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Powell, Timothy Jack. "Characterisation of rat bone marrow derived dendritic cells." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298613.
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Raveney, Ben J. E. "Interactions between CD8+ T cells and bone marrow-derived dendritic cells." Thesis, University of Bristol, 2006. http://hdl.handle.net/1983/dbbc656f-a103-4787-aeb9-f203c3f0082b.
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Li, Yanli. "Characterisation of PRRSV1 infection in bone marrow-derived dendritic cells." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458631.
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Esta tesis tiene como objeto caracterizar la adhesión, la replicación y la inducción de apoptosis en células dendríticas inmaduras (i) y maduras (m) derivadas de médula ósea (BMDC) enfrentadas al virus del PRRS (VPRRS). Se utilizaron tres aislados de PRRSV1 (3249, 3262 y 3267) cuya cinética de replicación se determinó inicialmente en macrófagos alveolares porcinos (PAM). El título obtenido en iBMDC fue significantemente mayor que en mBMDC (12 y 24hpi). Para los aislados 3249 y 3262, la replicación alcanzó el pico antes en las iBMDC (24h) que en las mBMDC (48h). Además, la eficacia de replicación dependía de la cepa usada siendo la cepa 3262 la que siempre tuvo menor replicación e infectó a una menor proporción de células. El estudio de adhesión y replicación con relación a la expresión de tres receptores: PoSn, CD163 y sulfato de heparán, se estudió mediante microscopía confocal de tres colores (PoSn, CD163 and PRRSV), y reveló que en iBMDC existía adhesión en las 4 subpoblaciones definidas por PoSn y CD163, incluso después del bloqueo del sulfato de heparán. Estos resultados sugerían la posibilidad de que existieran otros receptores víricos. Seguidamente, se realizó un estudio de microscopía confocal con marcaje de CD163/PRRSV o PoSn/PRRSV, observándose replicación en células aparentemente PoSn- y CD163-. A continuación se estudió la expresión de CD163 en las iBMDC infectadas por la cepa 3267 mediante citometría. Es este caso, el 8.4±0.5% de células aparentemente CD163- se marcaron como infectadas. Tras esto, se realizó una separación por citometría de flujo en función de la expresión de CD163 (CD163-, CD163lo and CD163hi). La primera separación se centró en aquellas CD163- cuya clasificación estaba "más allá de la duda". La segunda, se enfocó en el grupo de células CD163- junto con CD163lo. Como controles se emplearon iBMDC sin separar. No se observó infección en las células CD163- “más allá de la duda”. Cuando las CD163- se clasificaron junto con células CD163lo, la población CD163- infectada fue de 0,6 ± 0,07% a las 40 hpi aumentando a 1,6% ± 0,08% a las 60 hpi, siendo la proporción de células infectadas mayor que el número inicial de células CD163+. Este hecho podría ser debido a la generación de nuevas células CD163lo que se infectarían tan pronto como expresaran esta molécula, o alternativamente, el medio creado por la infección de células CD163+ indujo la aparición de la población CD163- susceptible. El estudio de inducción de la apoptosis, en PAM se observó un marcaje positivo para la caspasa-3 activada tanto en células infectadas como no infectadas para los tres aislamientos (microscopía confocal). Por el contrario, en BMDC el marcaje se localizó principalmente en células no infectadas. Este hallazgo sugiere la diferente activación de las vías intrínseca y extrínseca para PAMs y BMDC. Además, la señal de caspasa-3 en BMDC alcanzó un máximo a las 48 hpi, más tarde que en PAM (24 hpi). Este desarrollo más lento de la apoptosis podría permitir más ciclos de replicación vírica, resultando en mayores rendimientos víricos en BMDC. Un examen posterior para apoptosis/necrosis de cultivos de BMDC mostró que los aislados 3249 y 3267 indujeron apoptosis y necrosis, mientras que 3262 sólo produjo cambios menores. La neutralización de la IL-10 inducida por el 3262 dio lugar a la aparición de células apoptóticas, pero este efecto no ocurrió con 2988 que inducía también la producción de IL-10. Por lo tanto, todavía no está claro el papel de IL-10 juega en la apoptosis inducida por PRRSV. Los resultados de esta tesis pueden ser útiles para comprender el papel de DC en la patogénesis de PRRSV.The present thesis aims to characterize the attachment, replication and the induction of apoptosis during PRRSV infection in immature (i) and mature (m) bone marrow-derived dendritic cells (BMDC). Three PRRSV1 isolates (3249, 3262 and 3267) were used. The kinetics of replication were assessed by titrating cell culture supernatants in macrophages. The viral yield in iBMDC at 12 and 24 hpi was significantly higher than in mBMDC, and the replication of two isolates (3249 and 3262) peaked earlier in iBMDC (24 hpi) compared to mBMDC (48hpi). These results indicated that iBMDC were more efficient than mBMDC in supporting viral replication. This feature was not related to the proportion of CD163+ cells nor the levels of IFN-α in the cultures. In addition, the replication efficiency was strain-dependent. Isolate 3262 showed the lowest titres in both cell types at all times, consistently with the lowest proportions of 3262-infected cells in flow cytometry. The attachment and replication was further studied in association with the expression of three receptors, PoSn, CD163 and heparan sulphate. A three-colour confocal microscopy staining (PoSn, CD163 and PRRSV) on iBMDC showed that attachment occurred on the four subsets defined by PoSn and CD163. Removal of heparan sulphate from the cell surface did not fully avoid the attachment. These results indicated that attachment of PRRSV1 on BMDC might occur beyond the intervention of heparan sulphate, PoSn and CD163 and point towards the existence of other potential receptors. Next, a two-colour confocal microscopy labelling CD163/PRRSV or PoSn/PRRSV was performed. Replication was observed in cells that were apparently PoSn- and CD163-. As CD163 is the only recognized essential receptor for PRRSV, its expression together with the infection by isolate 3267 on iBMDC was further examined by flow cytometry. In that case, 8.4 ± 0.5% of apparently CD163- cells were labelled as infected. To further clarify this, a sorting experiment based on CD163 expression (CD163-, CD163lo and CD163hi) was done. The first sorting focused on “beyond doubt” CD163- cells. The second sorting grouped CD163- cells together with CD163lo. Unsorted iBMDC were used as controls. The “beyond doubt” CD163- cells were not infected by 40 hpi. When CD163- were sorted together with CD163lo, the proportion of infected CD163- cells was 0.6 ± 0.07% at 40 hpi and 1.6% ± 0.08% at 60 hpi. The proportion of infected cells at 60 hpi was higher than the initial number of CD163+ cells. These results can be explained by the generation of new CD163lo that were probably infected when expressing levels of this molecule below the sensitivity of the cytometer. Alternatively, the milieu created by CD163+ infected cells resulted in CD163- susceptible cells expressing yet unknown receptors for the virus. Regarding the induction of apoptosis, in PAM cleaved caspase-3 labelling was observed in both infected and bystander cells for all three isolates (confocal microscopy), while in BMDC bystanders were mainly labelled. This is indicative of different apoptosis triggering pathways for PAM and BMDC. Moreover, at m.o.i. 0.1, the caspase-3 signal in BMDC peaked later (48 hpi) than in PAM (24 hpi), which might allow more cycles of viral replication and result in higher viral yields in BMDC. Further examination of inoculated BMDC cultures for apoptosis/necrosis showed significant differences between isolates. Thus, 3249 and 3267 isolates apparently induced apoptosis/necrosis of BMDC but 3262 did not. Neutralization of IL-10 released by BMDC and induced by 3262 infection resulted in the occurrence of apoptotic cells, but this did not happen with a second IL-10-inducing isolate (2988). The above-mentioned results will be useful to understand the role of DC in PRRSV pathogenesis.
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Liu, Limin 1954. "Expression of follicular dendritic cell determinants by mouse bone marrow stromal cells." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=27544.
