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Morel, Anne-Sophie. "Manipulation of human dendritic cell function." Thesis, Imperial College London, 1999. http://hdl.handle.net/10044/1/11840.
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Jones, Angela. "Human dendritic cell interactions with respiratory syncytial virus." Thesis, University of Sheffield, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289663.
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Heijstek, Helena Cornelia. "Modulation of human dendritic cell function by therapeutic agents." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2002. http://dare.uva.nl/document/64240.
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Schäkel, Knut, Claudia Poppe, Elfriede Mayer, Christine Federle, Gert Riethmüller, and Ernst Peter Rieber. "M-DC8+ Leukocytes – A Novel Human Dendritic Cell Population." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-135252.
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Dendritic cells (DC) constitute a heterogeneous leukocyte population having in common a unique capacity to induce primary T cell responses and are therefore most attractive candidates for immunomodulatory strategies. Two populations of blood DC (CD11c+ CD123dim and CD11c– CD123high) have been defined so far. However, their direct isolation for experimental purposes is hampered by their low frequency and by the lack of selective markers allowing large scale purification from blood. Here we describe the monoclonal antibody (mAb) M-DC8, which was generated by immunizing mice with highly enriched blood DC. This mAb specifically reacts with 0.2–1% of blood leukocytes and enables their direct isolation by a one-step immunomagnetic procedure from fresh mononuclear cells. These cells can be differentiated from T cells, B cells, NK cells and monocytes using lineage-specific antibodies. M-DC8+ cells express HLA class II molecules, CD33 and low levels of the costimulatory molecules CD86 and CD40. Upon in vitro culture M-DC8+ cells spontaneously mature into cells with the phenotype of highly stimulatory cells as documented by the upregulation of HLA-DR, CD86 and CD40; in parallel CD80 expression is induced. M-DC8+ cells display an outstanding capacity to present antigen. In particular, they proved to be excellent stimulators of autologous mixed leukocyte reaction and to activate T cells against primary antigens such as keyhole limpet hemocyanin. Furthermore, they induce differentiation of purified allogeneic cytotoxic T cells into alloantigen-specific cytotoxic effector cells. While the phenotypical analysis reveals similarities with the two known blood DC populations, the characteristic expression of Fc=γRIII (CD16) and the M-DC8 antigen clearly defines them as a novel population of blood DC. The mAb M-DC8 might thus be a valuable tool to determine circulating DC for diagnostic purposes and to isolate these cells for studies of antigen-specific T cell priming<br>Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Schäkel, Knut, Claudia Poppe, Elfriede Mayer, Christine Federle, Gert Riethmüller, and Ernst Peter Rieber. "M-DC8+ Leukocytes – A Novel Human Dendritic Cell Population." Karger, 1999. https://tud.qucosa.de/id/qucosa%3A27632.
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Dendritic cells (DC) constitute a heterogeneous leukocyte population having in common a unique capacity to induce primary T cell responses and are therefore most attractive candidates for immunomodulatory strategies. Two populations of blood DC (CD11c+ CD123dim and CD11c– CD123high) have been defined so far. However, their direct isolation for experimental purposes is hampered by their low frequency and by the lack of selective markers allowing large scale purification from blood. Here we describe the monoclonal antibody (mAb) M-DC8, which was generated by immunizing mice with highly enriched blood DC. This mAb specifically reacts with 0.2–1% of blood leukocytes and enables their direct isolation by a one-step immunomagnetic procedure from fresh mononuclear cells. These cells can be differentiated from T cells, B cells, NK cells and monocytes using lineage-specific antibodies. M-DC8+ cells express HLA class II molecules, CD33 and low levels of the costimulatory molecules CD86 and CD40. Upon in vitro culture M-DC8+ cells spontaneously mature into cells with the phenotype of highly stimulatory cells as documented by the upregulation of HLA-DR, CD86 and CD40; in parallel CD80 expression is induced. M-DC8+ cells display an outstanding capacity to present antigen. In particular, they proved to be excellent stimulators of autologous mixed leukocyte reaction and to activate T cells against primary antigens such as keyhole limpet hemocyanin. Furthermore, they induce differentiation of purified allogeneic cytotoxic T cells into alloantigen-specific cytotoxic effector cells. While the phenotypical analysis reveals similarities with the two known blood DC populations, the characteristic expression of Fc=γRIII (CD16) and the M-DC8 antigen clearly defines them as a novel population of blood DC. The mAb M-DC8 might thus be a valuable tool to determine circulating DC for diagnostic purposes and to isolate these cells for studies of antigen-specific T cell priming.<br>Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Sampangi, Sandeep. "Autologous human kidney proximal tubule epithelial cells (PTEC) modulate dendritic cell (DC), T cell and B cell responses." Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/82033/1/Sandeep_Sampangi_Thesis.pdf.
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This is a comprehensive study of human kidney proximal tubular epithelial cells (PTEC) which are known to respond to and mediate the pathological process of a range of kidney diseases. It identifies various molecules expressed by PTEC and how these molecules participate in down-regulating the inflammatory process, thereby highlighting the clinical potential of these molecules to treat various kidney diseases. In the disease state, PTEC gain the ability to regulate the immune cell responses present within the interstitium. This down-regulation is a complex interaction of contact dependent/independent mechanisms involving various immuno-regulatory molecules including PD-L1, sHLA-G and IDO. The overall outcome of this down-regulation is suppressed DC maturation, decreased number of antibody producing B cells and low T cell responses. These manifestations within a clinical setting are expected to dampen the ongoing inflammation, preventing the damage caused to the kidney tissue.
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Hu, Yaling. "Fucoidin enhances dendritic cell-mediated T-cell cytotoxicity against NY-ESO-1 expressing human cancer cells /." View abstract or full-text, 2008. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202008%20HU.
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Varani, Stefania. "Human cytomegalovirus and dendritic cell interaction : role in immunosuppression and autoimmunity /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-505-4/.
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NIZZOLI, GIULIA. "Human dendritic cell subsets: cytokine production and their role in T-cell priming." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/50066.
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Dendritic cells (DC) have the unique capacities to induce primary T cell responses. In mice, CD8α+DC are specialized to cross-prime CD8+ T-cells and produce IL-12 that promotes cytotoxicity. Human BDCA-3+DC share several relevant characteristics with CD8α+DC, but the capacities of human DC subsets to induce CD8+ T cell responses are incompletely understood.
Here we compared CD1c+mDC1, BDCA-3+mDC2 and plasmacytoid DC (pDC) in peripheral blood and lymphoid tissues for phenotype, cytokine production and their capacities to prime cytotoxic T cells.
mDC1 were surprisingly the only human DC that secreted high amounts of IL-12p70, but they required combinational Toll-like receptor (TLR) stimulation. mDC2 and pDC produced IFN-λ and IFN-α, respectively. Importantly, mDC1 and mDC2 required different combinations of TLR-ligands to cross-present protein antigens to CD8+ T cells. pDC were inefficient, and also expressed lower levels of MHC- and co-stimulatory molecules. Nevertheless, all DC induced CD8+ memory T-cell expansions upon licensing by CD4+ T cells, and primed naive CD8+ T-cells following appropriate TLR stimulation. However, since mDC1 produced IL-12 they induced the highest levels of cytotoxic molecules.
In conclusion, CD1c+mDC1 are the relevant source of IL-12 for naïve T cells, and are fully equipped to cross-prime cytotoxic T cell responses.
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Thacker, Robert I. "Modulation of Human Dendritic Cell Activity by Adsorbed Fibrin(ogen)." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1218553202.
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Che, Karlhans Fru. "Immunomodulatory Effects of Human ImmunodeficiencyVirus (HIV-1) on Dendritic Cell and T cell Responses : Studies of HIV-1 effects on Dendritic cell functionality reflected in primed T cells." Doctoral thesis, Linköpings universitet, Molekylär virologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-71279.
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The human immunodeficiency virus (HIV)-1 is the causative agent of acquired immune deficiency syndrome (AIDS) worldwide. Till date there are no vaccines or cure for this infection as the virus has adapted myriad ways to remain persistent in the host where it causes severe damage to the immune system. Both humoral and cellular immune responses are mounted against HIV-1 during the initial phase of infection but fail to control viral replication as these responses are severely depleted during disease progression. Of great importance in HIV-1 research today is the in depth understanding of the types of immune responses elicited, the mechanisms behind their decline and how these responses can be maintained overtime. The focus of this thesis was to examine the possibility of priming HIV-1 specific T cell responses in vitro from whole viral particles and in detail, scrutinize the type of T cell responses and epitope specificities generated. Next was to investigate in vitro the factors responsible for impaired immune responses in HIV-1 infected individuals. We were also interested in understanding the underlying mechanisms through which HIV-1 initiate suppression of T cell functionality. Results showed that using HIV-1 pulsed monocyte derived dendritic cells (DCs), we were able to prime HIV-1 specific CD4+ and CD8+ T cells from naïve T cells in vitro. The epitopes primed in vitro were located within the HIV-1 envelope, gag, and pol proteins and were confirmed ex vivo to exist in acute and chronically infected individuals. We established that many of the novel CD4+ T cell epitopes primed in vitro also existed in vivo in HIV-1 infected individuals during acute infection. These responses declined/disappeared early on, which is in line with HIV-1 preferential infection of HIV-1 specific CD4+ T cells. Besides declining HIV-1 specific T cell responses, many HIV-1 infected individuals also have impaired T cell functionality. We established that one reason behind the decline and impairment in immune responses was the increased expression of inhibitory molecules PD-1, CTLA-4, and TRAIL on HIV-1 primed T cells. These T cells had the capacity to suppress new responses in a cell-cell contact dependent manner. The ability of the HIV-1 primed T cells to proliferate was severely impaired and this condition was reversed after a combined blockade of PD-1, CTLA-4 and TRAIL. Furthermore, more inhibitory molecules TIM-3, LAG-3, CD160, BLIMP-1, and FOXP3 were also found increased at both gene and protein levels on HIV-1 primed T cells. Additionally, we showed decreased levels of functional cytokines IL-2, IFN-γ and TNF-α, and the cytolytic proteins perforin and granzyme in DC T cell priming cocultures containing HIV-1. This could be as a result of the decreased T cell activation or impaired production by T cells. The mechanisms responsible for the elevated levels of inhibitory molecules emanated mainly from the P38MAPK/STAT3 pathways. Blockade of these pathways in both allogeneic and autologous DC-T cell assays significantly suppressed expression of inhibitory molecules and subsequently rescued T cell proliferation. In conclusion, HIV-1 pulsed DCs have the capacity to prime HIV-1 specific responses in vitro that do exist in HIV-1 infected individuals and we found evidence that many of these responses were eliminated rapidly in HIV-1 infected individuals. HIV-1 triggers through P38MAPK/STAT3 pathway the synthesis of inhibitory molecules, namely CTLA-4, PD-1, TRAIL, TIM-3, LAG-3, CD160, and suppression associated transcription factors FOXP3, BLIMP-1 and DTX1. This is followed by decreased T cell proliferation and functionality which are much needed to control viral replication.
