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‣ Contact sensitizer nickel sulfate activates the transcription factors NF-kB and AP-1 and increases the expression of nitric oxide synthase in a skin dendritic cell line

Cruz, M. Teresa; Gonçalo, Margarida; Figueiredo, Américo; Carvalho, Arsélio P.; Duarte, Carlos B.; Lopes, M. Celeste
Fonte: Blackwell Munksgaard Publicador: Blackwell Munksgaard
Tipo: Artigo de Revista Científica
Português
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Nuclear factor kappa B (NF-kB) and activating protein-1 (AP-1) transcription factors are ubiquitously expressed signaling molecules known to regulate the transcription of a large number of genes involved in immune responses, namely the inducible isoform of nitric oxide synthase (iNOS). In this study, we demonstrate that a fetal skin-derived dendritic cell line (FSDC) produces nitric oxide (NO) in response to the contact sensitizer nickel sulfate (NiSO4) and increases the expression of the iNOS protein, as determined by immunofluorescence and Western blot analysis. The sensitizer NiSO4 increased cytoplasmic iNOS expression by 31.9+10.3% and nitrite production, as assayed by the Griess reaction, by 27.6+9.5%. Electrophoretic mobility shift assay (EMSA), showed that 30min of FSDC exposure to NiSO4 activates the transcription factor NF-kB by 58.2+7.0% and 2 h of FSDC exposure to NiSO4 activates the transcription factor AP-1 by 26.0+1.4%. Together, these results indicate that NiSO4 activates the NF-kB and AP-1 pathways and induces iNOS expression in skin dendritic cells.

‣ Dexamethasone prevents granulocyte-macrophage colonystimulating factor-induced nuclear factor-kB activation, inducible nitric oxide synthase expression and nitric oxide production in a skin dendritic cell line

Vital, Ana Luísa; Gonçalo, Margarida; Cruz, M. Teresa; Figueiredo, Américo; Duarte, Carlos B.; Lopes, M. Celeste
Fonte: Taylor & Francis Publicador: Taylor & Francis
Tipo: Artigo de Revista Científica
Português
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AIMS: Nitric oxide (NO) has been increasingly implicated in inflammatory skin diseases, namely in allergic contact dermatitis. In this work, we investigated the effect of dexamethasone on NO production induced by the epidermal cytokine granulocyte / macrophage colony-stimulating factor (GM-CSF) in a mouse fetal skin dendritic cell line.Methods: NO production was assessed by the method of Griess. Expression of the inducible isoform of nitric oxide synthase (iNOS) protein was evaluated by western blot analysis and immunofluorescence microscopy. Western blot analysis was also performed to evaluate cytosolic IkappaB-alpha (IkB-a) protein levels. The electrophoretic mobility shift assay was used to evaluate the activation or inhibition of nuclear factor kappa B (NF-kB).Results: GM-CSF induced iNOS expression and NO production, and activated the transcription factor NF-kB. Dexamethasone inhibited, in a dose-dependent manner, NO production induced by GM-CSF. Addition of dexamethasone to the culture, 30 min before GM-CSF stimulation, significantly inhibited the cellular expression of iNOS. Dexamethasone also inhibited GM-CSF-induced NFkB activation by preventing a significant decrease on the IkB-a protein levels, thus blocking NF-kB migration to the nucleus.Conclusions: The corticosteroid dexamethasone inhibits GM-CSF-induced NF-kB activation...