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Stromal reticular cells in mouse bone marrow and follicular dendritic cells (FDC) in peripheral lymphoid tissues both interact with B lymphocytes and influence their development at various stages of the B cell lineage. The possibility that BM reticular cells and FDCs may share common surface properties has been examined in mouse bone marrow by in vivo administration of $ sp{125}$I-labelled purified monoclonal antibodies (mAb) raised against mouse FDC, detecting mAb-binding by light microscope (LM) and electron microscope (EM) radioautography. Young mice were injected intravenously with $ sp{125}$I-mAb FDC-M1, FDC-M2, FDC-M3 and then perfused to remove unbound antibody. Quantitative analyses of radioautographic LM sections of femoral bone marrow revealed discrete FDC-labelling throughout bone marrow sections, especially in outer areas near the surrounding bone and intermediate areas, forming both linear arrangements and irregular patches. Electron microscopy revealed labelling aligned over delicate processes of certain reticular cells intimately associated with lympho hemopoietic cells, as well as localized regions of sinusoidal endothelium, particularly in central areas and at sites of contact with hemopoietic cells. The results demonstrate that a subset of stromal reticular cells in mouse BM express FDC-associated surface determinants, suggesting possible common lineage or functional properties.
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Liu, Limin. "Expression of follicular dendritic cell determinants by mouse bone marrow stromal cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ37142.pdf.
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Colledge, Lisa H. "Investigation of antigen presentation by murine bone marrow-derived dendritic cells." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312678.
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Maroof, Asher. "The effects of IL-4 on murine bone marrow derived dendritic cells." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398141.
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Chan, Shing, and 陳誠. "Generation and functional characterization of dendritic cells from bone marrow of patients with leukaemia diseases and various haemato-oncological conditions." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31970394.
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Chan, Shing. "Generation and functional characterization of dendritic cells from bone marrow of patients with leukaemia diseases and various haemato-oncological conditions." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25176511.
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Kohara, Hiroshi. "Development of plasmacytoid dendritic cells in bone marrow stromal cell niches requires CXCL12-CXCR4 chemokine signaling." Kyoto University, 2008. http://hdl.handle.net/2433/135825.
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Nandigam, Harika. "Capability of the Tumor Microenvironment to Attract a Precursor of B-cells and Dendritic Cells from Bone Marrow." Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1307108043.
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Luo, Mengyao. "Innate Immune Responses in the Alternaria-Dendritic Cell Interaction." Thesis, Virginia Tech, 2018. http://hdl.handle.net/10919/83811.
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Exposure to spores and hyphae of Alternaria alternata, an airborne ubiquitous fungus, is clinically associated with allergic airway disorders including allergic rhinitis, asthma, and chronic rhinosinusitis. Dendritic cells are known as the type of antigen presenting cells most often associated with allergic inflammation. In this study, we used mouse bone marrow-derived dendritic cells (BMDCs) as a model to study the ability of A. alternata spores and different components of the spore cell wall to stimulate innate immune responses. We found that BMDCs were highly sensitive to A. alternata spores, chitin and the major allergen Alt a 1. Following stimulation with these molecules, the expression of MHC II and other co-stimulators, like CD40, CD86, and OX40L, were highly up regulated. In order to determine how different cell wall components affect the T cells, we conducted co-culture experiments of BMDCs and lymphocytes in this study. Both spores and Alt a1 did not induce IL-4 in mixed lymphocytes reactions. Interestingly, we found that Alt a 1 induced the switching of the CD4+ T cell population to the Th17 type, with a major increase in IL-17A secretion. This study reveals that A. alternata components may balance the innate immune responses between Th2 and Th17 pathways, and/or contributes to the development and exacerbation of more serve neutrophilic forms of asthma.Master of Science
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Reeves, R. Keith. "Pathogenesis and therapeutic potential of plasmacytoid dendritic cells in SIV/SHIV-infected macaques." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2008r/reeves.pdf.
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Kocieda, Virginia Polonia. "Prostaglandin E2-induced IL-23p19 is regulated by CREB and C/EBP beta in bone marrow derived dendritic cells." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/214805.
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Microbiology and ImmunologyPh.D.
We reported previously that prostaglandin E2 (PGE2) upregulates IL-23 in vitro in bone marrow-derived dendritic cells (DC), and in vivo in models of collagen-induced arthritis and inflammatory bowel disease, leading to preferential Th17 development and activity. There is very little information on the molecular mechanisms involved in the PGE2-induced upregulation of Il23a gene expression. In the present study we investigated the signaling pathways and transcription factors involved in the stimulatory effect of PGE2. Although PGE2 does not induce IL-23p19 expression by itself, it synergizes with both extra- and intracellular TLR ligands and with inflammatory cytokines such as TNFα. We established that the effect of PGE2 in conjunction with either LPS or TNFα is mediated through the EP4 receptor and the cAMP-dependent activation of both PKA and EPAC. Using the EP4 agonist PGE1OH in conjunction with TNFα, we found that PKA-induced PCREB and EPAC-induced PC/EBPβ mediate the stimulatory effect of PGE2 on IL-23p19 expression. This is the first report of CREB and C/EBPβ involvement in Il23a promoter activation. Mutation within the putative CREB and C/EBP sites combined with in vivo DNA binding (ChIP) assays identified the distal CREB site (-1125) and the two proximal C/EBP sites (-274 and -232) as essential for PKA-activated CREB and EPAC-activated C/EBPβ induced IL-23p19 expression.
Temple University--Theses
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Johnson, Kenneth. "The Role of Gilt in the Cross Presentation of the Melanoma Antigen gp100." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/623465.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.In this study we examine the utility of using CD8+ T cell hybridomas to measure the ability of bone marrow dendritic cells (BMDCs) to internalize cancer proteins and display them to cytotoxic T cells, a process termed cross‐presentation. We test the ability of a newly generated T cell hybridoma called BUSA14 to detect cross‐presentation of the melanoma antigen gp100. BUSA14 produces a dose‐dependent response to human and mouse gp100 peptides. However, cross‐presentation of gp100 by BMDCs using SK‐MEL‐28 human melanoma cell lysates or direct MHC class I‐restricted presentation by B16 murine melanoma cells was not detected. Both SKMEL‐28 and B16 cells express gp100 protein by immunoblot, and gp100 as a membrane bound protein may be concentrated by cell fractionation techniques. We validated our crosspresentation assay with another T cell hybridoma B3Z to detect cross‐presentation of the model antigen ovalbumin. Lastly, we determined that although BUSA14 expresses the coreceptor CD8, BUSA14 lacks CD3 expression, which likely impairs the ability of this hybridoma to respond to engagement of the T cell receptor and contributes to the inability to detect presentation of native gp100 protein. To resolve these issues, we plan to use primary gp100‐specific T cells from pmel mice expressing the same T cell receptor as the BUSA14 hybridoma to detect presentation of gp100 protein. Ultimately, we plan to evaluate the requirements for cross‐presentation of gp100, including a role for gamma‐interferon‐inducible lysosomal thiol reductase (GILT), a disulfide bond reducing enzyme.
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Gibson, Joanne. "Characterisation of the differential phagocytic, cytokine and T cell activation potentials of bone marrow derived dendritic cells in response to C.albincans cell wall glycosylation." Thesis, University of Aberdeen, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542629.
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This thesis study investigated the involvement of glycosylation of cell wall proteins, major components of the outermost cell wall layer of C. albicans, in the induction of murine bone marrow derived dendritic cell (BMDC) responses. Utilising mutants which are deficient in glycosylation process, the binding of specific N-glycosylation moieties was demonstrated to be important in triggering phagocytosis while changes in O-glycosylation moieties altered the secretion of multiple pro-inflammatory chemokines and cytokines. Importantly, BMDC-O-glycosylation and/or BMDC-inner cell wall constituent interactions were demonstrated to result in the modulation of T cell responses, through the stimulation of the secretion of interleukin (IL)-17. It was further shown using receptor-deficient BMDC and receptor-blocking antibodies that although dectin-1, mannose receptor (MR) and Toll-like receptor (TLR)4 do not play a role in the induction of phagocytosis, receptor engagement induced receptor-specific cytokine secretion. Specifically, the secretion of IL-12p70 and IL-6 was dependent on dectin-1 signalling, while the secretion of the pro-inflammatory monocyte chemotactic protein (MCP)-1, tumour necrosis factor (TNF)-α and IL-6 were found to be induced in a MR-dependent manner. Intriguingly, a redundant role was found for TLR4. Cumulatively these results indicate a critical role of the recognition of fungal cell wall glycosylation moieties in the induction of protective phagocytosis and cytokine response in BMDC. Future studies to determine the role of other lectin receptors such as dectin-2 or receptor combinations will provide further insights into the complex interactions between BMDC and C. albicans.