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Foged, Camilla. "Human dendritic cells : cell culture, models for studies of particulate antigen, formulation in vitro /." Cph., Stockholm : Department of Pharmaceutics, The Danish University of Pharmaceutical Sciences, Division of Hematology, Center for Molecular Medicine, Karolinska Hospital and Institute, 2003. http://www.dfh.dk/phd/defences/Camillafoged.htm.
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Johansson, Ulrika. "Modulation of human dendritic cell function by microbial or autologous stimuli." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270951.
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Shirley, Shawna A. "The Role Of Curcumin In Human Dendritic Cell Maturation And Function." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002666.
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Yamamoto, Kazuyo. "Anti-inflammatory modulation of human myeloid-derived dendritic cell subsets by lenalidomide." Kyoto University, 2020. http://hdl.handle.net/2433/259726.
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Wang, Changna. "Follicular Dendritic Cells, Resting CD4+ T Cells and Human Immunodeficiency Virus Expression." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2906.
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Many events associated with Human Immunodeficiency Virus (HIV) infection/replication occur in and around the germinal centers (GCs) of secondary lymphoid tissues where follicular dendritic cells (FDCs) reside, suggesting that this microenvironment may contribute unique signaling that is important to viral progression. My research focused on characterizing signaling, both positive and negative, contributed by FDCs that affects HIV infection and replication. Specifically, I determined if FDC signals could induce the expression of latent HIV in T cells and if so, to characterize the signaling pathways involved. Moreover, I also examined the ability of FDCs to produce inhibitory signals that might block active virus expression. I approached these problems using FDCs from tonsils and coculturing these with primary CD4+ T cells or latently-infected Jurket cells with a GFP reporter. Results indicated that FDCs dramatically augmented HIV production of these cells. FDC signaling was costimulatory in nature and was mediated by soluble TNFα. However, when ex vivo latently infected T cells were treated with PMA/ionomycin or IL2/IL7, little virus expression was observed until FDCs were added, which greatly increased virus production. The transcription factor NFAT is important for the reactivation of latent HIV. Inhibition studies as well as ELISA suggested that JAK/STAT signaling pathway was involved in virus reactivation. Because FDCs produce prostaglandins (PGs) E2 and I2, I determined the effect of PGE2 and PGI2 analogs on HIV infected T cells. Results indicated that both the PGE2 and PGI2 analogs inhibited proliferation and activation-induced cell death of HIV infected T cells in a dose- and time-dependent manner. Additionally, it was shown that indomethacin and CAY10404, cyclooxygenase and cyclooxygenase-2 inhibitors, partially restored HIV production in the presence of FDCs, suggesting that FDC-produced PGE2 and PGI2 may inhibit virus replication. Thus, FDCs produce PGs that can block virus gene expression in T cells, which may be ideal for viral persistence. Therefore, FDC signaling appears to both promote and inhibit HIV production. A better understanding of FDC signaling and regulation in GCs may suggest new treatment strategies that would be beneficial to infected subjects.
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Kouremenou, Chrisoula. "The effects of tick immunomodulators on human dendritic cell differentiation and function." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442819.
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Metelo, J. "Contribution of integrins and actin regulators to human dendritic cell podosome biology." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1381835/.
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Dendritic cells (DC) are key cells of the innate immune system required to prime adaptive immunity. Migration is central to their function to enable immune surveillance of the whole body and for prompt activation of the adaptive immune system. Immature DC assemble specialised actin structures called podosomes which are thought to be critical for efficient adhesion-mediated migration. Podosomes are, therefore, considered to be essential for DC function. Despite the great increase in literature regarding podosomes and related structures over recent years, still much is unknown about critical components, regulation and function of these structures in DC. Cytoskeletal studies of DC have been complicated by the fact that tools commonly employed for biological manipulation may constitute activation stimuli for DC and dramatically alter the DC cytoarchitecture. A panel of human THP1DC knock-down cell lines was generated using RNAi technology targeting factors suspected or known to be important for podosome formation and/or function such as the integrins CD18 and CD29 and the actin regulators HS1, WASp and WIP. Results obtained from functional analysis of the knock-down cell lines confirm CD18 to be specifically recruited to the DC podosomes and to be essential for their assembly. On the contrary, CD29 knock-down did not attenuate podosome assembly, even when reduced to levels that resulted in a defect in static adhesion. As previously reported, WASp and WIP expression was demonstrated to be necessary for podosome formation. Furthermore, a role for the cortactin homolog HS1 in CD18 activation in myeloid cells is suggested, as HS1 knock-down resulted in defective CD18-dependent adhesion and reduced podosome formation when cells were plated on ICAM but not on fibronectin. The results presented here define a robust method for manipulating immature DC for cytoskeletal studies and advance our current understanding of the regulation of podosome assembly in human DC.
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Martinez, Cingolani Carolina. "Differential Effects of the Cytokine Thymic Stromal Lymphopoietin on Human Dendritic Cell Subsets." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T083/document.
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Une fois activées, les cellules dendritiques (DCs) migrent dans les organes lymphoïdes ou elles exercent leur rôle de cellules présentatrices d’antigène professionnelles. Elles sont capables d’activer et d’induire la différenciation des lymphocytes T naïfs en différentes sous-populations de lymphocytes T auxiliaires. L’ajustement de la réponse lymphocytaire T au type d’inflammation est assuré par les DCs à deux niveaux. Premièrement, grâce à leur plasticité, les DCs adaptent leur comportement en fonction de la combinaison de signaux issus du microenvironnement inflammatoire. Deuxièmement, il existe différentes sous-populations de cellules dendritiques ayant de différentes spécialisations fonctionnelles.Mon travail de thèse s’est concentré sur l’étude de la diversité des réponses des sous-populations de cellules dendritiques humaines suite à la stimulation par la cytokine lymphopoïetine stromale thymique (TSLP). Cette cytokine est secrétée par les cellules épithéliales et la peau au cours de l’inflammation. La TSLP active principalement les DCs myéloïdes, induisant celles-ci à secréter les chimiokines inflammatoires CCL17 et CCL22. Les DCs activées par la TSLP (TSLP-DCs) induisent une réponse inflammatoire de type Th2, et sont impliquées dans le développement de l’allergie. La comparaison systématique de la réponse à la TSLP par les sous-populations de DCs du sang, BDCA1+ et BDCA3+, nous a permis de montrer que ces deux sous-populations sont activées par la TSLP. Toutefois, nos résultats montrent que la TSLP, en synergie avec le TGF-β, induit la différenciation des DCs BDCA-1+ en cellules de Langerhans, mais pas celle des DCs BDCA-3+. De plus, la TSLP induit la migration cellulaire et la sécrétion de chimiokines seulement chez la sous-population de DCs BDCA-1+. Des analyses complémentaires des mécanismes impliqués dans la migration des DCs BDCA-1+ en réponse à la TSLP révèlent que, d’une part la TSLP est indispensable à l’induction de la migration et d’autre part, qu’un récepteur de chimiokines, sensible à la Toxine Pertussique serait impliqué. Au final, nos résultats révèlent (i) de nouvelles capacités des DCs en tant que cellules précurseurs, (ii) de différentes propriétés fonctionnelles des sous-populations de DCs en réponse à la stimulation par la TSLP, (iii) et démontrent la complexité des mécanismes impliqués dans la migration des DCs induite par la TSLP<br>Once activated, Dendritic Cells (DCs) migrate to the lymphoid organs and exert their role as professional antigen presenting cells. They are able to induce the activation and differentiation of naïve T cells into different types of T helper cells. The T cell response must be suited to the type of inflammation. This is ensured by DCs at two levels. First DCs are functionally plastic. This means that their behavior is subdued to the integrated signals coming from the inflammatory microenvironment. Secondly, the DC population is diverse. Indeed, different DC subsets have different functional specializations. My thesis was focused on the differential response of human DC subsets to Thymic stromal lymphopoietin (TSLP). This cytokine is secreted by inflamed skin and epithelia, and strongly activates myeloid DCs. The TSLP-activated DCs secrete the inflammatory chemokines CCL17 and CCL22, prime an inflammatory Th2 response, and have been involved in the pathogenesis of allergic inflammation. By systematically comparing the response of human blood BDCA-1+ and BDCA-3+ DCs to TSLP stimulation we found that both of these DC subsets get activated by TSLP. However TSLP synergizes with TGF-β to induce the differentiation of blood BDCA-1+ and not BDCA-3+ DCs into Langerhans Cells. Moreover, TSLP induces cell migration and chemokine secretion only on the blood BDCA-1+ subset. Further analysis of the mechanisms implicated in TSLP-induced DC migration revealed that TSLP is required to induce DC migration, but this effect is dependent on the expression of a PTX-sensitive chemokine receptor. Overall our results reveal new precursor capacities of blood DC subsets, different functional properties of blood DC subsets stimulated by TSLP and highlight intricate mechanisms underlying TSLP-induced DC migration
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Salvatore, Giulia. "Remodeling of lipid metabolism by interleukin-17A in human dendritic cells." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10268.