‣ Retinoic acid inhibits dendritic cell differentiation driven by interleukin-4

SOUSA-CANAVEZ, Juliana Moreira de; MASSOCO, Cristina de Oliveira; MORAES-VASCONCELOS, Dewton de; CORNETA, Elaine Cristina; LEITE, Katia Ramos Moreira; CAMARA-LOPES, Luiz Heraldo
Fonte: ACADEMIC PRESS INC ELSEVIER SCIENCE Publicador: ACADEMIC PRESS INC ELSEVIER SCIENCE
Tipo: Artigo de Revista Científica
Português
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All-trans-retinoic acid (atRA) appears to affect Th1-Th2 differentiation and its effects on immune responses might also be mediated by dendritic cell (DC). Nonetheless, studies have been showing contradictory results since was observed either induction or inhibition of DC differentiation. Our aim was to investigate atRA action on human monocyte derived DC differentiation. For this purpose we tested pharmacological and physiological doses of atRA with or without cytokines. Cell phenotypes were analyzed by flow cytometry and function was investigated by phagocytosis and respiratory burst. DC, positive control group, was differentiated with GM-CSF and IL-4 and maturated with TNF-alpha. We demonstrated that atRA effects depend on the dose used as pharmacological doses inhibited expression of all phenotypic markers tested while a physiological dose caused cell differentiation. However, atRA combined or not with cytokines did not promote DC differentiation. In fact, atRA was detrimental on IL-4 property as a DC inductor. (C) 2009 Elsevier Inc. All rights reserved.; Genoa Biotechnology SA; Genoa Biotechnology SA

‣ Avaliação da transfecção de células dendríticas com RNA tumoral como estratégia para indução de imunidade específica em pacientes com leucemia linfóide crônica.; Evaluation of dendritic cell transfection with tumor RNA as a strategy to induce specific immunity in chronic lymphoid leukemia patients.

Toniolo, Patrícia Argenta
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 07/12/2010 Português
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O desenvolvimento da imunoterapia do câncer baseada em células dendríticas (DCs) é alvo de vários estudos. Para tumores sólidos, a abordagem baseada no uso de DCs alogenêicas fundidas com células tumorais tem se mostrado relativamente eficaz. Por outro lado, esta estratégia necessita uma massa tumoral considerável de cada paciente para a geração das células híbridas. Para contornar este problema o uso de DCs transfectadas com mRNA tumoral, o qual pode ser amplificado in vitro a partir de uma pequena amostra inicial do tumor, tem sido investigado. Para isto, uma transfecção eficiente e tradução correta do mRNA tumoral nas DCs são etapas críticas. Sabendo-se que as DCs de pacientes com câncer possuem atividade aloestimuladora defeituosa, DCs derivadas de doadores saudáveis poderiam ser uma alternativa para induzir uma resposta imune mais eficiente. Assim, este trabalho pretendeu aprimorar a metodologia de transfecção de DCs alogenêicas, derivadas de monócitos de doadores saudáveis, com mRNA de antígenos tumorais (survivina e RPSA) super-expressos na leucemia linfóide crônica (LLC) e avaliar sua capacidade em estimular a resposta linfocitária. Ao mesmo tempo, foram estabelecidas as metodologias para amplificação e síntese do RNA destes antígenos tumorais específicos...

‣ Elucidation of plasmacytoid dendritic cell development

Netravali, Ilka Arun
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
Português
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Most currently defined hematopoietic progenitor pools are heterogeneous, contributing to uncertainty regarding the development of certain blood cells. The origins of plasmacytoid dendritic cells, for instance, have long been controversial and progenitors exclusively committed to this lineage have never been described. We show here that the fate of hematopoietic progenitors is determined in part by their surface levels of 9-O-acetyl sialic acid. Pro-plasmacytoid dendritic cells were identified as lineage negative 9-O-acetyl sialic acid low progenitors that lack myeloid and lymphoid potential but differentiate into pre-plasmacytoid dendritic cells. The latter cells are also lineage negative, 9-O-acetyl sialic acid low cells but are exclusively committed to the plasmacytoid dendritic cell lineage. Levels of 9-O-acetyl sialic acid provide a distinct way to define progenitors and thus facilitate the study of hematopoietic differentiation.

‣ Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm

Stenzinger, Albrecht; Endris, Volker; Pfarr, Nicole; Andrulis, Mindaugas; Jöhrens, Korinna; Klauschen, Frederick; Siebolts, Udo; Wolf, Thomas; Koch, Philipp-Sebastian; Schulz, Miriam; Hartschuh, Wolfgang; Goerdt, Sergij; Lennerz, Jochen K.; Wickenhauser,
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Português
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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1% each), as well as in VHL, BRAF, MLH1, TP53 and RET (3% each). Moreover, NRAS, KRAS and ATM mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored.