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Hara, Toshiaki, Fumiyuki Yamakura, Osamu Takikawa, Rie Hiramatsu, Tsutomu Kawabe, Ken-ichi Isobe, Fumihiko Nagase, and 文彦 長瀬. "Diazotization of kynurenine by acidified nitrite secreted from indoleamine 2,3-dioxygenase-expressing myeloid dendritic cells." Elsevier, 2008. http://hdl.handle.net/2237/11379.
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Hara, Toshiaki, Nanako Ogasawara, Hidetoshi Akimoto, Osamu Takikawa, Rie Hiramatsu, Tsutomu Kawabe, Ken-ichi Isobe, Fumihiko Nagase, and 文彦 長瀬. "High-affinity uptake of kynurenine and nitric oxide-mediated inhibition of indoleamine 2,3-dioxygenase in bone marrow-derived myeloid dendritic cells." Elsevier, 2008. http://hdl.handle.net/2237/11381.
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Scroggins, Sabrina Marie. "Generation and characteriztion of regulatory dendritic cells for the amelioration of acute graft versus host disease." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/2011.
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Despite Human Leukocyte Antigen (HLA) matching and use of immunosuppressive drugs, graft-versus-host disease (GVHD) following hematopoietic stem cell transplant (HSCT) is prevalent and often fatal. Additionally, older HSCT recipients experience increased morbidity and mortality. Prophylactic treatment with age-matched syngeneic (recipient strain-derived) cultured regulatory DC (DCreg) has been shown to decrease GVHD-associated mortality in young bone marrow transplanted (BMT) mice. The purpose of this study was to investigate: 1) the potential to generate DCreg from older mice and their subsequent ability to ameliorate GVHD in older BMT mice, 2) the mechanism(s) by which DCreg mitigate GVHD in vivo, 3) the ability of DCreg-treated BMT mice to respond to infectious pathogens, and 4) whether DCreg can be generated under clinically relevant conditions from healthy donor and HSCT recipient PBMCs.
To evaluate the efficacy of DCreg treatment in older mice, complete MHC-mismatched BMT mice were treated with DCreg (hereafter referred to as DCreg-treated BMT mice). Although DCreg treatment ameliorated GVHD in older BMT mice, these mice had increased morbidity and decreased survival compared to their young counterparts.
Following transfer into BMT mice, older DCreg failed to increase inhibitory molecule (PD-L1 and PIR B) expression while significantly upregulating co-stimulatory molecule (CD40 and CD80) expression, conversely young DCreg upregulated inhibitory molecules as well as co-stimulatory molecules. These phenotypic differences between young and older DCreg in vivo provide a potential mechanism for modestly increased morbidity and mortality in older DCreg-treated BMT mice relative to their young counterparts. Indeed, BMT mice treated with DCreg deficient in PD-L1 or PIR B had significantly reduced overall survival, thus both molecules are required for optimal GVHD mitigation.
A murine H1N1 influenza (IAV) infection model was used to assess the donor immune system's capacity to respond to relevant antigens other than those responsible for GVHD. Surprisingly, sub-lethally IAV-infected DCreg-treated BMT mice began to die after d. +21 and all were deceased by d. +25. Virus-specific CD8+ T cell and antibody (Ab) responses were undetectable following primary infection. Interestingly, following a prime-boost infection strategy, DCreg-treated BMT mice survived lethal IAV challenge with no signs of morbidity and had demonstrable IAV-specific Ab and CD8+ T cell responses. Thus a prime-boost IAV infection strategy establishes a protective immune response in the DCreg-treated BMT mice and underscores the potential role vaccination may play in establishing immune competence in DCreg-treated BMT mice.
We investigated whether human DCreg can be generated under clinically relevant conditions: 1) following peripheral blood mononuclear cell (PBMC) cryopreservation, 2) in bovine serum-free media, and 3) from older individuals and HSCT recipients. DCreg were generated from healthy donor and HSCT patient PBMCs isolated from young (old) and older (> 50 years old) individuals by culturing cells in X-vivo serum-free.
Human DCreg generated from both young and older healthy donor PBMCs had comparable numbers, surface molecule phenotype, cytokine production, and able to induce Treg. Cryopreserved and fresh PBMCs generated DCreg with similar phenotypes and cytokine production. DCreg generated from HSCT recipients maintained low co-stimulatory molecule and high inhibitory molecule expression as well as immunosuppressive cytokine production. These studies confirm DCreg can be generated under clinically relevant conditions.
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Rogers, James L. "Major tea catechin inhibits dendritic cell maturation in response to microbial stimulation." [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002176.
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Svitlova, Olena B. "Six-Nine Months Long Term Culture of Mouse Bone Marrow Cells Differentiated to Macrophages and Eosinophils." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1567524586159929.
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Bartmann, Juliane [Verfasser], and Elfriede [Akademischer Betreuer] Nößner. "Immunobiological functions of matrix metalloproteinase-13 in bone marrow-derived dendritic cells and its contribution to the pathogenesis of bronchiolitis obliterans syndrome / Juliane Bartmann. Betreuer: Elfriede Nößner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2015. http://d-nb.info/1077987072/34.
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Jellmayer, Juliana Aparecida. "Avaliação de células dendríticas ativadas como tratamento da esporotricose murina em modelo experimental /." Araraquara, 2019. http://hdl.handle.net/11449/191406.
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Orientador: Iracilda Zeppone CarlosResumo: A esporotricose é uma micose de distribuição universal causada por fungos termodimórficos do complexo de espécies Sporothrix schenckii (S. schenckii). No Brasil, a esporotricose é considerada endêmica, sendo normalmente adquirida pela inoculação acidental do seu agente causal através da pele ou através da transmissão zoonótica por gatos infectados. As formas clínicas podem variar entre cutânea, linfocutânea e sistêmica, esta última sendo mais comumente observada em pacientes imunodeprimidos. A ineficácia do tratamento antifúngico contra esta micose, especialmente em pacientes imunocomprometidos, tem levado à busca de terapias mais eficazes e seguras. Com base em vários estudos que mostram a eficiente utilização de células dendríticas como ferramenta para o desenvolvimento de vacinas contra diferentes fungos, o objetivo deste trabalho foi avaliar a capacidade protetora de células dendríticas derivadas da medula óssea (BMDCs) ativadas com as proteínas da superfície celular de S. schenckii (PSCs) em camundongos infectados com S. schenckii strictu sensu. As BMDCs foram estimuladas com PSCs e analisadas quanto à expressão superficial de moléculas co-estimulatórias, bem como à secreção de citocinas pró-inflamatórias. Posteriormente, camundongos sádios foram vacinados com uma ou duas doses de BMDCs para avaliar a sua imunogenicidade e, por último, foi avaliado o efeito das BMDCs em camundongos infectados por S. schenckii. Nossos resultados mostram que as PSCs foram capazes de ativar... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Sporotrichosis is a universally distributed mycosis caused by thermodimorphic fungi of the Sporothrix schenckii (S. schenckii) species complex. In Brazil, sporotrichosis is considered endemic and is usually acquired by accidental inoculation of its causative agent through the skin or through zoonotic transmission by infected cats. Clinical forms may vary between cutaneous, lymphocutaneous and systemic, the latter being more commonly observed in immunosuppressed patients. The ineffectiveness of antifungal treatment against this mycosis, especially in immunocompromised patients, has led to the search for more effective and safe therapies. Based on several studies showing the efficient use of dendritic cells as a tool for the development of different fungal vaccines, the aim of this work was to evaluate the protective capacity of bone marrow derived dendritic cells (BMDCs) activated with cell surface proteins of S. schenckii (ScCWP) in mice infected with S. schenckii strictu sensu. The BMDCs were stimulated with PSCs and analyzed for surface expression of costimulatory molecules and the secretion of proinflammatory cytokines. Subsequently, healthy mice were vaccinated with one or two doses of BMDCs to assess their immunogenicity, and finally the effect of BMDCs on S. schenckii infected mice was evaluated. Our results show that the ScCWPs were able to activate BMDCs. Immunization of healthy mice with ScCWPs-stimulated BMDCs induced a Th17 profile immune response, with increased T... (Complete abstract click electronic access below)
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Decatris, Marios Petrou. "A comparative quantitative study of human myeloid dendritic cell progenitors in cord blood, bone marrow, peripheral blood and their mobilization kinetics in the peripheral blood of cancer patients undergoing leucaphaeresis." Thesis, University of Leicester, 2003. http://hdl.handle.net/2381/29456.