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Nous avons découvert que les DC pathologiques (LCH DC) qui s’accumulent dans les granulomes de patients atteints d’histiocytose langerhansienne (LCH) produisent l’IL-17A (Coury et al, Nat Med 2008). In vitro, les LCH DC fusionnent en cellules géantes (MGC) sous l’influence de leur production autocrine d’IL-17A. In vivo, les granulomes de LCH DC et MGC détruisent les tissus. Pendant la thèse, nous avons étudié les transcriptomes des monocytes, DC, traitées ou non par l’IL-17A et des LCH DC. L’IL-17A induit BCL2A1, un membre de la famille Bcl-2 qui prolonge la survie des DC. Elle induit aussi les chémokines CCL20 et CCL2, qui regroupent les DC avant leur fusion. L’induction du récepteur nucléaire LXR-α, de protéines impliquées dans le métabolisme, le transport et le stockage des lipides témoignent d’un profond remodelage lipidique. Après la confirmation de ces régulations par PCR et western, les goutelettes lipidiques sont quantifiées à l’huile rouge, puis l’analyse lipidomique révèle l’augmentation de phospholipides, triglycérides, esters de cholestérol et cholestérol par l’IL-17A dans les DC qui sont aussi capables de capturer du palmitate extracellulaire fluorescent. Les transcriptomes des DC traitées à l’IL-17A et des LCH DC sont similaires. La simvastatine qui bloque la synthèse de cholestérol tue les LCH DC. Ce travail établit pour la première fois que l’IL-17A affecte profondément le métabolisme lipidique des DC, une activité qui pourrait avoir d’importantes applications dans les maladies chroniques inflammations associées à une dérégulation lipidique comme l’athérosclérose, l’obésité, la tuberculose et la LCH<br>We found that the pathological DCs (DC LCH), accumulating in the granulomas of patients affected with Langerhans cell histiocytosis (LCH), produce IL-17A (Coury et al, Nat Med 2008). In vitro, LCH DCs form multinucleated giant cells (MGC) by a fusion process, under the influence of their IL-17A autocrine production. In vivo, granulomas, which are mainly composed of LCH DCs and MGCs, destroy tissues of the patients. During the PhD, we studied the transcriptomes of monocytes, DCs, treated or not with IL-17A, and LCH DCs. IL-17A induceed BCL2A1, a member of the Bcl-2 family that prolonged DC survival. It also induced the CCL2 and CCL20 chemokines that clustered DC, a process required to license DC fusion. The inductions of LXR-α nuclear receptors, proteins involved in metabolism, transport and storage of lipids signed a deep lipid remodeling induced by IL-17A in DCs. We confirmed these regulations by PCR and western studies, then the lipid droplets were quantified after Oil Red-O staining. Further lipidomic analysis revealed an increase of phospholipids, triglycerides, cholesteryl esters and cholesterol by IL-17A in DCs, which are also able to capture extracellular fluorescent palmitate. Transcriptomes of DCs treated with IL-17A and LCH DCs were similar. Simvastatin, which inhibits the synthesis of cholesterol, killed LCH DC. For the first time, this work establishes that IL-17A profoundly affects the lipid metabolism of DCs, an activity that may have important applications in chronic inflammations associated with lipid deregulations such as atherosclerosis, obesity, tuberculosis and LCH
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Alculumbre, Solana. "Division of Labor Between Distinct Human Plasmacytoid Dendritic Cell Subsets Following Viral Activation." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS014.
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L’existence d’un partage des tâches a été démontrée au sein de nombreux systèmes biologiques et ce notamment en immunologie où il a été décrit dans le contexte de différentes sous-populations d’un même type cellulaire. Les cellules dendritiques plasmacytoïdes (pDC) jouent un rôle clé lors des infections virales. Les pDCs ont la capacité de sécréter de grandes quantités d’interférons de type I et de se différencier en cellules dendritiques matures capables d’activer une réponse immunitaire adaptative. Il a été proposé que ces fonctions innées et adaptatives soient séquentiellement induites après activation virale. Au cours de ma thèse, je me suis intéressée à ces deux fonctions principales des pDC et je suis arrivée à la description de différentes sous-populations de pDC activées : PD-L1+CD80- (P1), PD-L1+CD80+ (P2) and PD-L1-CD80+ (P3), démontrant qu’il existe un partage des tâches entre ces sous-types. P1 produit spécifiquement de l’IFN-α, indiquant une spécialisation en immunité innée, et promeut une réponse tolérogénique des cellules T CD4. Inversement, P3 induit une forte activation des cellules T CD4 naïves et une polarisation de type Th2, démontrant une spécialisation fonctionnelle dans l’immunité adaptative. P2 possède un profil fonctionnel intermédiaire. Plutôt qu’un lien séquentiel, nos résultats indiquent une exclusion réciproque des fonctions innées et adaptatives entre ces différents sous-types de pDC<br>Under microbial stimulation plasmacytoid pre-dendritic cells (pDC) secrete large amounts of type I interferon (IFN) and differentiate into mature dendritic cells capable of activating T cells. These innate and adaptive functions are thought to be induced sequentially in pDC through triggering of the IRF-7 and NFkB pathways, respectively. We found that viral activation of pDC induced their differentiation into three phenotypically distinct subsets: PD-L1+CD80- (P1), PD-L1+CD80+ (P2) and PD-L1-CD80+ (P3). P1 specifically produced IFN-α, indicating a specialization in innate immunity, while promoting weak activation and high IL-10 expression in CD4 T cells. Conversely, P3 showed increased expression of surface costimulatory molecules, improved migratory capacity, strong naïve CD4 T cell activation, and induction of Th2 differentiation. P2 had an intermediate functional profile. No conversion could be induced between subsets. We identified P1 in psoriatic skin, and blood from active lupus patients. Our results indicate reciprocal exclusion, rather than sequential link, of innate and adaptive pDC functions, with important implications in immune regulation and immunopathology
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Fenton, Thomas. "Integrin αvβ8 on human dendritic cells : a role in intestinal immune homeostasis". Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/integrin-alphav8-on-human-dendritic-cells-a-role-in-intestinal-immune-homeostasis(3820bc76-2c42-4db6-a344-b66e5b77769d).html.
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Intestinal inflammatory disorders such as Crohn’s disease contribute significantly to human mortality and morbidity. Although the cells and molecules involved in suppression of intestinal inflammation have been extensively documented in mouse models, a full understanding of how these work together in the healthy and diseased gut remains elusive. It is known, however, that tight regulation over TH17 cells and regulatory T cells (Treg) is required to maintain immune homeostasis in the intestine. Activation of the cytokine transforming growth factor-β (TGFβ), which is secreted by immune cells as an inactive complex, plays a crucial role in the induction of both Treg and TH17 cells. Recent work has shown that the αvβ8 integrin is required for activation of TGFβ by murine dendritic cells (DC). Murine integrin αvβ8 is thus of fundamental importance for Treg and TH17 induction and, subsequently, for intestinal immune homeostasis. However, little is known about the signals controlling the expression of integrin αvβ8 on intestinal DC. Furthermore, whether this system is also important for regulation of the human system is entirely unknown. Here, expression of integrin αvβ8 is shown on human intestinal CD1c+CD103+SIRPα+ DC and CD1c+CD103-SIRPα+ DC, but not on CD141+CD103+SIRPα- DC. Expression of integrin αvβ8 is increased on DC from Crohn’s disease patients, and on DC from non-IBD donors treated with LPS. Both LPS and a number of probiotic bacteria were also able to induce integrin αvβ8 expression on human monocyte-derived DC (moDC), which suggested that the microbiota may play a role in the regulation of human integrin αvβ8. Importantly, we have also shown that TGFβ is activated by integrin αvβ8 on human moDC, and that integrin αvβ8 promotes expression of forkhead box P3 (FOXP3) in naïve human T cells in vitro. Together, these data suggest that integrin αvβ8-mediated activation of TGFβ by DC may play an important role in the regulation of human T cell responses in the human intestine, and that this pathway may be perturbed during intestinal inflammation.
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ORSENIGO, FEDERICA. "Characterisation of the myeloid CSF1R+ dendritic cell subsets and monocytes in health and disease." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2023. https://hdl.handle.net/10281/404675.
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Le cellule dendritiche (DC) e i monociti sono cellule immunitarie innate coinvolte nel riconoscimento di patogeni e molecole associate a danno, nello scatenare l’immunità adattativa e nel mantenimento dell’omeostasi. Queste cellule sono collettivamente chiamate cellule del sistema fagocitico mononucleare (MPS), e la loro origine ed il loro sviluppo nell’uomo richiedono ancora studio. I recettori delle citochine determinanti l’origine (LDCR) sono fattori di crescita con importante ruolo nel differenziamento e nella sopravvivenza delle cellule ematopoietiche. Questi recettori sono presenti anche su cellule mature, suggerendone un ruolo post-differenziamento.
Il legame tra DC e monociti è stato qui dimostrato usando CSF1R, un LDCR conosciuto in precedenza come espresso solo su macrofagi, ma ora caratterizzato anche su tutte le cellule del MPS. Il MPS c’è stato analizzato in diversi contesti patologici, per caratterizzarne lo stato di sviluppo e attivazione.
Le DC e i monociti sono stati studiati in due diversi vaccini antimalarici. Entrambi i vaccini contengono lo stesso antigene del Plasmodium falciparum, la proteina AMA1. Uno dei vaccini si basa su vettori virali, mentre l’altro contiene la proteina ricombinante somministrata con un adiuvante lipidico. Il MPS è risultato modulato, con percentuali di cellule diverse a seconda del vaccino somministrato. Inoltre, il vaccino a vettore virale ha causato una maggiore attivazione delle cellule rispetto al vaccino proteico. L’espressione di LDCR e proteine di superficie nelle cellule CSF1R+ è stata modificata in maniera dipendente dalla formulazione dei vaccini.
Le DC hanno un importante ruolo anche nelle malattie infettive. Nella pandemia globale di COVID-19, capire come il MPS è modulato dal virus SARS-CoV-2 era cruciale, specialmente per gli anziani e le persone con patologie pre-esistenti. Due gruppi di pazienti COVID del Sud Africa sono stati studiati, ed erano presenti coinfezioni da HIV e tubercolosi, trattamento con steroidi e altre comorbidità. Un impatto sulle cellule specifico della variante virale è stato individuato. Nei pazienti COVID+, c’è stata una diminuzione di cellule CSF1R+ circolanti esacerbata da condizioni come l’ipertensione e il diabete. Un’altra causa di mortalità oltre a patologie pre-esistenti è la “tempesta citochinica”, dove l’alto livello di citochine circolanti, rilasciate dalle cellule del MPS, interagendo con il complemento ed il sistema di coagulazione porta a coagulazione sanguigna, crisi respiratoria e insufficienza multiorgano. Per questo, la capacità di DC e monociti di attivare il proprio inflammasoma e quindi produrre citochine infiammatorie è stata testata. Il compartimento CD14+ dei monociti e le DC hanno risposto agli stimoli per l’attivazione dell’inflammosoma rilasciando interleuchina 1 β ed attivando un meccanismo specifico di morte cellulare, segnali di attivazione dell’inflammosoma.