‣ The role of the podoplanin-CLEC-2 pathway in stromal cell regulation of dendritic cell motility and lymph node architecture

Astarita, Jillian Leigh
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
Português
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665.6753%
In addition to leukocytes, secondary lymphoid organs are populated by non-hematopoietic stromal cells. This diverse group of cells supports lymphocyte migration and homing, facilitates antigen delivery, and promotes T cell survival. However, there is relatively little known about the specific molecules governing the roles that these cells play in regulating dendritic cell (DC) motility and lymph node architecture. Here, we examine the interaction between two molecules, CLEC-2 and podoplanin (PDPN), that are critical for DC migration and maintaining structural integrity of lymph nodes. Together, these studies identify novel functions of lymph node stromal cells and a unique function for PDPN in the immune system. In response detecting an potentially harmful antigen, DCs in peripheral tissues mature and travel to downstream lymph nodes by following chemokine gradients secreted by lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs) present in the lymph node paracortex. We discovered that, in addition to chemokines, DC migration requires CLEC-2 on DCs, as engagement of CLEC-2 with PDPN, which is expressed by LECs and FRCs, incites DC motility and is required for DC entry into the lymphatics, efficient arrival in the lymph node...

‣ Uremia impairs monocyte and monocyte-derived dendritic cell function in hemodialysis patients

Lim, W.; Kireta, S.; Leedham, E.; Russ, G.; Coates, P.
Fonte: Blackwell Publishing Inc Publicador: Blackwell Publishing Inc
Tipo: Artigo de Revista Científica
Publicado em //2007 Português
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Patients with chronic renal failure maintained on intermittent hemodialysis have frequent infections and a suboptimal response to vaccinations. Dendritic cells are potent antigen-presenting cells essential for the initiation and maintenance of innate and adaptive immunity. In this study we used uremic sera from hemodialysis patients to measure its impact on monocyte and monocyte-derived dendritic cell function in vitro. Monocytes from healthy and uremic subjects were isolated using immunomagnetic beads and differentiated into dendritic cells in the presence of either complete sera or sera from hemodialysis patients. Dendritic cells from normal patients cultured in uremic sera had decreased endocytosis and impaired maturation. These cells, however, had enhanced IL-12p70 production and increased allogeneic T-cell proliferation compared to cells of normal subjects cultured in normal sera. Monocyte derived dendritic cells of hemodialysis patients cultured in either normal or uremic sera were functionally impaired for endocytosis and maturation but had enhanced IL-12p70 production and allogeneic T-cell proliferation only when cultured with uremic sera. High concentrations of urea in normal sera inhibited all aspects of normal dendritic cell function in vitro. Our study suggests that hemodialysis regimes tailored to remove uremic toxins more efficiently may improve immune functions of these patients.; Copyright © 2007 International Society of Nephrology

‣ Regulation of Potassium Channels through mTOR and PDK1 in Dendritic and Mast Cells; Regulation von Kalium-Kanälen durch mTOR und PDK1 in Dendritischen und Mast-Zellen

Tyan, Leonid
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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Dendritic cells are antigen-presenting cells, central for the development of optimal T cell immunity, that are able to initiate primary immune responses and to establish immunological memory. Mast cells are tissue-based effector cells in allergic diseases, playing a central role in the propagation of IgE-dependent allergic reactions, such as allergic rhinitis, asthma, anaphylaxis and delayed hypersensitivity reactions. Upon stimulation of IgE receptors , mast cells release granules containing several mediators including histamine and cytokines, which regulate responses of other inflammatory cells. Dendritic and mast cell functions are regulated by phosphatidylinositol-3 (PI3) kinase signalling pathway.. The PI3 kinase is partially effective in dendritic and mast cells through alteration of their ion channel activity. Both PI3 kinase on the one hand and ion channels on the other hand are important for the regulation of mast and dendritic cell functions. However, little is known about downstream elements of the PI3 kinase that regulate ion channels in those cells. In the present project the question was addressed whether two PI3 kinase downstream targets, phosphoinositide-dependent kinase 1 (PDK1) and mammalian target of rapamycine (mTOR)...