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Dendritic cell (DC)-based immunotherapy has potential for use in the treatment of cancer, infections and transplantation. Generating large numbers of DC from haemopoietic progenitor cells (HPC) is a key step in this process, often achieved by the aphaeresis of HPC, following their mobilization from the bone marrow into peripheral blood (PB) with chemotherapy and growth factor support (usually, granulocyte-colony stimulating factor, G-CSF). The objective of this work was to identify the optimum time for leucaphaeresis of DC progenitors. An established clonogenic assay specific for colony-forming cell (CFC) DC was used and validated with linearity, dose-response experiments and morphological confirmation. The optimal numbers of mononuclear and CD34+ (or AC133+) cells for plating were 5x104 and l-2xl03 respectively. The optimal concentrations of recombinant cytokines were also determined. Kinetic studies were done in patients with solid tumours, and HPC mobilization was achieved with conventional chemotherapy and G-CSF. The best time for harvesting large numbers of DC progenitors was when the leucocyte count rose rapidly from its nadir at a median 10 days (range 7-13) post chemotherapy. Comparative studies identified mobilized PB as the richest source of CFC-DC (mean, 1,481/ ml PB), with at least, 1.5-fold more progenitors per unit volume than cord blood (CB). These data suggest that venesection alone could provide sufficient CFC-DC to generate mature DC, after ex vivo culture and expansion. This might obviate the need for leucaphaeresis thus making DC-based immunotherapy potentially more widely available. In all the haemopoietic tissues examined the majority of DC and granulo (G)-monocytic (M) progenitors, was found within the CD34+AC133+ cell population. It is concluded that the kinetics of mobilization of CFC-DC are very similar to those of other HPC like CFC- GM and erythroid progenitors. This has important implications for designing immunotherapy protocols to isolate DC precursors from CD34+ HPC for ultimate use in DC-based immunotherapy.
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Eger, Lars. "Immunogeneic Cell Populations of the Skin." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2008. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1213729820693-69540.
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Dendritic cells (DCs), a hematopoietic cell type belonging to the sub-group of cells called antigen presenting cells (APCs), inhabit a central role in innate and adaptive immunity. Although the DC family is very heterogeneous, all members share unique features. Most importantly, DCs can stimulate an immune response. This is due to the cells’ ability to capture and process antigens and to maturate in the presence of danger signals presented by pathogens. Maturation in turn results in the migration of DCs from the tissue they reside in to the draining lymph nodes, as well as in the subsequent presentation of the acquired antigens to T cells. In the skin, which is one of the most immunogeneic organs, DCs are present in sizable numbers in both the epidermis and the dermis. This study focused on two types of DCs: epidermal Langerhans cells (LCs) and dermal DCs (DDCs). While much is understood about LCs, far less is known about the role that DDCs play in skin immunity. Therefore one purpose of this study was to characterize DDCs and to compare their phenotype and functions to that of LCs. This study used two different methods to characterize human skin resident immune cells with regard to their number and distribution. First, a stable analytical immunohistochemistry-based method was developed and applied to a substantial number of healthy skin donors. This enabled a quantitative analysis of skin DC types and skin resident T cells at different anatomical locations in situ. A novel method to count dermal cell populations in situ was developed that resulted in the first published quantification of APCs, DDCs, as well as T cells in human dermis. Second, the traditional form of the emigration assay, which selectively enriches vital cells capable of ex vivo emigration from the skin, was upgraded toward a stable analytical method to separate epidermal LCs from DDCs. In this way, both skin DC types became accessible in sufficient numbers to allow for a comparison of phenotypes and functions in vitro. The resulting phenotypic observations clearly showed that both, LCs and DDCs are not fully mature after their emigration ex vivo and that both can be transformed into a phenotypically more mature state by treating them with inflammatory cytokines. What’s more, LCs are also functionally in an immature state after their emigration. They efficiently took up antigen, showed a low capacity to trans-migrate in response to chemokines, and demonstrated a low capacity to stimulate allogeneic T cells in a mixed leukocyte reaction (MLR). For the first time this study observed all these main APC functions not only for LCs but additionally for DDCs. As these observations were made in relation to LCs of the same donor, it could be concluded that DDCs are functionally more mature than LCs after emigration. DDCs showed a lower antigen uptake capacity than LCs but were superior in terms of their migratory and stimulatory capacity. However, treatment with cytokines could skew LC functions toward functional capacities observed for DDCs, i.e., it decreased LCs’ Ag uptake and increased their migratory and stimulatory capacity, whereas the cytokine treatment did not alter DDCs’ functional capacities. After improving immuno-histochemistry and the emigration assay using healthy skin samples, these newly developed techniques were implemented in clinical trials to observe the number, distribution and migratory capacity of skin DCs and T cells in patients undergoing allogeneic hematopoietic cell transplantation (aHSCT). Such a study is of importance because the turnover of DCs and T cells is closely associated with the occurrence of acute graft-versus-host disease (aGvHD), the major cause of morbidity and mortality after aHSCT. Due to the study design used, this study concisely demonstrate that at the onset of aGvHD, different DC types accumulate along with effector T cells in skin lesions of aGvHD but not in uninvolved skin of the same patient. These results suggest that in addition to donor T cells LCs and DDCs play a role during the early phase of cutaneous aGvHD directly within the site of inflammation. The view of many authors that DC depletion in the transplant recipient, especially in target organs, is a promising approach for aGvHD prophylaxis and therapy is further underscored by these results. One targeting strategy to inhibit GvHD by eliminating recipient DCs may be the use of DC specific monoclonal antibodies. Alemtuzumab (anti-CD52) is a monoclonal antibody and has proven effective in preventing aGvHD after aHSCT. It may, despite depleting donor T cells, also work by targeting recipient DCs. To determine whether the last mechanism of action is significant, a second clinical study investigated the effects of intravenous alemtuzumab on DCs by comparing the number of these cells in skin and blood of patients before and after a 4-week course of alemtuzumab treatment. The result was that although skin DCs weakly express the target antigen CD52 the number of these cells was not consistently reduced by alemtuzumab. In contrast, circulating blood DCs have a stronger CD52 expression and were significantly reduced by the treatment. In conclusion, this work provides new insights into the phenotypical and functional characteristics of human skin DCs, as well as into the fate of these cell types during aHSCT. The investigation of the APC system during aGvHD as carried out here will help to understand the process of aGvHD in more detail. All these efforts may hopefully support the development of new approaches for therapy and prevention of this major limitation of aHSCT and may help to improve this only curative therapy for several life-threatening diseases.
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Letscher, Hélène. "Étude des propriétés régulatrices d’une population de précurseurs de cellules dendritiques plasmacytoïdes conditionnée par le CpG dans le cadre de réponses auto-immune et allogénique Innate activation primes bone marrow plasmacytoid dendritic cell precursors for tolerance Rôle protecteur des CpG-pre-pDC dans le cadre d’une réponse allogénique : la maladie du greffon contre l’hôte." Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2171&f=13417.