Infine, il ruolo di DC e monociti è stato valutato nel contesto dei tumori, con un confronto, eseguito con dati di single-cell RNA sequencing pubblici, tra due tipi di cancro con due diversi infiltrati immunitari. Il primo, adenocarcinoma del polmone (LUAD), è solitamente definito come tumore “caldo” o infiltrato da cellule immunitarie, mentre il secondo, carcinoma del colon-retto (CRC), è solitamente definito come tumore “freddo”, senza importante infiltrato immunitario. CSF1R e CSF2R erano espressi in maniera diversa tra tumori, e un tipo di DC recentemente scoperto e ancora poco caratterizzato a livello funzionale ha avuto comportamento opposto tra i due tumori, accumulandosi in LUAD ma non in CRC. Per questo gruppo di DC, è stato proposto in questo lavoro un ruolo tollerogenico che necessita di validazione con studi funzionali.<br>Dendritic cells (DCs) and monocytes are innate immune cells involved in recognising pathogens or damage-associated molecules, triggering adaptive immune responses, and maintaining homeostatic conditions. DCs and monocytes are collectively referred to as Mononuclear Phagocyte System (MPS) cells, and their origin and development in humans still need elucidating. Lineage-determining cytokine receptors (LDCRs) are growth factors with a pivotal role in haematopoietic cell differentiation and survival. These receptors are retained on mature cell surface, suggesting an active role after differentiation.
Here, the link between DCs and monocytes at a developmental level was assessed at steady state using CSF1R, a LDCR previously known as expressed only on macrophages, but now proved to be on all cells of the MPS. The MPS was further studied across multiple diseases, to assess its development or effector state.
DCs and monocytes were assessed in two distinct anti-malarial vaccine challenges. Both vaccines targeted the same blood-stage Plasmodium falciparum antigen apical membrane protein 1 (AMA1), involved in erythrocyte invasion by malaria. One vaccine formulation was based on a prime-boost viral delivery of the antigen, while the other vaccine consisted of the recombinant protein administered with a liposome-based adjuvant system. The MPS was greatly affected and reshaped, with cell fluctuations in percentages depending on the vaccine formulation. The viral-vectored vaccine also seemed to activate cells more effectively compared to the protein vaccine. LDCR and surface marker expression in CSF1R+ cells was also affected by the different vaccine vector components.
DCs also play a role in infectious diseases. In the global pandemic of COVID-19, understanding how the MPS is modulated by the SARS-CoV-2 virus was crucial, especially for elderly people and individuals with underlying conditions. Two South African COVID patients’ cohorts were investigated, where HIV and Tb coinfections, steroid treatment, and other comorbidities where present. There was a direct variant-dependent impact of COVID-19 on the MPS. In COVID-19 patients, there was a decrease in circulating CSF1R+ MPS cells, enhanced by the presence of certain comorbidities such as hypertension and diabetes. Aside from underlying conditions, one of the causes of poor prognosis is a phenomenon called cytokine storm and it is linked to the MPS cells. The elevated levels of circulating cytokines released by the MPS cells interact with the complement and coagulation systems to induce coagulation, respiratory and multi-organ failure. Therefore, DCs and monocyte ability to activate their NLRP3 inflammasome and release pro-inflammatory cytokines was investigated. The CD14+ monocytic compartment and DCs were able to respond to NLRP3 activating stimuli by releasing interleukin 1 β and undergoing cell death, signs of activation of an inflammasome pathway.
Finally, the role of DCs and monocytes was investigated in the context of another pathological setting, with the comparison of two different types of tumours that usually display different immune infiltrated. The first tumour, lung adenocarcinoma (LUAD), is conventionally referred to as “hot” or immune infiltrated tumour, while the second, colorectal cancer (CRC), as “cold” or immune excluded. The comparison between these two tumours was pursuit using public single-cell RNA sequencing datasets. Different expression of CSF1R and CSF2R were noted across tumoral tissues, and a specific type of DCs recently discovered and poorly characterised at functional level displayed opposite behaviour, accumulating in LUAD but not in CRC. For this DC subset, a putative tolerogenic role was proposed that would need to be validated with functional studies.
This work underlined the importance of investigating the involvement of CSF1R+ MPS cells in health and diseases and provided a pan-MPS marker for human studies.
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Gustafsson, Linnéa. "Internalisation of antigen-adjuvant conjugate in human dendritic cells : An assay development for using live cell imaging." Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-434224.
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Introduction: Cancer vaccines are a therapeutic approach to initiate an antigen specific cytotoxic immune responses against tumors. Cancer vaccines are composed by an antigen (tumor peptide) and adjuvant. A peptide in combination with adjuvants effectively activate dendritic cells (DCs), the most efficient antigen presenting cells in our immune system. DCs prime and activate CD8+ cytotoxic T cells which generates an antigen specific response.Aim: Developing an assay to study the internalisation rout of an antigen-adjuvant conjugate in human dendritic cells by using live cell imaging. Method: Immobilisation of cells is necessary for the ability to perform live cell imaging for several hours. The immobilisation ability of three coatings, collagen type I, fibronectin and matrigel, at different concentrations were evaluated by using live cell imaging in a fluorescence microscope. The potential induction of activation of the cells were evaluated by using flow cytometry and ELISA. Results: Immature DCs internalise antigen-adjuvant conjugate more efficiently than mature and activated DCs. Therefore, it is important that the coating do not induce activation. Cells must also be immobilised for the possibility of long term detection. Collagen type I immobilised cells and induced activation in all investigated concentrations. Fibronectin and matrigel had concentration-dependent abilities to immobilise the cells. Matrigel did not activate the cells whilst fibronectin was concentration dependent. Conclusion: Matrigel immobilise the cells which enables long term single cell imaging without activation.
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Rossi, Axel. "Intracellular fate of AAV particles in human Dendritic Cell and impact on Gene Transfer." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSEN028.
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Les vecteurs viraux dérivés du virus adéno-associé (AAV) apparaissent depuis deux décennies, comme des outils efficaces pour le transfert de gène in vivo. Cependant, malgré une faible immunogénicité et une absence de toxicité in vivo, leur optimisation requiert encore un effort important vers une meilleure compréhension de leur biologie et, en particulier, de leur interaction avec le système immunitaire. Au cours de ce travail de thèse, nous avons utilisé une méthode de sélection dirigée in vitro dans le but d’obtenir un variant de capside capable de transduire efficacement un type cellulaire non-permissif aux vecteurs AAV : les cellules dendritiques (DC). En effet, ces cellules jouent un rôle primordial dans l’établissement de la réponse immunitaire et, par conséquent, dans la persistance de l’expression du transgène in vivo. Cette technologie, très répandue dans la communauté AAV, a permis de sélectionner un variant de capside aux propriétés très intéressantes. La mutation sélectionnée, caractérisée in vitro comme induisant une instabilité de la capside, a permis d’identifier et de surmonter un point de blocage majeur dans le processus de transduction des DC par les vecteurs AAV consistant dans l’étape de décapsidation du génome du vecteur dans le noyau cellulaire. De manière intéressante, le variant obtenu exhibe un avantage en terme de transduction non seulement dans les DC mais aussi dans différents modèles de cellules primaires humaines (e.g. HUVEC) ou animales (OBC), peu ou pas permissive à l’AAV. De plus, des expériences de transfert de gène in vivo réalisées dans un modèle murin, indiquent que le variant sélectionné conduit à une meilleure expression du transgène, possiblement due à la mise en place d’un processus de tolérisation. Les propriétés remarquables de ce variant de capside, font de lui un candidat intéressant pour des applications médicales<br>Vectors derived from the Adeno-associated virus (AAV) have emerged as an efficient system for in vivo gene transfer. However, despite their low immunogenicity and good tolerance in vivo, a better characterization of the host-AAV interaction is required to be able to fully exploit AAV’s potential fora gene therapy or gene vaccination. In this PhD project, we have used an in vitro directed evolution strategy to select an AAV capsid variant able to transduce human dendritic cell (DC), a non-permissive cell type which plays a critical role in the initiation of immune responses and, consequently, on the persistence of the expression of transgene in vivo. This procedure allowed us to identify an AAV variant characterized by a decreased stability of the capsid in vitro. The use of this mutant as a vector to transduce human DC resulted in an improved uncoating of the vector genome in the cell nucleus, thus identifying this step as major barrier toward DC transduction. Interestingly, the selected variant also displayed an increased transduction efficiency not only in DC but also in different primary human and animal cell types, poorly or non-permissive to AAV. Finally, when injected in mice, this AAV variant resulted in a higher expression of the transgene, associated to a low level of immune responses, suggesting the induction of tolerant state. The remarkable features suggest that our selected variant capsid is a promising candidate for medical applications
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Wahid, S. Fadilah Binti Abdul. "Development of functional human dendritic cell subsets in vitro and in vivo in hu/NOD/SCID chimeric mice : important implications in dentritic cell-based immunotherapy /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19089.pdf.
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Poulsen, Christopher. "Differential cytotoxicity of long-chain bases for human oral keratinocytes, fibroblasts, dendritic and oral squamous cell carcinoma cell lines." Thesis, University of Iowa, 2014. https://ir.uiowa.edu/etd/4723.
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Long-chain bases (sphingosine, dihydrosphingosine, and phytosphingosine) are present in the oral cavity and have potent antimicrobial activity against oral pathogens. However, little is known about their cytotoxicity for oral cells, an important step in considering their potential as future antimicrobial agents for oral infections.
In this study, primary oral keratinocytes, primary oral fibroblasts, dendritic cells, and oral squamous cell carcinoma cells were exposed to 10.0-640.0 µM long-chain bases and glycerol monolaurate (GML) in cell culture medium containing resazurin (e.g., Alamar Blue, Invitrogen Corp., Carlsbad, CA). Cell metabolism was assessed at 48 hours by the reduction of resazurin to resorufin. Percent cytotoxicity was defined as the median fluorescence intensity (MFI) of resazurin in cell culture media of cells treated with dilutions of long-chain bases/MFI of resazurin in cell culture media of untreated cells x 100, and the lethal dose 50 (LD50) was determined from the dose response curve where the 50 percent cytotoxicity intercepts with the long-chain base concentration on the x-axis.
For all cells, the LD50 (mean µM + std err) of sphingosine, dihydrosphingosine, phytosphingosine, and GML were 69.7 (1.7), 29.2 (1.7), 20.6 (1.7), and 134.3 (1.7), respectively. Primary oral keratinocytes were more resistant to long chain bases, whereas oral fibroblasts, dendritic cells, and oral squamous cell carcinoma cells were more susceptible.
Overall, long chain bases have LD50 for oral keratinocytes, oral fibroblasts, dendritic cells, and oral squamous cell carcinoma cells that are considerably higher than the minimal inhibitory concentrations for oral pathogens, a finding important to their future potential as therapeutics for prevention or treatment of periodontal disease infections.
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Botting, Rachel Anne. "Investigating the phenotype and frequency of mononuclear phagocytes in human skin and anogenital tissue: potential targets to prevent HIV transmission." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/15627.
