8
VUERICH, Marta. "Extracellular ATP modulates Myeloid Derived Suppressor Cells functions." Doctoral thesis, Università degli studi di Ferrara, 2014. http://hdl.handle.net/11392/2389384.
Full textAbstract:
The main obstacle to the success of the immunotherapy is the well established tumor-induced tolerance. In 2007 a new cell population, Myeloid Derived Suppressor Cells (MDSCs), that accumulate under inflammatory conditions, especially in cancer, was identified. These cells are potent inhibitors of tumor immunity and are now considered a major contributor to the failure of the immunotherapy. Understanding the exact mechanism of immunosuppressive activity of MDSC is a crucial point in order to find new ways to improve anticancer therapies.
In the last years several models of MDSC functions were described, such as Arg-1 and ROS production or TGF-β release, but other factors may play a role. Two of these additional modulators might be the extracellular ATP and adenosine.
In this study I have performed an extensive characterization of purinergic signaling, mainly focused on the P2X7 receptor, in two MDSC cell lines: MSC-1 and MSC-2. I have found that these cells express P2X2, P2X3, P2X5, P2X7, P2Y6, P2Y12 and P2Y13 mRNA and P2X3, P2X4, P2X5 and P2X7 proteins. Stimulation of P2 receptors induced increase in the intracellular calcium concentration, plasma membrane depolarization and permeabilization to the extracellular dyes ethidium bromide and lucifer yellow. These responses were followed by contraction of cell volume and membrane blebbing. Moreover I observed that both cell lines released ATP in the extracellular environment and that stimulation with BzATP induced release of IL-1β. Unexpectedly P2X7R in these cells was uncoupled from cytotoxicity.
With regard to the immunosuppressive function, I have found that stimulation of P2X7 receptor induced increase in the production of Arg-1 and ROS, and enhanced the release of TGF-β1. Subsequently, I generated MDSC in vitro from murine bone marrow precursors and I have found that these cells express the P2X3, P2X5, P2X7 and P2Y6 receptors protein. Interestingly, P2 receptors expression is present only after the differentiation of BM in suppressor cells. Furthermore I have found that these cells release ATP and are attracted by extracellular nucleotides.
Generation of adenosine from ATP by CD39 and CD73 expressed by endothelium and immune regulatory cells is an established immunosuppressive mechanism. I have found that MSC-2 express CD39 while both ectonucleotidases are detectable in bone marrow-derived MDSC.
All these data suggest an involvement of ATP in tumor mediated immune suppression and open a new avenue for the investigation of the role of adenosine in this setting.
9
Labrousse, Delphine. "Characterisation of myeloid-derived suppressor cells in chronic inflammatory diseases." Thesis, University of Southampton, 2010. https://eprints.soton.ac.uk/385140/.
Full text
10
Sherger, Matthew George. "Identification of Myeloid Derived Suppressor Cells in Tumor Bearing Dogs." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1337617975.
Full text
11
Pallett, L. "Metabolic regulation of hepatic immunopathology by myeloid-derived suppressor cells." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1455552/.
Full textAbstract:
The liver provides a highly immunotolerant environment, that is exploited by hepatotropic viruses such as Hepatitis B virus (HBV), which establishes persistent infection in more than 350 million people worldwide. In this thesis the potential for myeloid-derived suppressor cells (MDSC) to exert metabolic regulation in this setting has been investigated. We found a mean approximate 9-fold expansion of granulocytic MDSC (gMDSC) in patients with chronic HBV infection (CHB) compared to uninfected, healthy controls (p<0.001). The most striking increases were seen in patients replicating HBV in the absence of immunopathology (p<0.01). gMDSC expressed high levels of the chemokine receptor, CXCR1, providing the potential for them to be chemoattracted by liver-derived interleukin-8 (IL-8); consistent with this, they were further enriched in the intrahepatic compartment. gMDSC from patients with CHB expressed increased amounts of arginase I, correlating with an increase in serum levels of this enzyme (p<0.01). Arginase I metabolises the conditionally essential amino acid L-arginine that is required for proliferating T cells; in line with this was an observed decrease in circulating L-arginine, particularly in those patients without liver inflammation. Liver pathology in CHB is ampli ed by the recruitment and activation of bystander (non-HBV-speci c) T cells; therefore the potential of gMDSC to down-regulate such responses was explored. Puri ed gMDSC from patients with CHB potently inhibit the expansion of bystander T cells capable of producing pro-inflammatory cytokines or mediating cytotoxicity. This inhibition was blocked using an arginase I-specific inhibitor, N-hydroxy-nor-arginine (nor-NOHA). Taken together, these data demonstrate the capacity for expanded arginase I expressing gMDSC to regulate liver immunopathology in CHB by depriving T cells of L-arginine.
12
Stiff, Andrew Robert. "Enhancing Immune Therapy for Cancer by Targeting Myeloid Derived Suppressor Cells." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1494081640848458.
Full text
13
Centuori, Sara Mozelle. "NEGATIVE REGULATION OF REGULATORY T CELLS BY MYELOID-DERIVED SUPPRESSOR CELLS IN CANCER." Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/145099.
Full textAbstract:
Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play an essential role in the immunosuppressive networks that contribute to tumor immune evasion. The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-regulation between MDSC and Treg remain incompletely defined. The current work evaluates the influence of MDSC, expanded in two mouse cancer models, on immunosuppressive Treg. We demonstrate that tumor-induced MDSC endowed with the potential of suppressing conventional T lymphocytes surprisingly impair TGF-β1-mediated generation of induced Treg (iTreg) from naïve CD4⁺ T lymphocytes. Suppression of iTreg generation by MDSC occurs early in the differentiation process, and is cell contact dependent. This inhibition of FoxP3-expressing T lymphocyte differentiation by MDSC does not depend on arginase 1, cystine/cysteine depletion, iNOS/NO, or PD-1/PD-L1 signaling. These findings therefore indicate that MDSC from tumor-bearing hosts have the heretofore unreported ability to restrict some immunosuppressive Treg subpopulations.