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Les progéniteurs hématopoïétiques présentent la faculté de détecter des signaux infectieux et inflammatoires. Leur éducation précoce par de tels signaux au sein de la moelle osseuse avant leur sortie vers la périphérie peut influencer l'évolution des réponses immunes. Alors que les cellules dendritiques plasmacytoïdes matures peuvent soit aggraver soit améliorer des maladies auto-immunes ou allogéniques, nous avons exploré la possibilité que de tels signaux innés confèrent des propriétés immunorégulatrices à des précurseurs médullaires des pDC. Nous avons caractérisé une population médullaire émergeant après interaction avec un agoniste du Toll-like receptor-9, l'oligonucléotide CpG, qui présente le phénotype c-kit+Sca-1+B220intPDCA-1+, est engagée dans la voie des cellules dendritiques plasmacytoïdes (pDC) et l'avons dénommée CpG-pre-pDC. Nous avons évalué le potentiel immunorégulateur des CpG-prepDCs en opérant leur transfert adoptif dans deux types de pathologies murines : l'Encéphalite Auto-immune Expérimentales (EAE), un modèle de sclérose en plaques qui est une maladie auto-immune, ainsi que la maladie du greffon contre l'hôte (GVHD) qui est une réponse allogénique. Il s'est avéré que le transfert d'un nombre assez faible de précurseurs (80 000 en EAE et 200 000 en GVHD) est capable de limiter la maladie à différents temps cliniques. De façon intéressante, les CpG-pre-pDC migrent spécifiquement à la moelle épinière dans l'EAE et à la rate dans la GVHD où leur descendance conserve un phénotype de pDC encore relativement immature. Dans le cadre de l'EAE, la descendance des précurseurs injectés produit essentiellement de l'IL-27 et du TGFß et plus modestement du GM-CSF. Au niveau du système nerveux central inflammé, elles font dévier la réponse immunitaire des lymphocytes T CD4+ infiltrants d'un profil pro-inflammatoire (IFNy+ GM-CSF+ IL-17+) vers un profil anti-inflammatoire (TGFß+, IL-27+, IL-17-, GM-CSFlo). L'utilisation de précurseurs déficients dans chacune de ces deux cytokines a permis de démontrer que TGFß et IL-27 interviennent séquentiellement dans la protection conférée par les CpG-prepDCs, le TGFß à des temps précoces et l'IL-27 aux phases tardives de la maladie. Des mécanismes semblables interviennent dans la protection envers la GVHD conférée par les CpG-prepDCs, car leur descendance est toujours capable de produire du TGFß mais cette fois en association avec l'IL-12, une autre cytokine de la même famille que l'IL-27. Par ailleurs, ces cellules sont capables de diminuer la production d'IL-17 tant par les lymphocytes T CD4+ que par les CD8+. Une thérapie cellulaire avec l'équivalent humain des CpG-pre-pDCs pourrait constituer un nouvel outil thérapeutique pour le traitement à la fois de la sclérose en plaques réfractaire et de la maladie du greffon contre l'hôte soit injectés seuls soit en enrichissement des greffes de cellules souches hématopoïétiques qui sont pratiquées dans ces deux maladiesHematopoietic progenitors can sense innate signals. Their early education by such signals within the bone marrow, prior to their egress, may have considerable impact on the outcome of immune responses. While mature plasmacytoid dendritic cells (pDC) are known to either aggravate or ameliorate disease both auto-immune and allogeneic, it remains unknown whether immune regulatory function can be stably imprinted at the precursor stage in the pDC lineage onwards. We herein investigated whether activation with the oligonucleotide CpG, a Toll-like receptor-9 agonist, confers to bone marrow pDC precursors (CpG-prepDCs) characterized by the c-kit+Sca-1+B220intPDCA-1+ phenotype the capacity to protect against two kinds of murine immune pathologies: Experimental Autoimmune Encephalomyelitis (EAE), a model of multiple sclerosis which is an autoimmune disease and graft versus host disease (GVHD), an allogeneic response. We demonstrate that the adoptive transfer of relatively low number of CpG-pre-pDCs (80.000 in EAE and 200.000 in GVHD) was able to clinically reduce both diseases. Interestingly, CpG-pre-pDCs migrated to the spinal cord in EAE and to the spleen in GVHD where their progeny retained a relatively immature pDC phenotype. In EAE, the progeny of CpG-pre-pDCs massively produces IL-27 and TGFß and moderately GM-CSF. In the inflamed central nervous system, the progeny switches the immune response of infiltrating CD4+ T cells from pro-inflammatory (IFNy+ GM-CSF+ IL-17+) to anti-inflammatory (TGFß+, IL-27+, IL-17-, GM-CSFlo). The key role of TGFß and IL-27 was assessed using precursors incapacitated for the production of each of those cytokines. These experiments demonstrated that the two soluble factors acted sequentially: TGFß ensures early phases of the immunomodulation mediated by the CpG-pre-pDC while IL-27 is required for later protection. In GVHD, the mechanisms of protection are different yet similar in some ways. As for EAE, the progeny of CpG-pre-pDCs is still able to produce TGFß but this time in combination with IL-12, another cytokine from the IL-27 family. Additionally, those cells were able to reduce the IL-17 production by both pathogenic CD4+ and CD8+ T cells. The human equivalent of CpG-pre-pDC could be a new therapeutic tool in patients with multiple sclerosis or graft versus host disease either per se or enriched in the hematopoietic stem cell transfer already implemented to treat those two immune conditions
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Hysenaj, Lisiena. "Alterations of hematopoiesis during brucellosis." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0251.
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La brucellose est une maladie qui se transmet de l’animal à l’homme. Elle est causée par la bactérie Brucella. Lors de ma thèse, j’ai montré que Brucella persiste dans les cellules de la moelle osseuse des animaux infectés. Ces observations sont très importantes car la moelle est un organe responsable de la génération des cellules du système immunitaires et c’est la principale niche des cellules souches hématopoïétiques. Au cours de ma thèse, j'ai montré que la protéine de la membrane externe 25 de Brucella (Omp25) est capable de lier au récepteur SLAMF1, une molécule exprimée par les cellules souches hématopoïétiques. Cette interaction conduit à la génération d'un plus grand nombre de cellules myéloïdes par les cellules souches hématopoïétiques. Les cellules myéloïdes sont la niche préférée de Brucella. Ainsi, cette stratégie permet à la bactérie d'envahir l’hôte et d'établir une infection chronique de longue durée. SLAMF 1 apparaît comme une nouvelle cible thérapeutique pour le contrôle des maladies infectieuses chroniques, ce qui représenterait une avancée importante dans la génération de nouveaux médicamentsBrucellosis is a disease that is transmitted from animals to humans. It is caused by the pathogenic bacterium Brucella. During my thesis, I showed that Brucella persists in the bone marrow cells of infected animals. These observations are very important because the bone marrow is an organ of the immune system responsible for the generation of the immune cells, as it is the principal niche of hematopoietic stem cells. During my thesis, I showed that Brucella outer membrane 25 (Omp25) is able to bind SLAMF1, a hematopoietic stem cell molecule. This interaction leads to the production of more myeloid cells by the hematopoietic stem cell. Myeloid cells are the favorite niche of Brucella. Thus, this strategy allows the bacteria to invade the host and establish a long lasting chronic infection. SLAMF 1 appears as a new therapeutic target for controlling chronic infectious diseases, which would represent an important advance in the generation of new drugs
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Weber, Matthew Charles. "Engineering human bone marrow stromal cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=case1055867071.
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Amofah, Eunice. "Bone marrow stem cells in liver disease." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497234.
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Clutter, Suzanne Davis. "Chemotherapy disrupts bone marrow stromal cell function." Morgantown, W. Va. : [West Virginia University Libraries], 2006. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=4528.
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Thesis (Ph. D.)--West Virginia University, 2006.Title from document title page. Document formatted into pages; contains x, 180 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.
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Hall, Brett Matthew. "Effects of high dose chemotherapy on the bone marrow microenvironment." Morgantown, W. Va. : [West Virginia University Libraries], 2002. http://etd.wvu.edu/templates/showETD.cfm?recnum=2558.
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Thesis (Ph. D.)--West Virginia University, 2002.Title from document title page. Document formatted into pages; contains ix, 173 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 163-169).
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Al-Khaldi, Abdulaziz A. "Therapeutic angiogenesis using autologous bone marrow stromal cells." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32749.
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Objectives. To study marrow stromal cells (MSCs) induced angiogenesis. To examine the possible mechanisms involved in the process. To evaluate neovascularization following implantation of MSCs in ischemic hind limb model.Methods and result. Using murine Matrigel angiogenesis model, we compared MSCs related angiogenesis to that produced by vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We found that MSCs result in an efficient and organized angiogenesis, arteriogenesis and vasculogenesis. MSC-related angiogenesis is VEGF dependent. MSCs in vivo produce VEGF that through paracrine effect induces local angiogenesis and through an autocrine loop stimulates FLK1+MSCs to differentiate into endothelial cells. MSCs implanted into ischemic hind limb resulted in marked improvement in blood flow and collateral vessels formation.
Conclusion. MSCs spontaneously induce efficient and mature angiogenesis in ischemic/hypoxic tissues with significant arteriolar component resulting in increased blood flow. They are also capable of spontaneous differentiation into endothelium. VEGF appears to be necessary for MSC-related angiogenesis and vasculogenesis.
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Davies, Julie Theresa. "Activation of adhesion of bone marrow stromal cells." Thesis, St George's, University of London, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.656858.