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Mononuclear phagocytes are located throughout the body, and include DCs, macrophages and monocytes. One of their key functions is the detection of pathogens via an array of surface molecules. Determining the repertoire of surface molecules on each subset could reveal targets for DC-based vaccines and potential pathogen interactions. Furthermore, identifying which subsets are present in each of the anogenital tissues may increase understanding of the pathogenesis of various sexually transmitted infections, including HIV. To investigate the phenotype and frequency of mononuclear phagocytes in human skin and anogenital tissue, and their ability to transfer HIV to T cells, cells were isolated by collagenase digestion or after spontaneous migration, and examined by flow cytometry. Two previously undescribed epidermal DC-like subsets were identified in abdominal skin, as well as a novel langerin+ dermal DC. The surface expression of CLRs and Siglecs was observed to differ significantly between the epidermis and dermis, and also between the subsets that reside within each. CD141+ DCs were distinct from other DC subsets, which differed further from macrophage subsets. Greater differences were observed between the subsets isolated from skin compared to those derived in vitro, and between collagenase isolated cells (immature) and spontaneously migrated cells (mature). The subsets isolated from skin were also functionally distinct in their ability to transfer HIV to T cells. Importantly, the frequency of subsets in abdominal skin differed from those found in the anogenital tract, and significant differences in subset ratios were observed between different anogenital tissue types and sites. Therefore, each subset and site represent a unique barrier and/or target for invading pathogens. This work has significant implications for DC-based vaccine design and pathogenesis of infectious agents that interact with mononuclear phagocytes, including HIV and its sexual transmission.
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Duraisingham, Sai Suda. "The Role of Toll-like Receptors in Immune Responses Mediated by Human Dendritic Cell Subsets." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516478.
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Gonzalez, Ana Maria. "Studies of human rotavirus candidate non-replicating vaccines and innate immunity in a gnotobiotic pig model of human rotavirus disease." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1172622915.
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Thomas, Saskia. "Aberrant response of human myeloid dendritic cells to microbial stimuli in patients with inflammatory bowel disease." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16340.
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In zahlreichen Studien konnte an Mausmodellen gezeigt werden, dass dendritische Zellen eine wichtige Rolle im Rahmen der mukosalen Immunabwehr spielen. Eine unkontrollierte Aktivierung immunologischer Effektorzellen durch antigenpräsentierende Zellen ist die Folge, welche die Antigene der luminalen Flora folglich falsch erkennen und damit zu einer Schädigung des Gewebes führen. In der Arbeit wurden humane CD1c+CD11c+CD14-CD19- myeloide dendritische Zellen (mDCs) aus dem peripheren Blut und der intestinalen Mukosa von CED Patienten sowie von gesunden Probanden phänotypisch und funktionell näher charakterisiert. mDCs von Patienten reagieren auf LPS im Gegensatz zu DCs von Gesunden mit der Ausbildung eines aktivierten Phänotyps und der Sekretion pro-inflammatorischer Zytokine. Die Daten lassen vermuten, dass ihre tolerogene Rolle gestört ist und die Zellen so möglicherweise aktiv zum Entzündungsgeschehen durch eine Fehlreaktion auf die kommensale Flora beitragen. Es konnte gezeigt werden, dass zirkulierende mDCs von Erkrankten mehr LPS aufnehmen. Des Weiteren ist die Häufigkeit von mukosalen und aktivierten mDCs bei CED Patienten signifikant erhöht. Die vermehrte Häufigkeit von aktivierten mDCs in der entzündeten Mukosa ist ein Hinweis auf intestinales „homing“, also ein Wiedereinwandern der gereiften Lymphozyten in die Darmwand. Es ist bekannt, dass die Hefe Saccharomyces boulardii (Sb) eine Wirksamkeit bei entzündlichen sowie infektiösen Erkrankungen des Gastrointestinaltraktes hat. Kulturexperimente von mDCs mit Zellkulturüberständen von Sb (SbS) und LPS zeigten eine deutliche Reduzierung in der Expression von CD40 und CD80 sowie des Reifemarkers CD197. SbS reduzierte die Sekretion von TNF- und IL-6. Während es die Sekretion von IL-10 bei gesunden Probanden erhöhte, konnte bei CED Patienten eine leichte Abnahme verzeichnet werden. SbS vermindert die Proliferation von naïven T-Zellen in einer gemischten Lymphozytenreaktion mit gesunden mDCs signifikant.<br>Various animal studies have provided insights that mucosal dendritic cells play a key role in this process. However, the specific function of certain dendritic cells in IBD is still unknown. Primary CD1c+CD11c+CD14-CD19- myeloid blood (mDCs) and mucosal DCs from IBD patients and healthy controls were compared. More mDCs from IBD patients exhibited an activated phenotype shown by expression of co-stimulatory molecules. mDCs from patients secrete higher levels of pro- and anti-inflammatory cytokines. Circulating mDCs from IBD patients take up more LPS and the frequency of mucosal mDCs and the number of activated, i.e. CD40 and CD80 expressing mucosal mDCs, is significantly greater in CED. The increased frequency of activated mDCs in the inflamed mucosa suggests intestinal homing of mDCs in acute stages of IBD. Further, the data suggests an aberrant LPS response of mDCs in patients suffering from IBD which results in an inflammatory phenotype. The most widely accepted hypothesis for the cause of IBD is a disturbed interaction of the host immune system with commensal microflora and other luminal antigens. The well controlled balance of the intestinal immune system is disturbed and luminal antigens like LPS gain access to the underlying mucosal tissue via the leaky barrier. It was investigated whether the yeast preparation Saccharomyces boulardii (Sb) modulates dendritic cell function which has shown efficacy in inflammatory and infectious disorders of the gastrointestinal tract. Culture experiments of mDCs in the presence of Sb culture supernatant (SbS) significantly reduced the expression of CD40 and CD80 as well as the DC maturation marker CD197 (CCR7) induced by the prototypical microbial antigen LPS. SbS reduced secretion of TNF- and IL-6, while the secretion of anti-inflammatory IL-10 increased. IBD patients showed also a reduction in their secretion level of IL-10. SbS inhibited proliferation of naïve T cells in a mixed lymphocyte reaction with healthy mDCs.
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Sontag, Stephanie Verfasser], Martin [Akademischer Betreuer] Zenke, and Ralph [Akademischer Betreuer] [Panstruga. "Modeling IRF8 Deficient Human Hematopoiesis and Dendritic Cell Development with Engineered iPS Cells / Stephanie Sontag ; Martin Zenke, Ralph Panstruga." Aachen : Universitätsbibliothek der RWTH Aachen, 2017. http://d-nb.info/1162450509/34.
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Sontag, Stephanie [Verfasser], Martin Akademischer Betreuer] Zenke, and Ralph [Akademischer Betreuer] [Panstruga. "Modeling IRF8 Deficient Human Hematopoiesis and Dendritic Cell Development with Engineered iPS Cells / Stephanie Sontag ; Martin Zenke, Ralph Panstruga." Aachen : Universitätsbibliothek der RWTH Aachen, 2017. http://d-nb.info/1162450509/34.
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Tabata, Sumie. "Distribution and kinetics of SR-PSOX/CXCL16 and CXCR6 expression on human dendritic cell subsets and CD4[+] T cells." Kyoto University, 2006. http://hdl.handle.net/2433/143841.
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Trichot, Coline. "Regulation of Human T Helper Cell Diversity : From In Vitro Dendritic Cell-Based Mechanisms to Candidate Biomarkers in Atopic Dermatitis." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS423.
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Le système immunitaire humain est majoritairement commandé par les cellules dendritiques et les lymphocytes T auxiliaires. Lorsque les cellules dendritiques détectent un pathogène, elles vont instruire les lymphocytes T auxiliaires afin qu’ils adoptent le phénotype approprié à la menace rencontrée. Les lymphocytes T auxiliaires peuvent être divisés en plusieurs sous-populations, caractérisées par la production de cytokines spécifiques. Chaque sous-population de lymphocyte T auxiliaire possède des fonctions propres et est impliquée dans l’élimination de pathogènes distincts. Si les réponses des lymphocytes T auxiliaires ne sont pas finement régulées, ils peuvent devenir pathogéniques, et dans ce cas, considérés comme cibles potentielles pour des thérapies. Dans ce contexte, j’ai concentré mon travail de doctorat sur l’étude de la diversité des sous- populations de lymphocytes T auxiliaires et de leur régulation. Premièrement, j’ai démontré que les cellules dendritiques activées par la TSLP sont capables d’induire la polarisation de lymphocytes T folliculaires. Ensuite, j’ai participé à la construction d’un modèle mathématique capable de prédire la réponse lymphocytaire T auxiliaire en fonction de signaux dérivés des cellules dendritiques. Ce modèle nous a permis d’identifier un rôle spécifique pour l’IL-12p70, dépendant du contexte IL-1, dans l’induction d’IL-17F sans IL-17A. Enfin, j’ai monitoré huit populations de lymphocytes T auxiliaires et folliculaires dans le sang périphérique de patients atteints de dermatite atopique traités par Dupilumab, une immunothérapie ciblant la sous-unité alpha du récepteur de l’IL-4 et j’ai pu montré que la diminution du pourcentage de lymphocytes Th17 correlait avec l’amélioration du score clinique EASI. Globalement, mon travail sur la diversité de phénotypes Th apporte une ressource mécanistique importante, avec une potentielle application en immunothérapie<br>Human immunity is essentially driven by dendritic cells and T helper cells. When dendritic cells detect a pathogen, they will instruct T helper cells to adopt the adapted phenotype for the specific threat encountered. T helper cells are subdivided in multiple subsets, characterized by particular sets of cytokines. Each T helper subset has specific functions and is involved in the clearance of distinct pathogens. If T helper responses are not precisely regulated, they can become pathogenic, in this case T helper pathways can be considered as potential targets for therapy. In this context, I focused my PhD work on studying T helper cell subset diversity and regulation. First, I demonstrated the ability of TSLP-activated dendritic cell to induce T follicular helper cell polarization. Then I participated in building a mathematical model capable of predicting T helper cell response to dendritic-cell derived signals. This model allowed us to identify the specific role of IL-12p70, in an IL-1 context, to induce IL-17F without IL-17A. Finally, I monitered eight T helper and T follicular helper cell populations in peripheral blood from atopic dermatitis patients treated with Dupilumab, an immunotherapy targeting the IL-4 receptor alpha subunit, and was able to show a correlation between decrease of Th17 cell percentage and improvement of EASI clinical score. Overall, my work on Th phenotype diversity provides key mechanistic insight with potential application in immunotherapy
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Leishman, Alison Jane. "Harnessing the immunomodulatory capacity of dendritic cells differentiated from human induced pluripotent stem cells and the therapeutic potential of dendritic cell-derived exosomes for the treatment of lysosomal storage diseases." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:97f6791f-ff69-4645-9a3d-2ff23ce69529.