14
Christiansson, Lisa. "Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia." Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-197604.
Full textAbstract:
Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, a minute chromosome that leads to the creation of the fusion gene BCR/ABL and the transcription of the fusion protein BCR/ABL in transformed cells. The constitutively active tyrosine kinase BCR/ABL confers enhanced proliferation and survival on leukemic cells. CML has in only a few decades gone from being a disease with very bad prognosis to being a disease that can be effectively treated with oral tyrosine kinase inhibitors (TKIs). TKIs are drugs inhibiting BCR/ABL as well as other tyrosine kinases. In this thesis, the focus has been on the immune system of CML patients, on immune escape mechanisms present in untreated patients and on how these are affected by TKI therapy. We have found that newly diagnosed, untreated CML patients exert different kinds of immune escape mechanisms. Patients belonging to the Sokal high-risk group had higher levels of myeloid-derived suppressor cells (MDSCs) as well as high levels of the programmed death receptor 1 (PD-1)-expressing cytotoxic T cells compared to control subjects. Moreover, CML patients had higher levels of myeloid cells expressing the ligand for PD-1, PD-L1. CML patients as well as patients with B cell malignacies had high levels of soluble CD25 in blood plasma. In B cell malignacies, sCD25 was found to be released from T regulatory cells (Tregs). Treatment with the TKIs imatinib or dasatinib decreased the levels of MDSCs in peripheral blood. Tregs on the other hand increased during TKI therapy. The immunostimulatory molecule CD40 as well as NK cells increased during therapy, indicating an immunostimulatory effect of TKIs. When evaluating immune responses, multiplex techniques for quantification of proteins such as cytokines and chemokines are becoming increasingly popular. With these techniques a lot of information can be gained from a small sample volume and complex networks can be more easily studied than when using for example the singleplex ELISA. When comparing different multiplex platforms we found that the absolute protein concentration measured by one platform rarely correlated with the absolute concentration measured by another platform. However, relative quantification was better correlated.
15
Merga, Ketema Abdissa [Verfasser]. "Role of Myeloid Derived Suppressor Cells in Mycobacterial Infection / Ketema Abdissa Merga." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2017. http://d-nb.info/1162732733/34.
Full text
16
Alkhateeb, Tuqa PharmD, Ajinkya MD Kumbhare, Isatou BS Bah, and Mohamed PhD Elgazzar. "S100A9 Sustains Myeloid-Derived Suppressor Expansion and Immunosuppression During Chronic Murine Sepsis." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/217.
Full textAbstract:
Myeloid-derived suppressor cells (MDSC) expand during sepsis, suppress both innate and adaptive immunity, and promote chronic immunosuppression, which characterizes the late/chronic phase of sepsis. We previously reported that the transcription factors Stat3 and C/EBPb synergize to induces the expression of microRNA (miR)-21 and miR-181b to promote MDSC expansion in a mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive stage. We also showed that Gr1+CD11b+ cells, the precursors of MDSCs, from mice genetically deficient in the inflammatory protein S100A9 lack miR-21 or miR-181b in late sepsis, and are not immunosuppressive. In the present study, we show that S100A9 induces miR-21 and miR-181b during the late sepsis phase. We find that S100A9 associates with and stabilizes the Stat3-C/EBPb protein complex that activates the miRNA promoters. Reconstituting Gr1+CD11b+ cells from the S100A9 knockout mice with late sepsis with S100A9 protein restores the Stat3-C/EBPb protein complex and miRNA expressions, and switches the Gr1+CD11b+ cells into the immunosuppressive, MDSC phenotype. Importantly, we find that this process requires IL-10 mediated signaling, which induces S100A9 translocation from the cytosol to the nucleus. These results demonstrate that S100A9 promotes MDSC expansion and immunosuppression in late/chronic sepsis by inducing the expression of miR-21 and miR-181b.
17
Zhao, J. "The roles of myeloid derived cells in retinal inflammation and inflammation-mediated retinal angiogenesis." Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677966.
Full textAbstract:
Intraocular inflammation encompasses a diverse group of diseases which account for up to 20% of severe vision loss, particularly following pathological neovascularisation in the retina. Nowadays, the use of corticosteroids is still the main armamentarium to manage these devastating conditions. Clearly safer, more target-specific and effective drugs are needed. Experimental autoimmune uveoretinitis (EAU) is an animal model for human intraocular inflammation. It is well known that myeloid derived cells substantially contribute to the pathological activities in this model. The aims of my PhD project were: to understand how myeloid-derived cells contribute to retinal damage in the EAU and to investigate whether modulating these cells can control retinal inflammation and associated retinal angiogenesis. Firstly, we showed that the deletions of both CCL2 and CX3CR1 resulted in reduced retinal inflammation in EAU. In the CCL2/CX3CR1 double knockout EAU mice, the macrophage infiltration was reduced and the inflammation was dominated by neutrophils at the acute stage. A reduction in macrophage infiltration was associated with reduced retinal angiogenesis at the chronic stage of EAU. Secondly, we found that SOCS3 in myeloid cells played an important role in EAU. The LysM-Cre-SOCS3f11f1 mice had an earlier onset and more severe retinal inflammation after immunisation. LysM-Cre-SOCS3f11f1 EAU mice also developed more severe retinal angiogenesis. Inflammation in the LysM-Cre-SOCS3f11f1 EAU mice was characterised by enhanced neutrophil infiltration and greatly increased cytokine expressions. In addition, the bone marrow-derived macrophages from LysM-Cre-SOCS3f11fl mice expressed M2 makers and produced more IL-10 and VEGF-A compared to the cells from wr mice. Finally, we found that blocking CCL2 or VEGF-A alone was not sufficient to suppress chronic inflammation-mediated retinal angiogenesis. However, systemic inhibition of arginase-1 activity was effective in reducing chronic EAU induced retinal angiogenesis. Thus, arginase inhibition could be a novel therapeutic strategy to control retinal neovascularisation related to long-standing uveoretinitis.