‣ Dendritic cell density and activation status in human breast cancer - CD1a, CMRF-44, CMRF-56 and CD-83 expression

Coventry, B.; Lee, P.L.; Gibbs, D.; Hart, D.
Fonte: Churchill Livingstone Publicador: Churchill Livingstone
Tipo: Artigo de Revista Científica
Publicado em //2002 Português
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575.139%
Low CD1a-positive putative dendritic celt numbers in human breast cancer has recently been described and may explain the apparent 'poor immunogenicity' previously reported in breast cancer. Little attention has been given to dendritic cell activation within the tumour microenvironment, which is another reason why the in-situ immune response may be severely deficient. We have therefore examined CD1a expression as a marker for dendritic cells, together with CMRF-44 and -56 as markers of dendritic cell activation status, in 40 human breast cancers. The results demonstrate few or no CD1a-positive putative dendritic cells and minimal or no expression of the dendritic celt activation markers. Both dendritic cell number and dendritic cell activation appear substantially deficient in human breast cancers, regardless of turnout histological grade.; B.J. Coventry, P.-L. Lee, D. Gibbs and D.N.J. Hart; © Churchill Livingstone

‣ The Role of Stroma in Hematopoiesis and Dendritic Cell Development

Despars, Genevieve; Tan, Jonathan; Periasamy, Pravin; O'Neill, Helen
Fonte: Bentham Science Publishers Ltd Publicador: Bentham Science Publishers Ltd
Tipo: Artigo de Revista Científica
Português
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Development of the immune system is depicted as a hierarchical process of differentiation from hematopoietic stem cells (HSC) to lineage-committed precursors, which further develop into mature immune cells. In the case of dendritic cell (DC) development,

‣ Dendritic Cell Development in the Context of the Spleen Microenvironment

Tan, Jonathan; O'Neill, Helen
Fonte: AlphaMed Press Inc Publicador: AlphaMed Press Inc
Tipo: Artigo de Revista Científica
Português
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The dendritic cell (DC) population in spleen comprises a mixture of cells including endogenous DC progenitors, DC precursors migrating in from blood and bone marrow, and DC in different states of differentiation and activation. A role for different microe

‣ Computational Methods for Investigating Dendritic Cell Biology

de Oliveira Sales, Ana Paula
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2011 Português
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The immune system is constantly faced with the daunting task of protecting the host from a large number of ever-evolving pathogens. In vertebrates, the immune response results from the interplay of two cellular systems: the innate immunity and the adaptive immunity. In the past decades, dendritic cells have emerged as major players in the modulation of the immune response, being one of the primary links between these two branches of the immune system.

Dendritic cells are pathogen-sensing cells that alert the rest of the immune system of the presence of infection. The signals sent by dendritic cells result in the recruitment of the appropriate cell types and molecules required for effectively clearing the infection. A question of utmost importance in our understanding of the immune response and our ability to manipulate it in the development of vaccines and therapies is: "How do dendritic cells translate the various cues they perceive from the environment into different signals that specifically activate the appropriate parts of the immune system that result in an immune response streamlined to clear the given pathogen?"

Here we have developed computational and statistical methods aimed to address specific aspects of this question. In particular...

‣ Enhancing Dendritic Cell Migration to Drive Antitumor Responses

Batich, Kristen Anne
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2017 Português
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677.1645%

The histologic subtypes of malignant glial neoplasms range from anaplastic astrocytoma to the most deadly World Health Organization (WHO) Grade IV glioblastoma (GBM), the most common primary brain tumor in adults. Over the past 40 years, only modest advancements in the treatment of GBM tumors have been reached. Current therapies are predominantly for palliative endpoints rather than curative, although some treatment modalities have been shown to extend survival in particular cases. Patients undergoing current standard of care therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of 12-15 months, with less than 25% of patients surviving up to two years and fewer than 10% surviving up to five years. A variety of factors contribute to standard treatment failure, including highly invasive tumor grade at the time of diagnosis, the intrinsic resistance of glioma cells to radiation therapy, the frequent impracticality of maximal tumor resection of eloquent cortical structures, and the fragile intolerance of healthy brain for cytotoxic therapies. Treatment with immunotherapy is a potential answer to the aforementioned problems, as the immune system can be harnessed and educated to license rather potent antitumor responses in a highly specific and safe fashion. One of the most promising vehicles for immunotherapy is the use of dendritic cells...