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Lysosomal storage diseases (LSDs) are a collection of disorders that feature the pathological accumulation of substrate frequently due to an enzymatic defect within the lysosomes. The most effective treatment regime for LSDs is enzyme replacement therapy. However, this treatment has faced two main challenges which have limited its treatment efficacy and clinical impact. One challenge constitutes the potential immunogenicity of the replaced enzyme, which can lead to the induction of an antibody response that prevents its effective targeting. Therefore, this thesis investigated the potential to derive patient-specific autologous dendritic cells (ipDCs) from fibroblasts which were obtained from a healthy donor and from a patient diagnosed with infantile-onset Pompe disease and were reprogrammed into induced pluripotent stem cells (iPSCs). This study demonstrated the feasibility of differentiating these iPSCs into ipDCs and investigated the potential to modulate their immunogenicity using a variety of agents. Using IL-10, this work was able to show the feasibility of generating patient-specific ipDCs with pro-tolerogenic characteristics which may be exploited for the induction of tolerance towards therapeutic enzymes. Secondly, the delivery of therapeutic enzymes to the central nervous system (CNS), which is frequently involved in disease pathogenesis, is limited by the selective-permeability of the blood brain barrier. As specifically-labelled exosomes have been shown capable of targeting to the CNS for the delivery of therapeutic molecules, this study has shown the possibility of harvesting exosomes from ipDC cultures. The potential of exploiting the endocytic capacity of dendritic cells for the loading of enzyme into exosomes was explored. Furthermore, this study has found that the administration of syngeneic and allogeneic exosomes from mouse bone-marrow derived DCs and ipDCs elicited an antibody-mediated immune response which may limit the clinical application of exosomes further highlighting the need for tolerance induction. Altogether, this study constitutes a first step towards potential improvements in the treatment of LSDs.
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Leishman, Alison Jane. "Harnessing the immonomodulatory capacity of dendritic cells differentiated from human induced pluripotent stem cells and the therapeutic potential of dendritic cell-derived exosomes for the treatment of lysosomal storage diseases." Thesis, University of Oxford, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711748.
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Wildemann, Martha. "Pollutants and immune regulation in the human airway : modulation of dendritic cell function by environmental particulate matter." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/43184.
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Ambient air pollution, including airborne particulate matter (PM) derived from combustion of fossil fuels (FF) or biomass (BM), has detrimental inflammatory effects on human health. Myeloid antigen presenting cells, including dendritic cells (DCs) regulate immune responses in the airway and sample inhaled PM. This study tests the hypothesis that PM interacts with multiple environmental sensing pathways in DCs with outcomes that depend on particle size and composition as determined by combustion source. The effects of different sized PM (< 10μm, PM10; < 2.5μm, PM2.5), derived from the combustion of FF or BM, on human monocyte-derived or ex vivo sputum DCs, were examined. DC activation status, cytokine production and aryl hydrocarbon receptor (AhR) signalling were assessed by flow-cytometry, multiplex ELISA and qRT-PCR, following exposure to PM. Pathway-specific antagonists were used to explore underlying mechanisms. Particle size and combustion source influenced the effects of PM on DCs. Irrespective of combustion source, PM10 but not PM2.5, induced MoDC maturation and stimulated production of inflammatory cytokines, including IL-1β and IL-18, indicative of inflammasome activation. These responses were dependent, at least in part, on TLR4 as was the induction of IDO by PM10. AhR signalling was induced by PM in both MoDC and ex vivo sputum DC. It was stimulated by both PM10 and PM2.5 and was induced more strongly by BM-derived PM. AhR activation was independent of DC maturation and TLR4 signalling. Additionally, BM- but not FF-derived PM increased NADH levels in DC suggestive of altered metabolism. Thus, PM induces a complex programme of DC activation, influenced by size and combustion source, which includes classical maturation, inflammasome dependent cytokine release and AhR signalling as well as potential metabolic changes. In the airway, exposure to different PM and the changes in DCs induced by them may lead to altered responses to inhaled antigen.
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Henriquez, Rodney Fabian. "Varicella Zoster Virus infection of human matured monocyte derived dendritic cells & its impact on their effector functions." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13624.
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Varicella Zoster Virus (VZV) is a species specific alpha human herpes virus that causes both Varicella (chickenpox) and Herpes Zoster (shingles) in human hosts. It has been hypothesized that host dendritic cells (DC) play a pivotal role in the pathogenesis of VZV during the early stages of infection. DC have previously been shown to be permissive to VZV infection and capable of transmitting the virus to human T lymphocytes. VZV has also been shown to employ a variety of mechanisms to evade detection and clearance by the host immune system. The primary aim of this study was to identify the underlying mechanisms beneath the virus induced modulation of mature DC effector functions. Observation of the kinetics of VZV mediated downregulation of the DC immune molecules CD80, CD83 and CD86 in addition to the block of Late viral gene products demonstrated that de novo viral protein synthesis of the immediate early or early class, were required to mediate modulation of CD80, CD83 and CD86. Blocking of the host cell proteasome had a restorative effect on the cell surface expression of CD86 in VZV infected mature DC. Analysis of a panel of gene transcripts involved in the effector functions of human DC in VZV infected mature DC identified significant changes in cytokine and chemokine expression (IL-8 & MIF), cytokine and chemokine receptor expression (CXCR-4 & FLT-3) and other functionally important immune molecule expression (CD44, CD80 & HLA-DPA1). Some of these changes suggest that VZV actively induces changes to host DC transcripts in order to maintain an immature state and thus negate the effector function of mature DC. The migratory capabilities of VZV infected mature DC was shown to be compromised. Furthermore, it was shown that the few still capable of migration had significantly reduced levels of cell surface CD83. Taken together, the results presented identify a wide range of mechanisms by which VZV modulates mature DC effector functions.
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Schanen, Brian. "Novel Immunogens of Cellular Immunity Revealed using in vitro Human Cell-Based Approach." Doctoral diss., University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5483.
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Nanotechnology has undergone rapid expansion largely as a result of its enormous potential for applications as biomaterials, drug delivery vehicles, cancer therapeutics, and immunopotentiators. Despite this wave of interest and broad appeal for nanoparticles, evidence of their effect to the human immune system remains scarce. Concerns rise as studies on nanoparticle toxicology continue to emerge indicating that nanomaterials can be acutely toxic and can have long term inflammatory effects as seen in animal models. Based on these findings and the rise in the development of nanoparticle technologies targeting in vivo applications, the urgency to characterize nanomaterial immunogenicity is paramount. Nanoparticles harbor great potential because they possess unique physicochemical properties compared to their larger counter parts as a result of quantum-size effects and their inherent large surface area to volume ratio. These physicochemical properties govern how a nanoparticle will behave in its environment. However, researchers have only just begun to catalogue the biological effect these properties illicit. We took it upon ourselves to investigate nanoparticle size-induced effects using TiO2, one of the most widely manufactured nanoparticles, as a model. We studied these effects in dendritic cells across a human donor pool. We examined dendritic cells because they have an inimitable functional role bridging the innate and adaptive arms of immunity. From this work we found that TiO2 nanoparticles can activate human dendritic cells to become pro-inflammatory in a size-dependent manner as compared to its micron-sized counterpart, revealing novel immune cell recognition and activation by a crystalline nanomaterial. Having identified nanomaterial size as a contributing feature of nanoparticle induced immunopotentiation, we became interested if additional physicochemical properties such as surface reactivity or catalytic behavior could also be immunostimulatory. Moreover, because we witnessed a stimulatory effect to dendritic cells following nanoparticle treatment, we were curious how these nanoparticle-touched dendritic cells would impact adaptive immunity. Since TiO2 acts as an oxidant we chose an antioxidant nanoparticle, CeO2, as a counterpart to explore how divergent nanoparticle surface reactivity impacts innate and adaptive immunity. We focused on the effect these nanoparticles had on human dendritic cells and TH cells as a strategy towards defining their impact to cellular immunity. Combined, we report that TiO2 nanoparticles potentiate DC maturation inducing the secretion of IL-12p70 and IL-1?, while treatment with CeO2 nanoparticles induced IL-10, a hallmark of suppression. When delivered to T cells alone TiO2 nanoparticles induced stronger proliferation in comparison to CeO2 which stimulated TReg differentiation. When co-cultured in allogeneic T cell assays, the materials directed alternate TH polarization whereby TiO2 drives largely a TH1 dominate response, whereas CeO2 was largely TH2 bias. Combined, we report a novel immunomodulatory capacity of nanomaterials with catalytic activity. While unintentional exposure to these nanomaterials could pose a serious health risk, development and targeted use of such immunomodulatory nanoparticles could provide researchers with new tools for novel adjuvant strategies or therapeutics.<br>Ph.D.<br>Doctorate<br>Molecular Biology and Microbiology<br>Medicine<br>Biomedical Sciences
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MacDonald, Kelly Lynn. "Inflammation in chronic granulomatous disease and modulation of human dendritic cell functions by Burkholderia cenocepacia and Burkholderia multivorans." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/11136.
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Inflammation and infection are integral to the human diseases cystic fibrosis (CF) and chronic granulomatous disease (CGD). Inflammation was examined in peripheral blood mononuclear cells (PBMCs) from CGD patients. Reactive oxygen species (ROS) generated by the phagocytic NADPH oxidase have been implicated in the activation of the NF-κB, a transcription factor required for proinflammatory cytokine production in response to inflammatory stimuli. Patients with CGD, an immunodeficiency characterized by the inability to produce ROS, frequently develop inflammatory complications indicative of exaggerated inflammatory responses. In the present study, human and murine CGD leukocytes displayed a hyperinflammatory phenotype with increased production of proinflammatory cytokines in response to Toll-like receptor agonists. The major steps involved in NF-κB activation were also intact in human CGD cells. ROS were therefore not required for NF-κB activation and ROS production may instead dampen inflammation. The interaction of Burkholderia cepacia complex (BCC) bacteria with primary human monocyte-derived dendritic cells (DCs) was also explored as a model of infection. B. cenocepacia and B. multivorans, the most clinically important BCC members, are serious opportunistic pathogens infecting CF and CGD patients. The present study investigated whether these pathogens could modulate normal functions of DCs, important phagocytic cells that act as orchestrators of the immune response. DCs co-incubated for 24 h with B. cenocepacia, but not B. multivorans, had reduced expression of co-stimulatory molecules when compared with BCC lipopolysaccharide-matured DCs, as determined using flow cytometry. B. cenocepacia, but not B. multivorans, also induced necrosis in DCs after 24 h, as determined by annexin V and propidium iodide staining. DC necrosis only occurred after phagocytosis of live B. cenocepacia; DCs exposed to heat-killed bacteria, bacterial supernatant, or those pre-treated with cytochalasin D then exposed to live bacteria remained viable. The intracellular lifestyle of BCC bacteria was also examined using transmission electron microscopy. After 6 h of co-incubation with DCs, B. cenocepacia occupied the phagosome while B. multivorans resided in the cytoplasm. The ability of B. cenocepacia to modulate DC functions may contribute to its pathogenicity. Understanding the sophisticated mechanisms of infection and inflammation may lead to better treatments for CF and CGD.