18
Morales, Johanna. "The Role of Myeloid-Derived Suppressor Cells in the Immunotherapy of Breast Carcinomas." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1744.
Full textAbstract:
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells at various stages of differentiation. These cells are broadly characterized by the simultaneous expression of the surface markers CD11b and Gr1 and have been found to accumulate in large numbers in response to many different tumors in both mice and humans, including HER2/neu+ breast cancers. The adoptive immunotherapy of cancers has been a promising field, yet the clinical efficacy of adoptive immunotherapies targeted against human breast cancers and many other cancers has been extremely limited. Given the influx of MDSC in tumor-bearing individuals, we hypothesized that these cells were the reason for the failure of adoptively transferred T cells to effectively reject primary tumors. Using either monoclonal antibodies or the chemotherapeutic drug, gemcitabine, we aimed to eliminate MDSC cells in vivo to determine if adoptively transferred T cells would be more effective in the absence of these cells. We further aimed to characterize the mechanism of T cell suppression by MDSC and the tumor-derived soluble factor(s) responsible for their accumulation. We have found that the elimination of MDSC in vivo does result in significant tumor inhibition when adoptively transferred T cells are administered. Furthermore, the use of gemcitabine in conjunction with adoptively transferred T cells resulted in complete tumor rejection in 100% of mice and was accompanied by large antibody titers against HER2/neu as well as strong recall responses characterized by IFN-g release and subsequent rejection of further tumor challenges. We report herein that suppression by MDSC is contact dependent and affects the proliferation of both CD4+ and CD8+ T cells. The accumulation of MDSC in tumor-bearing mice can be entirely attributed to tumor-derived soluble factors, with GM-CSF specifically causing the generation and maintenance of these cells. Our findings suggest that the adoptive immunotherapy of breast carcinomas in a clinical setting should be combined with the use of gemcitabine, and that the use of GM-CSF as an adjuvant in cancer vaccines should be carefully re-evaluated as this cytokine may result in increased MDSC accumulation in vivo.
19
John, Vini [Verfasser], and Manfred [Gutachter] Lutz. "Interaction of mycobacteria with myeloid-derived suppressor cells / Vini John ; Gutachter: Manfred Lutz." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1213247349/34.
Full text
20
Wang, Ling, Juan Zhao, Junping P. Ren, et al. "Expansion of Myeloid-Derived Suppressor Cells Promotes Differentiation of Regulatory T Cells in HIV-1+ Individuals." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etsu-works/6532.
Full textAbstract:
Objective: Regulatory T cells (Tregs) contribute to HIV-1 disease progression by impairing antiviral immunity; however, the precise mechanisms responsible for the development of Tregs in the setting of HIV-1 infection are incompletely understood.
Design: In this study, we provide evidence that HIV-induced expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) promote the differentiation of Foxp3+ Tregs.
Methods: We measured MDSC induction and cytokine expression by flow cytometry and analyzed their functions by coculturing experiments.
Results: We observed a dramatic increase in M-MDSC frequencies in the peripheral blood of HIV-1 seropositive (HIV-1+) individuals, even in those on antiretroviral therapy with undetectable viremia, when compared with healthy participants. We also observed increases in M-MDSCs after incubating healthy peripheral mononuclear cells (PBMCs) with HIV-1 proteins (gp120 or Tat) or Toll-like receptor 4 ligand lipopolysaccharides in vitro, an effect that could be abrogated in the presence of the phosphorylated signal transducer and activator of transcription 3 inhibitor, STA-21. Functional analyses indicated that M-MDSCs from HIV-1+ individuals express higher levels of IL-10, tumor growth factor-β, IL-4 receptor α, p47phex, programmed death-ligand 1, and phosphorylated signal transducer and activator of transcription 3 – all of which are known mediators of myelopoiesis and immunosuppression. Importantly, incubation of healthy CD4+ T cells with MDSCs derived from HIV-1+ individuals significantly increased differentiation of Foxp3+ Tregs. In addition, depletion of MDSCs from PBMCs of HIV-1+ individuals led to a significant reduction of Foxp3+ Tregs and increase of IFNγ production by CD4+ T effector cells.
Conclusions: These results suggest that HIV-induced MDSCs promote Treg cell development and inhibit T cell function – a hallmark of many chronic infectious diseases.
21
Ballbach, Marlene [Verfasser], and Dominik [Akademischer Betreuer] Hartl. "Myeloid-derived suppressor cells in cryopyrin-associated periodic syndromes / Marlene Ballbach ; Betreuer: Dominik Hartl." Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1165508362/34.
Full text
22
Alkhateeb, Tuqa. "Development, Expansion and Role of Myeloid-Derived Suppressor Cells in Post-Sepsis Immune Suppression." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etd/3787.