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Osteoblasts, the bone-forming cells, derive from multipotential bone marrow stromal precursors called colony-forming units-fibroblastic (CFU-F). CFU-F rapidly adhere to plastic upon culture ex vivo, adhesion of such stromal precursors to bone in vivo is likely to be an early event in the anabolic response to bone stimulatory factors. It has been suggested that osteoclasts are involved in the activation of bone formation during bone remodelling. In order to test this, osteoclast conditioned medium was prepared from osteoclasts cultured on either plastic or bone. It was then used as culture medium for bone marrow cells. It was found that the conditioned medium was unable to increase the adherence of bone marrow cells and therefore the number of CFU-F when cultured in 6-well plates. The ability of parathyroid hormone (PTH) to enhance bone formation has recently been exploited in the treatment of osteoporosis. However, the underlying mechanisms are unknown. PTH and other possible osteoblast activating factors were tested for the ability to activate adhesion of CFU-F in vitro. For this, bone marrow cells were incubated in PTH for varying times. Non-adherent cells were then removed, and the adherent cells were incubated in PTH-free medium for 14 days to assess, as colony formation, the number of CFU-F that had adhered in the preceding period. Incubation in PTH caused a substantial increase in the number of CFU-F that adhered within 24 h. This increase was abrogated by peptidic inhibitors of integrins. The increase did not appear to be mediated through a PTHinduced increase in interleukin-6, since interleukin-6 had no effect on CFU-F numbers when substituted for PTH. Similarly, adhesion was unaffected by incubation of bone marrow cells in dibutyryl cyclic AMP, nor by inhibitors or donors of nitric oxide. However, activation of CFU-F in vitro by PTH was strongly inhibited by indomethacin and mimicked by Prostaglandin E2 (PGE2). To test the effects of PTH in vivo, the number of CFU-F that could be extracted from murine bone marrow after administration of an anabolic dose of PTH were measured. A dramatic reduction in the number of CFU-F that could be extracted from their bone marrow commenced within 2 h of treatment. It was also found that indomethacin reversed the PTH mediated reduction of CFU-F that could be extracted from mouse bone marrow. Intermittent PTH administered over a 6 day period increased the dynamic parameters associated with bone formation and there was a concomitant increase in the number of osteoblasts on bone surfaces. These results suggested that PTH rapidly activates adhesion of CFU-F to plastic or bone surfaces. This activation may represent an early event in the anabolic response of bone cells to PTH.
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Bennett, Jonathan Hilary. "The differentiation of osteogenic cells from bone marrow." Thesis, University of Oxford, 1991. http://ora.ox.ac.uk/objects/uuid:3460f26e-a124-4605-8601-2e300241de14.
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Roulson, Jo-An. "Bone marrow endothelial transmigration of prostate carcinoma cells." Thesis, University of Manchester, 2008. https://www.research.manchester.ac.uk/portal/en/theses/bone-marrow-endothelial-transmigration-of-prostate-carcinoma-cells(997acbf2-bbbc-455b-bb84-b439ffb9f839).html.
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Gowers, Kate Hayley Christine. "Characterisation of bone marrow progenitor cells in disease." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11068.
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The bone marrow serves as a reservoir for leukocytes and stem cells, from where cells can be mobilised into the circulation and can be recruited to sites of inflammation. Mobilisation of cells out of the bone marrow is dependent on their migration across the bone marrow sinusoidal endothelium, which is thought to be structurally and functionally different to endothelial cells from other vascular beds. In order to characterise the bone marrow endothelium and to study the molecular mechanisms involved in the mobilisation of cells, a protocol to isolate bone marrow endothelial cells and to grow them in vitro was developed. The bone marrow contains a number of distinct progenitor cell populations, including endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs). Whether these populations of stem cells are recruited from the bone marrow to the lungs was investigated in two contrasting models of lung disease: the house dust mite (HDM) model of allergic airways disease and the bleomycin model of pulmonary fibrosis. In the HDM model increased recruitment of EPCs to the inflamed lungs was associated with increased peribronchial angiogenesis, and reduced EPC numbers in the bone marrow. Blocking VEGF inhibited EPC recruitment to the inflamed lungs and reduced the associated peribronchial angiogenesis. In this model, no recruitment of MSCs to the inflamed lungs was observed. However, in the bleomycin model, a significant elevation in MSC numbers was observed in the circulation, lung tissue and BAL fluid. Experiments to block the recruitment of MSCs to the lungs in response to bleomycin injury were performed, along with investigations into the recruitment of exogenously administered MSCs to the injured lungs. A population of MSCs residing in the naïve lungs was identified, which are phenotypically similar to bone marrow MSCs, but can be distinguished by their size and expression of specific cell surface antigens.
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Kwong, Rebecca Sze-Wai. "Interaction of bone marrow-derived mesenchymal stem cells on neuroblastoma cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48541485.
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Background
Mesenchymal stem cells (MSC) were first discovered in the 1970s by scientist A.J. Friedenstein and his colleagues. Friedenstein isolated the first mesenchymal stem cells and was credited for discovering its multilineage differentiation potential. To this day, an extensive amount of research has been conducted on the use of these cells in the treatment of degenerative diseases and various autoimmune disorders. Its migratory ability and immunosuppressive characteristics make MSCs advantageous in an inflammatory environment. Recently, MSCs were also found to have the ability to phagocytose apoptotic bodies generated from T-cells and B-cells.
Objectives
In this study, we sought to investigate the phagocytic capability of MSCs further in a cancer setting and observe whether or not MSCs could become immunostimulatory cells after phagocytosis of apoptotic cancer cells.
Methods
To conduct this study, we first used UV-irradiation to generate apoptotic cells from 3 neuroblastoma (NB) cell lines. After apoptotic NB cells were generated, they were then co-cultured with MSCs for phagocytosis to occur. To detect phagocytosis, we stained the apoptotic NB cells with a red fluorescent dye PKH-26 and MSCs with CFSE, a green fluorescent dye. Then, we used flow cytometry to detect the percentage of phagocytosis. After phagocytosis, we collected the supernatants from the MSCs treated with the apoptotic NB cells and observed how the IL-6 and IL-8 cytokine levels changed compared to the levels from the supernatant of the MSCs only.
Results and Conclusions
After conducting this experiment, our results showed that in a cancer environment MSCs were able to phagocytose apoptotic NB cells. Furthermore, after phagocytosis the IL-6 and IL-8 cytokine levels increased significantly in the MSCs treated with apoptotic NB cells compared to the control group with MSCs only. Since IL-6 and IL-8 are both considered pro-inflammatory cytokines, we can conclude that after phagocytosis of apoptotic NB cells, MSCs can become immunostimulatory cells. To further confirm our findings, various other cytokines should be tested and more experiments should be done. This way, a more complete picture can be generated describing how MSC cytokine secretion activity changes after phagocytosis of apoptotic neuroblastoma cells.published_or_final_version
Paediatrics and Adolescent Medicine
Master
Master of Medical Sciences
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Tsui, Yat-ping, and 徐軼冰. "Derivation of oligodendrocyte precursor cells from adult bone marrow stromal cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/197485.
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Myelin is essential for neuronal survival and maintenance of normal functions of the nervous system. Demyelinating disorders are debilitating and are often associated with failure of resident oligodendrocyte precursor cells (OPCs) to differentiate into mature, myelinating oligodendrocytes. Derivation of OPCs, from a safe source that evades ethical issues offers a solution to remyelination therapy. We therefore hypothesized that bone marrow stromal cells (BMSCs) harbour neural progenitor cells at a pre-commitment stage and that in vitro conditions can be exploited to direct differentiation of these cells along the oligodendroglial lineage.
For the current study, adult rat BMSCs used were >90% immunopositive for CD90, CD73, STRO-1 (stromal cell markers), 10% for nestin (neural progenitor marker) but negligible for CD45 (haematopoietic cell marker) as measured by flow cytometry. Transfer of the culture from a highly adhesive substratum to a moderately adhesive substratum resulted in increase in proportion of p75-positive cells but CD49b-positive cells remained at 97% and Sox 10-positive cells remained negligible. Transfer of the culture to a non-adherent substratum fostered the generation of neurospheres comprising cells that were positive for the neural stem/progenitor cell (NP) marker, nestin, and for the neural crest markers CD49b, p75 and Sox10. Prior to this stage, the BMSCs were not yet committed to the neural lineage even though transient upregulation of occasional marker may suggest a bias towards the neural crest cell lineage.