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Miyamoto, Kazue. "Optimal stimulation for CD70 induction on human monocyte-derived dendritic cells and the importance of CD70 in naive CD4+ T cell differentiation." Kyoto University, 2010. http://hdl.handle.net/2433/120928.
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Royle, Caroline. "Plasmacytoid dendritic cell activation and differentiation by the Human Immunodeficiency Virus type 1 and 2 : implications for HIV immunopathogenesis." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24938.
Full textAbstract:
Infection with HIV-1 results in the progressive dysfunction of the immune system eventually leading to AIDS, characterised by low CD4+ T lymphocyte counts and increased susceptibility to opportunistic infections. In contrast to HIV-1, individuals infected with HIV-2 often remain asymptomatic, with lower viral loads and higher CD4+ T cell counts throughout the course of disease. Furthermore, HIV-2+ individuals display enhanced HIV-specific T cell responses. In addition, HIV-1 disease progression is slower in patients with pre-existing HIV-2 infection. Plasmacytoid dendritic cells (pDCs) are key mediators of the early innate immune response. Upon viral infection, pDCs secrete high levels of type I IFN (IFN-α/β) which limit viral replication and prime the adaptive immune response. Activated pDCs, in particular excessive IFN-α/β, have been implicated in HIV-1 immunopathogenesis. Specifically pDCs may contribute to the recruitment of target cells to the site of HIV-1 infection, increased apoptosis of immune cells and suppression of memory T cell responses. The aim of this study was to compare the abilities of HIV-1 and HIV-2 to activate pDCs in vitro. HIV-1 was a more potent inducer of type I IFN responses in PBMCs compared to HIV-2, measured at both the transcriptional level, and by measuring IFN-α/β secretion into cell culture supernatants. Furthermore, HIV-2, but not HIV-1, inhibited IFN-α production in response to synthetic stimuli. Phenotypic analysis of pDCs by flow cytometry revealed that both HIV-1 and HIV-2 were equally able to induce an up-regulation of co-stimulatory marker expression. Measurement of co-stimulatory molecule expression in conjunction with IFN-α secretion showed that HIV-1 favoured an IFN response, whereas HIV-2 preferentially maturated pDCs towards an antigen-presenting cell (APC) phenotype. The ability of HIV-2 to mature pDCs into APCs while reducing IFN-α secretion may be an important contributor to more robust T cell responses and therefore slower progressing HIV disease.
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Bachmann, Michael, Holger Bartsch, Biji T. Kurien, et al. "A Novel Modular Antigen Delivery System for Immuno Targeting of Human 6-sulfo LacNAc-Positive Blood Dendritic Cells (SlanDCs)." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-186316.
Full textAbstract:
Background
Previously, we identified a major myeloid-derived proinflammatory subpopulation of human blood dendritic cells which we termed slanDCs (e.g. Schäkel et al. (2006) Immunity 24, 767–777). The slan epitope is an O-linked sugar modification (6-sulfo LacNAc, slan) of P-selectin glycoprotein ligand-1 (PSGL-1). As slanDCs can induce neoantigen-specific CD4+ T cells and tumor-reactive CD8+ cytotoxic T cells, they appear as promising targets for an in vivo delivery of antigens for vaccination. However, tools for delivery of antigens to slanDCs were not available until now. Moreover, it is unknown whether or not antigens delivered via the slan epitope can be taken up, properly processed and presented by slanDCs to T cells.
Methodology/Principal Findings
Single chain fragment variables were prepared from presently available decavalent monoclonal anti-slan IgM antibodies but failed to bind to slanDCs. Therefore, a novel multivalent anti-slanDC scaffold was developed which consists of two components: (i) a single chain bispecific recombinant diabody (scBsDb) that is directed on the one hand to the slan epitope and on the other hand to a novel peptide epitope tag, and (ii) modular (antigen-containing) linker peptides that are flanked at both their termini with at least one peptide epitope tag. Delivery of a Tetanus Toxin-derived antigen to slanDCs via such a scBsDb/antigen scaffold allowed us to recall autologous Tetanus-specific memory T cells.
Conclusions/Significance
In summary our data show that (i) the slan epitope can be used for delivery of antigens to this class of human-specific DCs, and (ii) antigens bound to the slan epitope can be taken up by slanDCs, processed and presented to T cells. Consequently, our novel modular scaffold system may be useful for the development of human vaccines.
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Karpf, Léa. "Systematic Study of OX40 Ligand Context-Dependent Function on Human T Helper Cell Polarization A Quantitative Multivariate Model of Human Dendritic Cell-T Helper Cell Communication TH Cell Diversity and Response to Dupilumab in Patients With Atopic Dermatitis Inborn Errors of Type I IFN Immunity in Patients With Life-Threatening COVID-19 Quantitative Modeling of OX40 Ligand Context-Dependent Function on Human T Helper Cell SARS-CoV-2 Induces Activation and Diversification of Human Plasmacytoid Pre-Dendritic Cells." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL044.
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L'immunité adaptative est principalement orchestrée par des lymphocytes T CD4 auxiliaires. Ils ont la capacité de se polariser en plusieurs sous-populations, chacune associée à un phénotype approprié au pathogène rencontré. L'activation des lymphocytes T auxiliaires peut être régulée par des checkpoints immunitaires co-stimulateurs, tel que OX40 Ligand, ou co-inhibiteurs. Ces molécules ont été étudiées individuellement, dans des conditions spécifiques. Cependant, la contexte-dépendance pourrait expliquer une grande partie de la variabilité fonctionnelle des biomolécules. Il n'y a actuellement aucune méthode permettant d’analyser et de quantifier la contexte-dépendance d’une molécule dans plusieurs contextes et sur une réponse donnée.Mon projet de thèse a porté sur la fonction de OX40L sur la polarisation des cellules T auxiliaires, dans 4 contextes moléculaires et 11 cellulaires. Nous avons mesuré 17 cytokines T auxiliaires et développé une stratégie de modélisation statistique pour quantifier la contexte-dépendance deOX40L. Les scores de contexte-dépendance se sont révélés très variables qualitativement et quantitativement, en fonction de la cytokine et du type de contexte. Parmi les contextes Th, Th2 était le plus influent sur la fonction OX40L. Parmi les contextes DC, le type de cellules dendritique était dominant dans le contrôle de la contexte-dépendance de OX40L plutôt que le stimuli d’activation. Mon travail de thèse dévoile les complexes déterminants de la fonction de OX40L, fournit une méthode unique pour quantifier la variabilité fonctionnelle contexte-dépendante de n’importe quelle biomolécule et appuie sur le fait que la contexte-dépendance devrait être davantage prise en considération dans les études futures<br>Adaptive immunity is mainly orchestrated by CD4 T helper cells. They have the ability to polarize in several subsets, each associated to a suitable phenotype for the encounter pathogen. T helper cell activation can be regulated by co-stimulator, such as OX40 Ligand, or co-inhibitor immune checkpoint molecules. These molecules have been studied individually, in specific conditions. However, context-dependency may explain large parts of the functional variability of biological molecules on a given output. Currently, there is no framework to analyze and quantify context-dependency of a molecule over multiple contexts and response outputs. My PhD project focused on OX40L function on T helper cell polarization, in 4 molecular and 11 cellular contexts. We measured 17 T helper cytokines and developed a statistical modeling strategy to quantify OX40L context-dependency on these cytokines. This revealed highly variable qualitative and quantitative context-dependency scores, depending on the output cytokine and context type. Among molecular contexts, Th2 was the most influential on OX40L function. Among cellular contexts, dendritic cell type rather than activating stimulus was dominant in controlling OX40L contextdependency. My thesis work unveils the complex determinants of OX40L function, provides a unique framework to quantify the context-dependent functional variability of any biomolecule, and supports that context-dependency should be more taken into consideration in future studies
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Bachmann, Michael, Holger Bartsch, Biji T. Kurien, et al. "A Novel Modular Antigen Delivery System for Immuno Targeting of Human 6-sulfo LacNAc-Positive Blood Dendritic Cells (SlanDCs)." PLOS, 2011. https://tud.qucosa.de/id/qucosa%3A29020.
Full textAbstract:
Background
Previously, we identified a major myeloid-derived proinflammatory subpopulation of human blood dendritic cells which we termed slanDCs (e.g. Schäkel et al. (2006) Immunity 24, 767–777). The slan epitope is an O-linked sugar modification (6-sulfo LacNAc, slan) of P-selectin glycoprotein ligand-1 (PSGL-1). As slanDCs can induce neoantigen-specific CD4+ T cells and tumor-reactive CD8+ cytotoxic T cells, they appear as promising targets for an in vivo delivery of antigens for vaccination. However, tools for delivery of antigens to slanDCs were not available until now. Moreover, it is unknown whether or not antigens delivered via the slan epitope can be taken up, properly processed and presented by slanDCs to T cells.
Methodology/Principal Findings
Single chain fragment variables were prepared from presently available decavalent monoclonal anti-slan IgM antibodies but failed to bind to slanDCs. Therefore, a novel multivalent anti-slanDC scaffold was developed which consists of two components: (i) a single chain bispecific recombinant diabody (scBsDb) that is directed on the one hand to the slan epitope and on the other hand to a novel peptide epitope tag, and (ii) modular (antigen-containing) linker peptides that are flanked at both their termini with at least one peptide epitope tag. Delivery of a Tetanus Toxin-derived antigen to slanDCs via such a scBsDb/antigen scaffold allowed us to recall autologous Tetanus-specific memory T cells.
Conclusions/Significance
In summary our data show that (i) the slan epitope can be used for delivery of antigens to this class of human-specific DCs, and (ii) antigens bound to the slan epitope can be taken up by slanDCs, processed and presented to T cells. Consequently, our novel modular scaffold system may be useful for the development of human vaccines.