‣ Dynamics of dendritic cell development from precursors maintained in stroma-dependant long-term cultures

Wilson, Heather; O'Neill, Helen
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
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Two distinct subsets of dendritic cells are produced within the non-adherent cell population of the stroma-dependent long-term culture system. These are the small subset containing dendritic cell precursors and their progeny, large long-term culture-dendritic cells, which resemble immature CD11c+CD11b+MHCIIloCD8α- dendritic cells. The replicative and developmental potential of cells produced in long-term culture were investigated as a model for production of dendritic cells from progenitors. Cell proliferation and apoptosis were examined by labelling with bromodeoxyuridine and Annexin-V, respectively. The developmental potential of cells was analysed following transfer on to stromal monolayers or into in vitro colony and transwell assays. Results demonstrate that small long-term culture-dendritic cells are stromal cell-dependent. In the absence of stroma, they become apoptotic and die. Furthermore, direct contact with stromal cells is necessary for the differentiation and proliferation of small precursor cells. The small cell subset contains no long-term self-renewing cells, but instead appears to contain cells committed to developing into large long-term culture dendritic cells. The large long-term culture dendritic cell subset also contains dividing cells. Survival of large long-term culture-dendritic cells is dependent on soluble stroma-derived factor(s) and not direct contact with the stromal layer. All data suggest that the long-term culture system supports dendritic cell development from a self-renewing progenitor population resident within the stroma that gives rise to committed dendritic cell precursors and immature dendritic cells.

‣ Murine dendritic cell development: Difficulties associated with subset analysis

Wilson, Heather; O'Neill, Helen
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
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Dendritic cells are bone marrow-derived professional antigen presenting cells that play major roles in both the induction of primary immune responses and tolerance. It has become clear that dendritic cells are a heterogenous group of cells that vary in cell surface marker expression and function. Multiple dendritic cell subsets have now been defined in mouse lymphoid organs and peripheral tissues. A knowledge of the function and relationship between dendritic cell subsets will be essential for understanding the regulation of immune homeostasis, immune responses and tolerance. While an increasing number of dendritic cell progenitors are being identified, the pathways that connect them remain unclear. In addition, it is unclear whether the functional divisions reflect maturation status, subset specialization or functional plasticity in response to specific pathogen and environmental signals. This review summarizes the current knowledge about the function and lineage relationship of dendritic cell subsets. It also discusses some of the difficulties associated with dendritic cell subset analysis.

‣ Molecular definition of an in vitro niche for dendritic cell development

Despars, Genevieve; Ni, Keping; Bouchard, Antoine; O'Neill, Terence; O'Neill, Helen
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Português
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666.4411%
Although dendritic cell (DC) precursors have been isolated from many lymphoid sites, the regulation and location of early DC development is still poorly understood. Here we describe a splenic microenvironment that supports DC hematopoiesis in vitro and identify gene expression specific for that niche. The DC supportive function of the STX3 splenic stroma and the lymph node-derived 2RL22 stroma for overlaid bone marrow cells was assessed by coculture over 2 weeks. The DC supportive function of SXT3 was identified in terms of specific gene expression in STX3 and not 2RL22 using Affymetrix microchips. STX3 supports DC differentiation from overlaid bone marrow precursors while 2RL22 does not. A dataset of 154 genes specifically expressed in STX3 and not 2RL22 was retrieved from Affymetrix results. Functional annotation has led to selection of 26 genes as candidate regulators of the microenvironment supporting DC hematopoiesis. Specific expression of 14 of these genes in STX3 and not 2RL22 was confirmed by reverse transcription-polymerase chain reaction. Some genes specifically expressed in STX3 have been previously associated with hematopoietic stem cell niches. A high proportion of genes encode growth factors distinct from those commonly used for in vitro development of DC from precursors. Potential regulators of a DC microenvironment include genes involved in angiogenesis...