Full textAbstract:
Myeloid-derived suppressor cells (MDSCs) numbers increase significantly in sepsis and are associated with high mortality rates. These myeloid cell precursors promote immunosuppression, especially in the late (post sepsis) stage. However, the mechanisms that underlie MDSC expansion and programming are not completely understood. To investigate these mechanisms, we used a cecal-ligation and puncture (CLP) mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive phase. Previous studies in our laboratory showed that microRNA (miR)-21 and miR-181b elevate levels of the transcription factor nuclear factor 1 (NFI-A) that promotes MDSC expansion. We report here that miR-21 and miR-181b regulate NFI-A expression via a post-transcriptional regulatory mechanism by recruiting RNA-binding proteins HuR and Ago1 to stabilize NFI-A mRNA, thus increasing its protein levels. Studies in our laboratory also showed that inflammatory mediator S100A9 accumulates in the nucleus in Gr1+CD11b+ myeloid precursors in the later phases of sepsis and is necessary for their expansion and programming into immunosuppressive MDSCs. We demonstrate here that nuclear S100A9 associates with specific transcription factors that activate miR-21 and miR-181b expressions. In our final manuscript, we uncover another layer of the mechanisms of MDSC expansion and programming. We found that long non-coding RNA (lncRNA) Hotairm1 binds to and recruits S100A9 to the nucleus to program Gr1+CD11b+ myeloid precursors into MDSCs in the later phases of sepsis. Together, our results reveal three regulatory layers involving NFI-A, S100A9 and Hotairm1 in the pathway leading to MDSCs development in sepsis and suggest that therapeutically targeting these molecular switches might improve sepsis survival.
23
Martel, André Bernard. "Targeting CD155 on Myeloid Derived Suppressor Cells to Prevent Postoperative Immunosuppression in Cancer Patients." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41151.
Full textAbstract:
Surgery, although required to treat most solid cancers, can increase tumour seeding and metastases. We have previously shown that surgery-induced myeloid derived suppressor cells (Sx-MDSCs) play an important role in this process by directly suppressing NK cells. The Sx- MDSCs increase significantly immediately after surgery but the exact mechanism by which Sx-MDSCs suppress NK cells is still unknown. In this work, we have discovered that CD155 poliovirus receptor is significantly and specifically upregulated on Sx-MDSCs following surgical stress but is minimally expressed on other immune cells. We also demonstrate that blocking CD155 in vivo leads to an improved NK cell phenotype, measured by DNAM-1 and NKG2D, and increased NK cytotoxicity. Additionally, ex vivo CD155 blockade significantly decreases the suppressive effect of Sx-MDSCs in cancer patients. Expansion of CD155 on Sx- MDSCs could be responsible for the profound postoperative NK cell suppression, which makes it a very appealing perioperative target for immunotherapy.
24
Assimacopoulos, Evangelia Maria. "Monitoring and Targeting of Myeloid-Derived Suppressor Cells (MDSC) in Different Mouse Cancer Models." Thesis, The University of Arizona, 2014. http://hdl.handle.net/10150/318817.
Full text
25
Benner, Brooke Nicole. "Enhancing Immunotherapy for Cancer by Targeting Suppressive Myeloid cells." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1583766367545941.
Full text
26
Singh, Anurag [Verfasser], and Dominik [Akademischer Betreuer] Hartl. "Role of myeloid-derived suppressor cells in pathogenic fungal infections / Anurag Singh ; Betreuer: Dominik Hartl." Tübingen : Universitätsbibliothek Tübingen, 2015. http://d-nb.info/1197057838/34.
Full text
27
Nobre, Lelis Felipe Jose [Verfasser], and Dominik [Akademischer Betreuer] Hartl. "Myeloid-derived suppressor cells regulate B-cell responses / Felipe Jose Nobre Lelis ; Betreuer: Dominik Hartl." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1199616230/34.
Full text
28
Sandwick, Sarah [Verfasser], and Manfred [Akademischer Betreuer] Lutz. "Suppression of Experimental Autoimmune-Encephalomyelitis by Myeloid-Derived Suppressor Cells / Sarah Sandwick. Betreuer: Manfred Lutz." Würzburg : Universitätsbibliothek der Universität Würzburg, 2012. http://d-nb.info/1026211026/34.
Full text
29
Tamadaho, Ruth Shalom Emilie [Verfasser]. "The relevance of myeloid-derived suppressor cells during Litomosoides sigmodontis infection / Ruth Shalom Emilie Tamadaho." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1161462236/34.
Full text
30
Taki, Mana. "Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation." Kyoto University, 2018. http://hdl.handle.net/2433/232477.
Full text
31
Tamadaho, Ruth [Verfasser]. "The relevance of myeloid-derived suppressor cells during Litomosoides sigmodontis infection / Ruth Shalom Emilie Tamadaho." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1161462236/34.
Full text
32
Lelis, Felipe [Verfasser], and Dominik [Akademischer Betreuer] Hartl. "Myeloid-derived suppressor cells regulate B-cell responses / Felipe Jose Nobre Lelis ; Betreuer: Dominik Hartl." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1199616230/34.
Full text
33
Arscott, Ramon. "The influence of invariant natural killer T cells on myeloid-derived suppressor cell generation and function." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:07ab563a-7455-4f69-bca0-3b409b72d2f7.
Full textAbstract:
The absence of invariant Natural Killer T cells (iNKT cells) in mice infected with Influenza A virus (flu) has previously been shown to augment the expansion of Myeloid-derived suppressor cells (MDSCs), a bone marrow derived population that powerfully suppress the development of viral and tumor immune responses. Moreover, iNKT cell adoptive transfer into flu-infected mice has been shown to abolish the expansion and flu-induced suppressive activity of the MDSCs in a CD1d- and CD40-dependent manner. However, the mechanisms by which this relatively small subset of T cells influence myelopoiesis and MDSC differentiation remain largely unknown. In this manuscript we firstly better define the MDSCs found in flu-infection as IL-10-secreting neutrophils that can suppress T cell proliferation. We then go further to show that the flu-induced ability to suppress T cells is acquired as early as the level of the Granulocyte-Macrophage Progenitors (GMPs) in the bone marrow and that iNKT cells can not only abrogate the suppressive activity of the IL-10-secreting neutrophils in the periphery but also that of the GMPs by a direct CD1d-dependent GCSF-mediated crosstalk. MDSC expansion has previously been shown to be associated with the expression of the myeloid-related protein S100A9, and the mechanism of action of granulocytic-MDSCs shown to be ARG1-dependent. We built upon both these findings to show that iNKT cells influence the expansion and function of the MDSCs in part by regulating S100A9 and ARG1 expression. Following this we then showed for the first time that the acute phase protein Serum Amyloid A (SAA), shown to increase during flu-infection, has a dual reciprocal role: having the ability to up-regulate S100A9 and ARG1 in myeloid cells and differentiate IL-10-secreting suppressive neutrophils, while simultaneously facilitating the ability of the MDSCs to crosstalk with iNKT cells in a CD1d-dependent GCSF-mediated manner to abrogate the SAA-induced suppressive activity. All together the data highlights the complexity of the immune response and the role iNKT cells play in influencing the differentiation of MDSCs during demand-driven myelopoiesis. More importantly however, it further affirms that research into harnessing the immunomodulatory capacity of iNKT cells remains an exciting prospect in bolstering future vaccination strategies and should continue to be pursued.