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Reuter, Morgan Ann. "Mycobacterium tuberculosis-induced changes in HIV-1 trafficking in human antigen presenting cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1278699683.
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SARGENTINI, VALERIA. "Activated T lymphocytes instruct monocytes to differentiate into inflammatory dendritic cells in a feedback control of human Th1/Th2 responses." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/988.
Full textAbstract:
Le cellule dendritiche (DCs) rappresentano una popolazione di cellule eterogenea con diversa origine, fenotipo e funzione che svolge un ruolo chiave nell' induzione, coordinazione e mantenimento delle risposte immunitarie adattative.
La maggior parte delle conoscenze riguardanti le DCs sono state acquisite grazie ad esperimenti eseguiti con DCs fatte differenziare in vitro da monociti trattati con diverse combinazioni di citochine; in particolare è ormai noto che i monociti umani differenziano a DCs se coltivati con il fattore di stimolazione di colonie granulocita rie/macrofagiche(GM-CSF) e interleuchina (IL)-4.
Tuttavia, la possibilità che i monociti rappresentino i precursori di DCs umane tissutali in condizioni fisiologiche rimane un' ipotesi controversa. Inoltre, non è stato ancora definitivamente stabilito quale sia la popolazione cellulare responsabile della sintesi delle citochine necessarie al differenziamento di monociti in vitro ed in che modo il loro rilascio venga regolato in vivo.
In questa tesi viene dimostrato come, in seguito ad attivazione specifica, i linfociti T sono in grado di rilasciare citochine che a loro volta inducono il differenziamento in DCs sia di monociti presentanti l' antigene che di monociti circolanti.
In base alla polarizzazione funzionale dei linfociti T attivati, i monociti differenziano in DCs con diverso fenotipo e funzionalità.
I monociti esposti alle citochine rilasciate da linfociti T helper (Th) 1 e Th0 differenziano in DCs caratterizzate da una ridotta capacità di captazione e presentazione dell' antigene. Inoltre, queste DCs mostrano una capacità limitata nellâ'indurre una polarizzazione in senso Th1 delle cellule T naive, bensì sono in grado di attivare cellule T naive secernenti IL-10, dimostrando in questo modo un potenziale tollerogenico. Al contrario, DCs derivate da monociti che risentono di citochine rilasciate da linfociti Th2 sono cellule presentanti l' antigene (APC) caratterizzate da una marcata capacità di polarizzazione in senso Th1.
Partendo dalla considerazione che i monociti vengono reclutati insieme ai linfociti in siti di infiammazione cronica, i risultati ottenuti in questo lavoro suggeriscono che, in ambienti caratterizzati da un rilascio prevalente di citochine associate a cellule Th1, Th0 o Th2, possono essere generate DCs funzionalmente differenti tra loro.
Poiché le capacità dimostrate da queste DCs come cellule presentanti l' antigene hanno conseguenze funzionali opposte, è stato proposto un modello in vitro in grado di riprodurre il contributo delle DCs infiammatorie, derivate da monociti, nella regolazione della risposta immunitaria in atto.<br>Dendritic cells (DCs) are a heterogeneous population of cells with different origin, phenotype and function that share the crucial role of inducing, coordinating and maintaining adaptive immune responses.
Most of the knowledge on human DCs relies on experiments performed with DCs differentiated in vitro from monocytes treated with diverse cocktails of recombinant cytokines; in particular it is well established that human monocytes differentiate into DCs when cultured with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. However, the possibility that monocytes represent precursors for tissue human DCs under physiological conditions remains controversial. Moreover, it is not completely established which cell population synthesizes the cytokines required for monocyte differentiation in vitro and how their secretion is regulated in vivo.
In this thesis is shown that, on specific activation, T lymphocytes are capable of secreting cytokines, which in turn induce the differentiation into DCs of antigen-presenting and bystander monocytes. Depending on the functional polarization of the activated T lymphocytes, monocytes differentiate into DCs with diverse phenotype and functionality.
Monocytes exposed to cytokines released by T helper (Th) 1 and Th0 lymphocytes differentiate into DCs with a reduced antigen uptake and antigen presentation capacity. Moreover, these DCs show a limited capacity to induce Th1 polarization of naive T cells but are capable of priming IL-10-secreting T cells, thus displaying tolerogenic potential. Conversely, DCs derived from monocytes sensing cytokines released by Th2 lymphocytes are antigen-presenting-cell (APC) endowed with a marked Th1 polarization capacity.
Starting from the point that monocytes are co-recruited with lymphocytes in chronic inflammation sites, the results obtained in this work suggest that functionally different DCs can be generated in environments characterized by the prevalent release of Th1-, Th0-, or Th2-associated cytokines. Because the APC capacities of these DCs showed opposite functional consequences, it has been proposed an in vitro model that can reproduce a contribution in the regulation of the ongoing immune response by monocyte-derived inflammatory DCs.
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Noël, Floriane. "Systems Level Analysis of Immune Cell Subsets and Intercellular Communication Networks in Human Breast Cancer." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS418/document.
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La communication intercellulaire est à la base de l'organisation d'ordre supérieur observée dans les tissus, les organes et l'organisme. Comprendre la communication intercellulaire et ses mécanismes sous-jacents qui sont impliqués dans le cancer est essentiel. Le microenvironnement des tumeurs du sein est composé d'une grande diversité cellulaire, telle que les cellules endothéliales, stromales ou immunitaires, qui peuvent influencer la progression tumorale ainsi que la réponse au traitement. Parmi les différentes populations de cellules immunitaires, les sous-populations de cellules dendritiques (DCs) intègrent les signaux du microenvironnement puis joue un rôle critique en orchestrant le développement d’une réponse immunitaire spécifique par activation des lymphocytes T. Cependant, les différentes fonctions de ces sous-populations et leurs interactions au sein du microenvironnement tumoral restent mal décrites. L’objectif principal de ma thèse a été de comprendre l'impact du microenvironnement tumorale du sein sur les sous-populations de DCs par analyse systémique. Nous avons utilisé le séquençage de l'ARN pour analyser systématiquement les transcriptomes des pré-DC plasmacytoïdes infiltrant les tumeurs (pDC), les populations cellulaires enrichies pour les DC classiques de type 1 (cDC1e), les DC classiques de type 2, les DC CD14+ et les monocytes-macrophages chez des patientes atteintes de cancer primitif du sein luminal et cancer du sein triple négatif. Nous avons constaté que la reprogrammation transcriptionnelle des cellules présentatrices d’antigène infiltrant la tumeur est spécifique à un sous-ensemble. Ces résultats suggèrent une interaction complexe entre l'ontogenèse et l'empreinte tissulaire dans le conditionnement de la diversité des DCs et de leur fonction dans le cancer.En second lieu, j'ai cherché à étudier les communications intercellulaires afin de comprendre comment les cellules intègrent les signaux de leur environnement. Nous avons développé ICELLNET, un outil pour reconstruire les réseaux de communication intercellulaires. Cette méthode quantitative originale, intégrant les interactions ligand-récepteur et l'expression génique spécifique à un type cellulaire, peut être appliquée automatiquement à tous profils transcriptomiques de population cellulaire, que ce soit dans divers contextes pathologiques ou d’autres domaines de la biologie<br>Cell-to-cell communication is at the basis of the higher order organisation observed in tissues, organs, and organism. Understanding cell-to-cell communication, and its underlying mechanisms that drive the development of cancer is essential. Breast tumor microenvironment (TME) is composed of a great cellular diversity, such as endothelial, stromal or immune cells that can influence tumor progression as well as its response to treatment. Among the different immune cell populations, dendritic cells (DCs) subsets integrate signals from their microenvironment and are subsequently essential in orchestrating specific immune response through T cell activation. However, the differential function of these subsets, and their interactions within the TME remain poorly described. My main thesis objective was to understand the impact of the breast TME on DC subsets using systems-level analysis. We used RNA sequencing to systematically analyze the transcriptomes of tumor-infiltrating plasmacytoid pre-DCs (pDCs), cell populations enriched for type 1 classical DCs (cDC1e), type 2 classical DCs (cDC2s), CD14+DCs, and monocytes-macrophages from human primary luminal breast cancer and triple-negative breast cancer. We found that transcriptional reprogramming of tumor-infiltrating antigen-presenting cells is subset-specific. These results suggest a complex interplay between ontogeny and tissue imprinting in conditioning DC diversity and function in cancer.As a second objective, I aimed at studying the cellular communications in order to understand how cells integrate signals from their environment. I developed ICELLNET, a tool to reconstruct intercellular communication networks. This original quantitative method, integrating ligand-receptor interactions and cell type specific gene expression, can be automatically applied to any cell population level transcriptomic profile opening perspectives of application in several disease contexts and biology fields
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Abozaid, Suhair Mohamed. "Studies on the interaction of surfactant protein SP-D with Inflenza A virus, Aspergillus fumigatus and dendritic cells." Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/13595.
Full textAbstract:
Surfactant proteins, SP-A and SP-D, are collagen-containing calcium-dependent (C-type) lectins, called, collectins. Their primary structure has four regions: a cysteine-linked N- terminal region involved in multimerization, a collagen region composed of Gly-X-Y repeats, coiled-coil neck region, and the C-terminal carbohydrate recognition domains (CRD) or C-type lectin domain. SP-A looks like a bouquet, while SP-D is a cruciform- like structure, with four arms of equal length. SP-A and SP-D have been shown to act as innate immune molecules at pulmonary as well as extra-pulmonary sites by binding to pathogens, allergens and apoptotic/necrotic cells via their CRD region. SP-A and SP-D can induce pathogen neutralization and enhanced phagocytosis. In addition, SP-A and SP-D can interact via CRDs with allergens and dampen allergic reaction in vitro and in vivo. This thesis examines in vitro interaction of a recombinant fragment of human SP-D containing neck and CRD regions (rhSP-D) with IAV and Aspergillus fumigatus, in addition to characterizing a dichotomy of the effects of SP-A and SP-D on dendritic cells in an attempt to explain how SP-A and SP-D modulate DC functions differentially. Experiments involving interaction of rhSP-D with IAV pandemic strain show that it can be a restrictive factor against the virus, in addition to modulating immune response by a macrophage cell line. The rhSP-D can have anti-A. fumigatus effect directly and indirectly in the context of pathogen as well as allergen. A comparison has been made between two recombinant fragments of SP-D that have been expressed with and without 8 Gly-X-Y repeats for their fungistatic properties. The effects of SP-A and SP-D on cultured DC maturation, and effector cytokine and proliferative response of co-cultured cells have also been examined in vitro.