The BM-NPs were then maintained in adherent culture supplemented with beta-Heregulin (β-Her), basic fibroblast growth factor (bFGF) and platelet-derived growth factor-AA (PDGF-AA) to direct differentiation along the oligodendroglial lineage. Within two weeks of glial induction, cells expressing the OPC markers - NG2, Olig2, PDGFRa and Sox10, were detectable and these could be expanded in culture for up to 3 months with no observable decline in marker expression. These BM-OPCs matured into myelinating oligodendrocytes after 2 weeks in co-culture with either dorsal root ganglion neurons or cortical neurons. In vivo myelination by BM-OPCs was demonstrated by exploitation of the non-myelinated axons of retinal ganglion cells of adult rats. By 8 weeks post-injection of BM-OPCs into the retina, myelin basic protein-positive processes were also observable along the retinal axons. The results not only suppport our hypothesis, but also provide pointers to the adult bone marrow as a safe and accessible source for the derivation of OPCs towards transplantation therapy in acute demyelinating disorders.published_or_final_version
Biochemistry
Doctoral
Doctor of Philosophy
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Baba, Shinji. "Commitment of bone marrow cells to hepatic stellate cells in mouse." Kyoto University, 2005. http://hdl.handle.net/2433/144726.
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Urbieta, Maitee. "Regulatory T Cells and Hematopoiesis in Bone Marrow Transplantation." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/463.
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CD4+CD25+FoxP3+ regulatory T cells (Treg) possess the capacity to modulate both adaptive and innate immunity. Due to their suppressive nature, Treg cells have been studied and tested in a variety of scenarios in an attempt to ameliorate undesired immune responses. While graft versus host disease (GVHD) has in fact emerged as the first clinical application for human Treg cells (Riley et al. 2009), equally important are issues concerning hematopoietic engraftment and immune reconstitution. Currently, little is known about the effect(s) that regulatory T cells may exert outside the immune system in this context. Based on cytokine effector molecules they can produce we hypothesized that Treg cells could regulate hematopoietic phenomena. The studies portrayed in this dissertation demonstrate that Treg cells can differentially affect the colony forming activity of myeloid and erythroid progenitor cells. In-vitro as well as in-vivo findings demonstrate the ability of Tregs to inhibit and augment the differentiation of primitive and intermediate myeloid (interleukin (IL)-3 driven) and late erythroid (erythropoietin driven) hematopoietic progenitor cells, respectively. The inhibitory and enhancing affects appeared to be mediated by independent pathways, the former requiring cell-cell contact, major histocompatibility complex (MHC) class II expression on marrow cells and involving transforming growth factor beta (TGF-beta), whereas the latter required interleukin (IL)-9 and was not contact dependent. Strikingly, we observed that in addition to regulating hematopoietic activity in normal primary BM cells, Tregs were also capable of suppressing colony forming activity by the myelogenous leukemia cell line NFS-60. Furthermore, studies involving endogenous Treg manipulations in-situ (i.e. depletion of these cells) resulted in elevated overall myeloid colony activity (CFU-IL3) and diminished colony numbers of erythroid precursors (CFU-E) in recipients following BMT. Consistent with these results, it was found that upon co-transplant with limiting numbers of bone marrow cells, exogenously added Treg cells exert in-vivo regulation of myeloid and erythroid CFU activity during the initial weeks post-transplantation. This regulation of hematopoietic activity by freshly generated Tregs upon transplantation led to the elaboration of a second hypothesis; following lethal total body irradiation (TBI) the host microenvironment facilitates regulatory T cell activation/effector function. Substantial evidence has accumulated in support of this hypothesis, for example we demonstrate up-regulation of surface molecules such as GARP and CD150/SLAM, which have been previously reported as indicators of Treg activation following TCR signaling and co-stimulation, occurs in donor (reporter) Treg populations. Acquisition of an activated phenotype and hence of effector/modulatory function is consistent with the previous in-vivo observations, indicating that both recipient and donor Treg cells can influence hematopoietic progenitor cell activity post-transplant. Finally, the present studies may be of great relevance in the emerging field of Treg cell based immunotherapy for prevention and/or treatment of HSCT complications.
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Chu, Jennifer. "Enhanced engraftment of genetically modified bone marrow stromal cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58851.pdf.
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Konan, S. "Augmenting osseointegration of implants using bone marrow stromal cells." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1382600/.
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Introduction: The greatest challenge facing the success of orthopaedic implants is improving their fixation to bone to enhance their longevity. Bone marrow stromal cells (BMSC), are a population of plastic-adherent cells derived from the bone marrow. The main hypothesis of this thesis is that viable BMSC can be applied to implants using a fibrin glue-spray system; and increase bone formation adjacent to the implants and improve bone-implant contact. Methods: The experiments were undertaken in a large animal model. Four scenarios were tested 1) The ability of BMSC to improve implant fixation using models of total hip replacement, massive endoprosthetic replacement and bone defect around pins. 2) The effect of varying cell dosages of BMSC in their ability to produce new bone and improve bone implant contact. 3) The effect of differentiating the BMSC along the osteogenic pathway in their ability to produce new bone and improve bone implant contact. 4) The effect of using semi-permeable barriers around BMSC sprayed on implants to prevent cell migration Results: 1) BMSC sprayed on the surface of implants resulted in increased bone formation in the total hip replacement, massive endoprosthetic replacement and bone defect around pin models. 2) Bone formation was higher with osteogenic 10x106 BMSC (112.67 ± 30.75 mm2) compared to osteogenic 2x106 BMSC (76.84 ± 2.25 mm2). No significant difference was noted in bone formation between undifferentiated 1x105 BMSC (30.76 ± 9.43%) and undifferentiated 10x106 BMSC (28.27 ± 14.64%). 3) Osteogenic differentiated 10x106 BMSC (112.67 ± 30.75 mm2) produced more bone than undifferentiated 10x106 BMSC (58.22 ± 17.22 mm2). 4) Using semipermeable barriers resulted in significantly increased bone formation when undifferentiated 1x105 BMSC (61.32 ± 6.94% vs 30.76 ± 9.43%) or undifferentiated 10x106 BMSC (57.46 ± 4.39% vs 28.27 ± 14.64%) was used. This difference was not noted when osteogenic differentiated 10x106 BMSC was used. The experiments confirm that viable BMSC can be successfully isolated from bone marrow aspiration, differentiated along the osteogenic pathway and sprayed on the surface of various orthopaedic implants to improve bone-implant contact. Conclusion: This technique of using BMSC may be an ideal alternative to improve osseointegration of implants in challenging clinical scenarios with deficient bone stock.
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Porter, Ryan Michael. "Examination of Glucocorticoid Treatment on Bone Marrow Stroma: Implications for Bone Disease and Applied Bone Regeneration." Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/36365.
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Long-term exposure to pharmacological doses of glucocorticoids has been associated with the development of osteopenia and avascular necrosis. Bone loss may be partially attributed to a steroid-induced decrease in the osteoblastic differentiation of multipotent progenitor cells found in the bone marrow. In order to determine if there is a change in the osteogenic potential of the bone marrow stroma following glucocorticoid treatment, Sprague-Dawley rats were administered methylprednisolone for up to six weeks, then sacrificed at 0, 2, 4, or 6 weeks during treatment or 4 weeks after cessation of treatment. Femurs were collected and analyzed for evidence of steroid-induced osteopenia and bone marrow adipogenesis. Although glucocorticoid treatment did inhibit bone growth, differences in ultimate shear stress and mineral content were not detected. The volume of marrow fat increased with increasing duration of treatment, but returned to near control levels after cessation of treatment. Marrow stromal cells were isolated from tibias, cultured in the presence of osteogenic supplements, and analyzed for their capacity to differentiate into osteoblast-like cells in vitro. Glucocorticoid treatment diminished the absolute number of isolated stromal cells, but did not inhibit the relative levels of bone-like mineral deposition or osteocalcin expression and secretion.
Although pharmacological glucocorticoid levels induce bone loss in vivo, physiologically equivalent concentrations have been shown to enhance the formation of bone-like tissue in vitro. However, glucocorticoids have also been reported to inhibit proliferation and type I collagen synthesis in marrow stromal cell cultures. In order to assess the effects of intermittent dexamethasone treatment on the progression of osteogenesis in rat marrow stromal cell culture, this synthetic glucocorticoid was removed from the culture medium after a variable period of initial supplementation. Cell layers were analyzed for total cell number, collagen synthesis, phenotypic marker expression, and matrix mineralization. Prolonged supplementation with dexamethasone decreased proliferation, but did not significantly affect collagen synthesis. Furthermore, increased treatment duration was found to increase bone sialoprotein expression and mineral deposition. The duration of glucocorticoid treatment may be a key factor for controlling the extent of differentiation in vitro.Master of Science
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Dennis, James Edmund. "Mesenchymal progenitor cells in adult marrow." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062516436.