34
Giallongo, Cesarina. "Immune escape mechanisms in hematological diseades: role of the myeloid derived suppressor cells and tumor microenvironment." Doctoral thesis, Università di Catania, 2017. http://hdl.handle.net/10761/3889.
Full textAbstract:
The interactions between the immune system and the tumor cells occur through complex events that lead to tumor eradication or immune evasion by cancer. Recently, the prognostic role of Myeloid derived suppressor cells (MDSC) accumulation has been documented for some hematological malignancies where they correlates with disease progression and persistence of minimal residual disease. We first evaluated the change of MDSC frequency in hematological patients during therapy founding a significant correlation between the number of persistent monocytic-MDSC and major molecular response (MMR) value in chronic myeloid leukemia patients treated with dasatinib. Moreover, our data demonstrated that tumor cells, through the release of soluble factors and exosomes, are able to expand monocytic-MDSC, creating an immunotolerant environment that results in T cell anergy and facilitates tumor growth. In addition, cancer cells are also able to promote immune dysfunction in MSC with their consequent commitment, via TLR4 signaling, toward an activated status promoting immune escape through the polarization of neutrophils in immunosuppressive cells.
35
Ko, Jennifer S. "Mechanism of Myeloid-Derived Suppressor Cell Accumulation in Cancer and Susceptibility to Reversal by Sunitinib." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1259869673.
Full text
36
Pinton, Laura. "The crosstalk between activated T cells and Myeloid Derived Suppressor Cells: characterization of molecular mechanisms involved in immune suppression." Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423699.
Full textAbstract:
One of the mechanisms used by cancer to evade the immune response is the expansion of myeloid-derived suppressor cells (MDSCs), a population of immature myeloid cells able to inhibit immune responses in cancer patients and experimental animals with neoplasia. The role of MDSCs in promoting tumor growth and metastasis has gained importance over the years, highlighting the need to find specific target of intervention that could be used in the treatment of cancer patients.
The aim of the present work was to analyze the signaling pathways active in MDSCs, using an in vitro model of MDSC generation developed by our group. Our previous studies revealed that the phenotype and suppressive ability of MDSCs were influenced by the presence of activated T cells, thus suggesting the existence of an interplay between the two populations. We therefore focused our attention on soluble molecules and surface markers mediating the interaction.
We demonstrated that IL-10 release is increased in the culture between MDSCs and activated T cells and that this cytokine leads to the activation of STAT3 both in myeloid and lymphoid cells. One of the targets of STAT3 is B7-H1, a molecule that can deliver an inhibitory signal to T cell, interacting with its receptor PD-1. We therefore analyzed the expression of B7-H1 on MDSCs and we found that it is up-regulated in the presence of activated T cells through a STAT3-dependent signaling. By analyzing the fate of suppressed T cells, we observed that they express at higher level two markers of T cell exhaustion, PD-1 and LAG-3. LAG-3 is a negative co-stimulatory receptor on T lymphocytes and the natural ligand of HLA class II, whose expression we found up-regulated in MDSCs after culture with activated T cells. These results thus suggest that the interplay between MDSCs and activated T cells could be mediated by the couples of receptor/ligand PD-1/B7-H1 and LAG-3/HLA class II, leading to T cell exhaustion.<br>Uno dei meccanismi utilizzati dalle cellule tumorali per evadere la risposta del sistema immunitario è costituito dall’espansione delle cellule soppressorie di derivazione mieloide (MDSC), una popolazione di cellule mieloidi immature capaci di inibire le risposte immunitarie nei pazienti con tumore e in modelli murini con neoplasie. Il ruolo delle MDSC nel promuovere la crescita tumorale e la metastatizzazione ha acquisito sempre maggiore importanza negli ultimi anni, evidenziando la necessità di trovare specifiche vie di segnalazione attive in queste cellule che possano diventare bersaglio di interventi terapeutici mirati nel trattamento dei pazienti con tumore.
Lo scopo di questo lavoro è stato quello di analizzare le vie di segnalazione attive nelle MDSC, utilizzando un modello sviluppato dal nostro gruppo per la generazione in vitro delle MDSC umane. I nostri studi precedenti hanno rivelato che il fenotipo e la capacità soppressoria delle MDSC sono fortemente influenzati dalla presenza dei linfociti T attivati, suggerendo l’esistenza di un’interazione tra le due popolazioni. Abbiamo quindi focalizzato la nostra attenzione su molecole solubili e marcatori di superficie che potrebbero essere coinvolti nell’interazione tra MDSC e cellule T attivate.