‣ Cell-intrinsic effects of non-MHC NOD genes on dendritic cell generation in vivo

Prasad, S; Goodnow, Christopher
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Genes outside the MHC create a general susceptibility to autoimmunity in non-obese diabetic (NOD) mice. Here we describe marked differences in dendritic cell generation in vivo, caused by non-MHC NOD genes. Analyses of splenic dendritic cells from the autoimmunity-prone NOD.H-2k mice revealed a relative over-representation of the CD8α- subsets, in contrast to the level of these subsets observed in the autoimmunity-resistant B10.H-2k congenic strain or other H-2k strains. The imbalance towards CD8α- dendritic cells was selectively manifested by NOD.H-2k-derived cells in radiation chimeras reconstituted with equal mixtures of NOD.H-2k and B10.H-2k bone marrow cells. In addition to the cell-intrinsic imbalance in dendritic cell subsets, the myeloid lineage overall was intrinsically altered by NOD genes, as this lineage was disproportionately derived from the NOD.H-2k donor in mixed chimeras. These results identify a striking effect of non-MHC NOD genes upon the balance of dendritic cell subsets that may contribute to the generalized defects in self-tolerance in the NOD strain.

‣ Proliferation of dendritic cell progenitors in long term culture is not dependent on granulocyte macrophage-colony stimulating factor

Wilson, Heather; Ni, Keping; O'Neill, Helen
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Português
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574.7529%
A unique long term culture (LTC) system has been developed which supports the production of dendritic cells (DC). Cell production is dependent on a stromal cell layer derived from murine spleen. This LTC system produces a high turnover of non-adherent cells that express DC morphology, cell- surface markers, and antigen-presenting capacity. Objective The long term production of these cells suggests that the LTC system supports hemopoiesis. It was of interest to examine the number and nature of hemopoietic progenitors present in LTC. Materials and Methods A combination of approaches, including FACS analysis, spleen colony-forming unit assays, and in vitro colony assays were undertaken. Results Pluripotent haemopoietic stem cells are not detectable among the non-adherent cell population produced in LTC. Instead, LTC support a replicating c-kit+ progenitor population, which generates only dendritic-like colonies in in vitro colony assays. In addition, this population does not respond to combinations of growth factors thought to stimulate DC proliferation, including granulocyte macrophage- colony stimulating factor (GM-CSF) and Flt3L. Production of DC occurs only in the presence of LTC-derived culture supernatant or a confluent stromal cell layer. Conclusions These results suggest that LTC contain a dendritic progenitor that is dependent upon the stromal cell network for proliferation and differentiation. The development of only DC within LTC allows easy collection of cells for experimentation. This...

‣ Intrinsic in vitro abnormalities in dendritic cell generation caused by non-MHC non-obese diabetic genes

Prasad, S; Goodnow, Christopher
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
676.4794%
Genes outside the MHC create a general susceptibility to autoimmunity in non-obese diabetic (NOD) mice. In this study, we describe marked differences in dendritic cell generation, in vitro, caused by non-MHC NOD genes. Bone marrow cells from NOD.H-2k mice cultured in vitro with GM-CSF and IL-4 generated a reduced yield of dendritic cells when compared to bone marrow cells from B10.H-2k mice. This was due to failure to pass through successive rounds of cell division and elevated levels of apoptosis in NOD.H-2k precursor cells. This aberrant response to GM-CSF and IL-4 was unique to the NOD.H-2k background when compared to bone marrow cells from other H-2k congenic strains, and coculture experiments showed that it was cell-autonomous. Overall, the results described in this study demonstrate a striking effect of non-MHC NOD genes on dendritic cell generation from myeloid precursors derived from the NOD.H-2k strain. These results identify a useful genetic model to explore the regulation of dendritic cell formation. Conceivably, the dysregulation of the dendritic cell system described here may contribute to the generalized defects in self-tolerance in the NOD strain.