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Chandran, Priya. "Bone Marrow Microenvironment in Acute Myleoid Leukemia." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24301.
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Acute myeloid leukemia (AML) often remains refractory to current chemotherapy and transplantation approaches despite many advances in our understanding of mechanisms in leukemogenesis. The bone marrow “niche” or microenvironment, however, may be permissive to leukemia development and studying interactions between the microenvironment and leukemia cells may provide new insight for therapeutic advances. Mesenchymal stem cells (MSCs) are central to the development and maintenance of the bone marrow niche and have been shown to have important functional alterations derived from patients with different hematological disorders. The extent to which MSCs derived from AML patients are altered remains unclear. The aim of this study was to detect changes occurring in MSCs obtained from human bone marrow in patients with AML by comparing their function and gene expression pattern with normal age-matched controls.
MSCs expanded from patients diagnosed with acute leukemia were observed to have heterogeneous morphological characteristics compared to the healthy controls. Immunohistochemistry and flow data confirmed the typical cell surface immunophenotype of CD90+ CD105+ CD73+ CD34- CD45-, although MSCs from two patients with AML revealed reduced surface expression of CD105 and CD90 antigens respectively. Differentiation assays demonstrated the potential of MSCs from AML patients and healthy donors to differentiate into bone, fat and cartilage. However, the ability of MSCs from AML samples to support hematopoietic function of CD34+ progenitors was found to be impaired while the key hematopoietic genes were found to be differentially expressed on AML-MSCs compared to nMSCs.
These studies indicate that there exist differences in the biologic profile of MSCs from AML patients compared to MSCs derived from healthy donors. The results described in the thesis provide a formulation for additional studies that may allow us to identify new targets for improved treatment of AML.
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Nyambo, Rachel Netsai. "Signalling interactions between human bone marrow stromal cells and prostate cancer cells." Thesis, University of Sheffield, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420799.
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Mauney, Joshua R. "Osteogenic differentiation of bone marrow stromal cells : implications to bone tissue engineering strategies /." Thesis, Connect to Dissertations & Theses @ Tufts University, 2004.
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Thesis (Ph.D.)--Tufts University, 2004.Adviser: David L. Kaplan. Submitted to the Dept. of Biotechnology Engineering. Includes bibliographical references (leaves 162-222). Access restricted to members of the Tufts University community. Also available via the World Wide Web;
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Prodromidi, Evangelia. "Contribution of bone marrow-derived stem cells to kidney regeneration." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444168.
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Lovell, Matthew J. "The role of bone marrow derived cells in cardiac repair." Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/2500.
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Current pharmacological therapies fail to address the final end-point of cardiac ischaemia — the death and dysfunction of cardiomyocytes. Advances in stem cell biology have provided hope, for the first time, of addressing this underlying pathology. The work performed here was designed to further understanding of the mechanisms by which bone marrow derived cells improve damaged myocardium. In situ hybridisation was used to detect sex chromosomes within ex-planted, human, sex-mismatch hearts. Host derived cells were found at low frequency in donor hearts, suggesting ongoing post-natal cardiac tissue repair. Human mesenchymal stem cells were examined in vitro and in a rat model of ischaemia-reperfusion injury. Cardiomyocytes were not formed when cultured with either 5-azacytidine or ascorbic acid, and the cells failed to home to the ischaemic heart or improve cardiac function. In the same model, rat mononuclear cells significantly reduced infarct size when administered immediately upon reperfusion. Cells were rarely identified within the myocardium. No functional improvement was seen acutely, but at seven days cardiac function had improved. The low frequency of cells retained in the heart suggested that a process other than transdifferentiation accounted for the observations. Hence, evidence for paracrine actions was sought. In the same model, apoptosis and necrosis in cardiomyocytes were found to be significantly reduced. Western blots demonstrated activation of the reperfusion salvage kinase pathway, analogous to that seen in ischaemic pre- and post-conditioning. Blocking this pathway abolished the infarct size reduction. Global proteomic analysis confirmed alterations in protein expression consistent with known cardioprotective pathways. In conclusion, endogenous myocardial repair processes are inadequate to compensate for pathological insults. Supplementation with mononuclear cells in an ischaemia-reperfusion model produced significant benefit to infarct size and cardiac function. The mechanism of benefit appears to be induced by paracrine effects activating pro-survival pathways.
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Lenz, Daniel. "Dissecting the heterogeneity of murine mesenchymal bone marrow stromal cells." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/21017.
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Knochenmarks-Stromazellen sind in den letzten Jahren in den Fokus der Forschung gerückt. Es konnte gezeigt werden, dass sie durch Bereitstellung von Überlebenssignalen essenziell für die Erhaltung hämatopoetischer Nischen sind. Stromales Interleukin-7 (IL-7) konnte dabei für T Zellen als Überlebenssignal identifiziert werden. Gemeinsam ist allen Stromazellen die Expression des Oberflächenmarkers CD106/VCAM-1.
Ein effizientes Protokoll erlaubte die qualitative wie quantitative Isolation von Stromazellen aus dem murinen Knochenmark mit anschließender ex vivo Microarray-Analyse. Die auf diese Weise ermittelten Kandidaten-Marker wurden auf Proteinebene via Histologie und (Hochdurchsatz-) Durchflusszytometrie validier. Dazu gehören z.B. die Marker CD1d, gas6 oder ANXA2R. CD1d wurde als guter Interimsmarker für VCAM-1+PECAM-1- Stromazellen identifiziert, wohingegen die IL-7-Produzenten in der Population von CD200int/BP 1+/CD73+/CD105- angereichert sind. Gleiches gilt für den Transkriptionsfaktor Prrx1. CD55, BP-1 and Cadherin-11 zeigten eine Expressionsmuster in Abhängigkeit des verwendeten IL-7-Reportermaus-Haplotyps. Für BP-1 und Cadherin 11 konnte die Abwesenheit von reifen Lymphozyten als Ursache des Feedbacks ausgeschlossen werden. Die Haplotypen der Reportermaus legten auch eine monoallele Expression des IL-7 nahe.
Die Ergebnisse dieser Arbeit zeigen VCAM-1+ (IL-7+/-) Stromazellen als heterogene Population, wenn es nach der Vielzahl der möglichen exprimierten Marker geht. Zwischen vielen dieser Marker gibt es aber wiederum auf Zelloberflächenebene einen großen Überlapp. Die funktionelle Relevanz dieser Oberflächenmarker-Diversität wird in weiteren Arbeiten zu klären sein, gibt aber den Stromazellen ein breites Repertoire vor, um Interaktionen mit Lymphozyten zu initiieren, modulieren und inhibieren. Abschließend ist zu erwarten, dass diese Erkenntnisse in die klinische Behandlung der Stroma-Nischen in Autoimmun-Fragestellungen einfließen.Bone marrow stromal cells receive increasing amounts of attention lately. They have been shown to support survival of hematopoietic stem cells as well as memory lymphocytes which is of great importance when targeting the perseverance of autoimmune diseases. CD4+ memory T lymphocytes reside in the proximity of VCAM-1 expressing stromal cells which provide them with survival signals such as Interleukin-7. Herein, a protocol was developed to quantitatively obtain VCAM-1+ and VCAM-1+ IL-7+/- stromal cells via enzymatic/mechanic digestion and cytoskeleton-inhibition. Ex vivo gene expression analysis was performed from sorted, pure cells with good recovery. Candidate genes/markers were validated in (high-throughput) flow cytometry and histological analysis including subsequent semi-automated colocalization was performed. CD1d was found to be good surrogate marker for VCAM-1+PECAM-1- non-endothelial stroma while the population of CD200int/BP-1+/CD73+/CD105- stromal cells is greatly enriched in IL-7 producers which was equally true for the stromal transcription factor Prrx1. CD55, BP-1 and Cadherin-11 were found to be differentially expressed in differing IL-7 reporter mice haplotypes. The reporter mice haplotypes revealed monoallelic expression features of IL-7. All methodologies suggest that VCAM-1+ as well as IL-7+/- stromal cells are heterogeneous by marker expression yet don’t cluster extensively in flow cytometry co-stains. The functional relevance of the marker diversity described in this thesis remains to be tested but insinuates a broad repertoire for bone marrow stroma cells for new interaction pathways with lymphocyte subsets. Ultimately, this knowledge will hopefully feedback to clinical questions of autoimmunity for targeted treatment of stromal niches.