Abbiamo dimostrato che il rilascio di IL-10 è aumentato nelle colture tra MDSC e cellule T attivate e che questa citochina porta all’attivazione di STAT3 sia nelle cellule mieloidi che in quelle linfoidi. Uno dei bersagli di STAT3 è B7-H1, una molecola che può fornire un segnale inibitorio alla cellula T, interagendo con il suo recettore PD-1. Abbiamo pertanto analizzato l’espressione di B7-H1 sulle MDSC e abbiamo notato che essa è aumentata in presenza delle cellule T attivate, mediante una via di segnalazione dipendente dall’attivazione di STAT3. Analizzando il destino dei linfociti T soppressi, abbiamo osservato che essi esprimono ad alto livello due marcatori di “exhaustion” delle cellule T, che sono PD-1 e LAG-3. E’ noto che LAG-3 è un recettore co-stimolatorio negativo sui linfociti T ed è il ligando naturale di molecole HLA di classe II, che sono significativamente aumentate nelle MDSC dopo coltura con le cellule T attivate. Questi risultati pertanto suggeriscono che l’interazione tra le MDSC e le cellule T attivate potrebbe essere mediata dalle coppie di recettore/ligando PD-1/B7-H1 e LAG-3/HLA di classe II, portando ad “exhaustion” delle cellule T.
37
Ling, Changchun, and 凌长春. "The role of graft injury in mobilization of endothelial progenitor cells, myeloid derived suppressor cells and regulatory T cells afterlive transplantation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47849769.
Full textAbstract:
Liver transplantation is the best therapy for patients with end-stage liver diseases and unresectable early hepatocellular carcinoma (HCC). Living donor liver transplantation (LDLT) has been successfully implemented as an alternative to deceased donor liver transplantation (DDLT) and likewise offers comparable excellent survival rate. However, the inferior post-transplant oncological outcomes are found in LDLT recipients with HCC. The liver grafts used in LDLT are usually small-for-size and less effective in coping with shear stress from transient portal hypertension, which results in small-for-size liver graft injury. Acute phase small-for-size liver graft injury may promote late phase tumor recurrence, whereas the underlying mechanism remains unclear.
CXCL10, an inflammatory chemokine, initiates liver inflammatory response during hepatic ischemia-reperfusion (IR) injury and may link acute phase small-for-size liver graft injury and late phase tumor recurrence, yet the precise mechanisms remain elusive. Endothelial progenitor cells (EPCs) participate in tissue repair for graft recovery and also provide an angiogenic environment for tumor growth. Myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) can suppress the activation of the immune system and play a critical role in graft rejection and cancer development.
We here established the rat orthotopic liver transplantation with whole graft or small-for-size graft model to study the impact of acute phase small-for-size liver graft injury on the mobilization of EPCs, MDSCs and Tregs, and intragraft CXCL10 and its receptor, CXCR3,gene expressions. We further subjected CXCL10-/-mice and CXCR3-/-mice to hepatic IR injury and major hepatectomy to study the role of CXCL10/CXCR3 signaling on the mobilization of EPCs, MDSCs and Tregs. We also investigated the effect of CXCL10 on EPC migration and tube formation in vitroas well as intratumoral microvessel density (MVD) in the rat liver transplantation with tumor growth model and EPCs on tumor growth in nude mice.
Key findings:
1. Liver transplantation with small-for-size graft resulted in severe intragraft vascular injury and higher CXCL10 andCXCR3 gene expressions as well as more EPC, MDSC and Treg cell mobilizationin circulation than whole graft.
2. CXCL10-/-mice and CXCR3-/-mice had less circulating EPCs, MDSCs and Tregs than WT mice after hepatic IR injury and major hepatectomy.
3. CXCL10 recruited EPCs in dose-dependent and CXCR3-dependent manners and promoted EPC tube formation in vitro.
4. Higher intratumoral MVD was observed in small-for-size graft than in whole graft in liver transplantation with tumor growth model.
5. Tumor grew more quickly by combining EPC infusionin nude mouse orthotopic liver tumor model.
In conclusion, acute phase small-for-size liver graft injury significantly mobilizes EPCs, MDSCs and Tregs after transplantation through CXCL10/CXCR3 signaling. More EPC mobilization and intragraft differentiation after transplantation with small-for-size liver graft may be related to higher intratumoral MVD in small-for-size liver graft after transplantation with tumor development. Therefore, targeting at post-transplant CXCL10/CXCR3 signaling may not only attenuate early phase liver graft injury but also prevent late phase tumor recurrence.<br>published_or_final_version<br>Surgery<br>Doctoral<br>Doctor of Philosophy
38
Tohumeken, Sehmus [Verfasser], Falk [Akademischer Betreuer] Nimmerjahn, Falk [Gutachter] Nimmerjahn, and Andreas [Gutachter] Mackensen. "Characterization and Targeting of Myeloid-Derived Suppressor Cells in Acute Myeloid Leukemia / Sehmus Tohumeken ; Gutachter: Falk Nimmerjahn, Andreas Mackensen ; Betreuer: Falk Nimmerjahn." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2019. http://d-nb.info/1218785675/34.
Full text
39
Yamani, Lamya Zohair. "Characterising the role of mTORC1 in myeloid cells." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/25987.
Full textAbstract:
The mammalian target of rapamycin (mTOR) signalling pathway takes part in both extracellular and intracellular signals. It is a major regulator of cell metabolism, growth, proliferation and survival. mTOR also regulates critical processes such as cytoskeletal organization, ribosomal biogenesis, transcription and protein synthesis. The mTOR pathway has been implicated in many diseases such as cancer, neurodegeneration and diabetes, which impact homeostasis and cellular functions. Moreover, mTOR has also been shown to play a critical role in immune cell regulation of T and B cells together with neutrophils and antigen presenting cells, as it integrates signals between them extending to the entire immune microenvironment. The aim of my study was to investigate the role of a component of the mTOR complex 1, Raptor, in myeloid cells. My findings show that the absence of Raptor knock out (KO) does not affect bone marrow derived macrophage (BMDM) differentiation and maturation. However, the absence of Raptor influences BMDM polarisation towards an inflammatory phenotype, at least at the level of transcription as observed by increases in mRNA expression of inflammatory cytokines such as TNFα, IL-12β, and IL-6. This finding was consolidated by an increase in NFκΒ pathway signalling in Raptor KO BMDMs. Downstream intracellular signalling in myeloid cells was affected by deletion of Raptor as I found reduced S6K phosphorylation in Raptor KO BMDMs compared to wild type (WT) BMDMs. As a consequence of Raptor absence in BMDMs, STAT3 phosphorylation was also reduced. Raptor deletion did not impact the PI3K/Akt signalling pathway, but decreased phosphorylation of ERK. BMDMs lacking Raptor had reduced phagocytic activity as they were also observed to migrate less towards a pancreatic cancer cell line. However preliminary experiments in pancreatic cancer models did not indicate a major role for Raptor in the activity of tumour associated myeloid cells. My results demonstrate that Raptor and by implication mTORC1, is involved in macrophage polarisation and function.
40
Müller, Nils Benjamin [Verfasser], and Daniela [Akademischer Betreuer] Männel. "Einfluss des TNF/TNF-Rezeptor-Systems auf Myeloid-Derived-Suppressor Cells / Nils Benjamin Müller ; Betreuer: Daniela Männel." Regensburg : Universitätsbibliothek Regensburg, 2017. http://d-nb.info/1137701765/34.
Full text
41
Öz, Hasan Halit [Verfasser], and Dominik [Akademischer Betreuer] Hartl. "Pseudomonas aeruginosa airway infection recruits and modulates myeloid-derived suppressor cells / Hasan Halit Öz ; Betreuer: Dominik Hartl." Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1199615609/34.
Full text
42
Cieza, Rubio Napoleon Eduardo. "Mechanistic Studies in the Inflammatory Response of Pancreatitis and Pancreatric Cancer - Role of Myeloid Derived Suppressor Cells." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/594648.
Full textAbstract:
Tumor-infiltrating myeloid-derived suppressor cells (MDSCs), are important mediators of a tumor-permissive microenvironment that contributes to tumor growth and could account for the limited success of immunotherapeutic strategies. MDSCs suppress adaptive immunity by blocking T cell activation, inducing Treg accumulation, and inhibiting natural killer cell cytotoxicity against tumor cells. We investigated the roles of MDSCs in the regeneration of the exocrine pancreas associated with acute pancreatitis and the progression of acinar to ductal metaplasia. Acute pancreatitis was induced in wild type and P48+/Cre;LSL-KRASG12D mice using caerulein and an early influx of MDSCs into the pancreas was observed flow cytometry and immunocytochemistry. Numbers of Gr1(+)CD11b(+) MDSCs increased over 20-fold in pancreata of mice with acute pancreatitis to account for nearly 15% of intrapancreatic leukocytes and have T cell suppressive properties. This marked accumulation of MDSCs returned to normal values within 24 hours of the insult in wild type mice; however, in the oncogenic KRAS mice, MDSCs levels remained elevated. When intrapancreatic MDSCs were depleted by administration of a CXCR2 antagonist (SB265610) in wild type mice the severity of acinar damage was increased. This was also accompanied by a delayed regeneration determined morphologically and with the mitotic immunomarker phospho-histone H3. Isolated intrapancreatic MDSCs from treated mice induce naïve acinar cells to undergo acinar ductal metaplasia when co-cultured in collagen 3D cultures. Purified splenic MDSCs failed to induce the phenotypic transdifferentiation. We conclude that MDSCs are required for adequate pancreatic regeneration in wild type mice with acute pancreatitis and their persistent elevation in oncogenic KRAS mice is not only associated with immune-evasion, but may also function as direct enhancer of malignant proliferation.
43
Nörenberg, Daniel [Verfasser], and Carole [Akademischer Betreuer] Bourquin. "The effect of innate immune activation on maturation of myeloid-derived suppressor cells / Daniel Nörenberg ; Betreuer: Carole Bourquin." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1115144707/34.
Full text
44
Ilkovitch, Dan. "Mechanisms Involved in the Anti-Tumor Activity of MUC1/sec." Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_dissertations/250.
Full textAbstract:
The transmembrane isoform of mucin 1 (MUC1/TM) is a well recognized tumor antigen, contributing to tumorigenesis and immune evasion. While MUC1/TM has been correlated with malignancy, it appears that a secreted splice variant of MUC1 (MUC1/sec) has antitumor properties and prevents tumor development. It was discovered that MUC1/sec expressing tumor cells (DA-3/sec) have a significant reduction in expression of urokinase plasminogen activator (uPA) relative to the parental tumor line, and tumor cells expressing MUC1/TM (DA-3/TM). The serine protease uPA, has been found to be involved in growth promoting signaling, angiogenesis, and induction of matrix remodeling leading to metastasis. Furthermore, the tumor suppressive and interferon responsive Stat1 transcription factor is dramatically upregulated in DA-3/sec cells. In addition, treatment of various murine and human cell lines with conditioned media containing MUC1/sec results in up-regulation of Stat1. DA-3/sec tumor cells are also sensitized to the anti-proliferative effects of IFN-g. Furthermore, transfection of the Stat1 gene into DA-3 tumor cells leads to a downregulation of uPA, and delays tumor progression. Since myeloid-derived suppressor cells (MDSC) play a critical role in tumor-induced immunosuppression, we investigated their recruitment by DA-3/sec and DA-3/TM cells. DA-3/sec tumor cells recruit dramatically lower levels of MDSC, relative to DA-3/TM cells. Since MUC1/sec down-regulates tumor expression of uPA, its potential role in MDSC recruitment was investigated. Tumor-derived uPA is capable of recruiting MDSC, and correlates with tumor development. In addition to diminishing recruitment of MDSC, the effect of MUC1/sec on MDSC suppressive mechanisms was investigated. MUC1/sec, or its unique immunoenhancing peptide (IEP), is capable of blocking expression of arginase 1 and production of reactive oxygen species (ROS) in MDSC, implicated in the suppression of T cells. These findings demonstrate a new mechanism of MDSC recruitment, and provide evidence that MUC1/sec has antitumor properties affecting both tumor cells and MDSC. Furthermore, it was discovered that MDSC home to the liver in addition to the tumor, bone marrow, blood, and spleen of tumor bearers, as previously described. The liver is thus an organ where MDSC accumulate and can contribute to immunosuppression directly and indirectly, via interactions with a variety of immune cells.
45
Dubinski, Daniel [Verfasser], Oliver [Akademischer Betreuer] Grauer, and Peter [Akademischer Betreuer] Hau. "Myeloid-derived Suppressor Cells in Glioblastoma Patients - Phenotype, Function and Clinical Relevance / Daniel Dubinski. Betreuer: Oliver Grauer ; Peter Hau." Regensburg : Universitätsbibliothek Regensburg, 2016. http://d-nb.info/110476847X/34.
Full text
46
Damle, Sheela Ruby. "TYPE 2 IMMUNE RESPONSES IN THE CONTEXT OF HELMINTH INFECTION, ASTHMA, DENDRITIC CELLS, AND MYELOID DERIVED SUPPRESSOR CELL FUNCTION." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4696.
Full textAbstract:
Type 2 (TH2) immune responses evolved to respond to helminth parasite infections by the production of TH2 cytokines, which stimulate anti-helminth immunity. Macrophage migration inhibitor factor (MIF) is a pleiotropic cytokine, which is produced by many cell types. We demonstrate that mice deficient in MIF have enhanced clearance of a helminth parasite. MIF deficiency in CD4+ T cells was found to be the most important for mediating parasite clearance. We mimicked MIF deficiency by administering an inhibitor of the MIF tautomerase activity, sulforaphane, and this also increased parasite clearance (Section I).
TH2 immune responses underlie allergy and allergic asthma, in which the same cytokines that help expel parasites are released in response to innocuous substances. Integral to the initiation of adaptive TH2 immunity are dendritic cells (DCs), which take up antigen and stimulate antigen-specific CD4+ T cell responses. We found that DC expression of ADAM10, a zinc-dependent metalloproteinase, is critical for the development of TH2 immune responses and IgE production from B cells. This effect is demonstrated in both allergic airway inflammation and anaphylaxis models. ADAM10-deficient DCs are unable to cleave Notch1 receptors, resulting in reduced IL-6 production and this ultimately results in decreased TH2 activity. ADAM17 is closely related to ADAM10 in both structure and function. Interestingly, mice from which ADAM10 and 17 are removed from DCs (ADAM10/17DC-/-) have a distinct phenotype from both ADAM10DC-/- and ADAM17DC-/- mice in models of allergic airway inflammation (Section I).
We also examined another effect of TH2 cytokines on the interaction between mast cells and myeloid derived suppressor cells (MDSCs). We sought to understand how histamine and IL-13, mediators made by mast cells, affect the immunoregulatory function of MDSCs. MDSCs in IL-13-deficient mice with tumor are more prevalent in circulation rather than in tumor or organs, which could be due to changes in CCL2/CCR2 chemotaxis. In addition, MDSC function after treatment with the DNA methyltransferase inhibitor, decitabine was examined. This treatment reduced their suppressive function and increased the expression of molecules needed for antigen presentation. Overall, TH2 immunity has multifaceted roles in anti-parasite immunity, allergic asthma, and MDSC function (Section II).
47
Inamoto, Susumu. "Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through CCL15-CCR1 Chemokine Axis." Kyoto University, 2016. http://hdl.handle.net/2433/215386.
Full text
48
Drabczyk-Pluta, Malgorzata [Verfasser], and Ulf [Akademischer Betreuer] Dittmer. "Characterization of myeloid-derived suppressor cells during acute Friend retrovirus infection of mice / Malgorzata Drabczyk-Pluta ; Betreuer: Ulf Dittmer." Duisburg, 2017. http://d-nb.info/1127527762/34.
Full text
49
TUMINO, NICOLA. "In HIV+ patients, Myeloid Derived Suppressor Cells induce T cell anergy by suppressing CD3ζ expression through ELF-1 inhibition". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2013. http://hdl.handle.net/2108/211078.
Full textAbstract:
The CD3ζ chain is indispensable for coupling antigen recognition to T cell
response. During HIV infection, a down-modulation of CD3ζ was found on
T cells, contributing to T cell anergy.
It has been shown that circulating myeloid derived suppressor cells
(MDSC) are elevated in HIV+ patients, and correlate with disease
progression. In this work, we studied the correlation between MDSC
frequency and T cell CD3ζ expression. Moreover, we investigated the
mechanisms of CD3ζ decrease exploited by MDSC.
CD3ζ expression and MDSC frequency were evaluated by flow cytometry
on PBMC from 105 HIV+ patients. We found that granulocytic-MDSC
(Gr-MDSC) were expanded in HIV+ patients compared to healthy donors;
in particular, a higher Gr-MDSC frequency was observed in patients with a
CD4 T cell count below 400 cells/μl. We found an inverse correlation
between the percentage of Gr-MDSC and CD3ζ level. Moreover, in vitro
Gr-MDSC depletion induced the up-regulation of CD3ζ in T cells,
restoring the functionality of αβ, but not γδ T cells. The in vitro effect of
isolated Gr-MDSC on CD3ζ expression was found cell contact-dependent,
and was not mediated by previously described molecules. CD3ζ downmodulation
corresponds to the decrease of its mRNA induced by silencing the transcription factor ELF-1.
50
Horikawa, Naoki. "Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225478.
Full text