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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD34+ precursors in normal human bone marrow (BM) generate large numbers of dendritic cells alongside macrophages and granulocytic precursors when cultured for 12 to 14 days in c-kit ligand, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha). This study reports an intermediate cell type that develops by day 6, and has the potential to differentiate into either macrophages or dendritic cells. When the d6 progeny are depleted of mature macrophages and residual CD34+ precursors, a discrete CD14+ HLA-DR+ population persists in addition to immunostimulatory CD14- HLA-DR() dendritic cells. Half of the CD14+ HLA-DR+ population is in cell cycle (Ki-67+), but colony-forming units (CFUs) are no longer detectable. The calls are c-fms+, but lack myeloperoxidase and nonspecific esterase. They also possess substantial phagocytic and allostimulatory activity. These post-CFU, CD14+ HLA-DR+ intermediates develop into typical macrophages when recultured in the absence of exogenous cytokines. M-CSF supports up to approximately 2.5-fold expansion of macrophage progeny. In contrast, the combination of GM-CSF and TNF-alpha supports quantitative differentiation into dendritic cells, lacking c-fms, CD14, and other macrophage properties, and expressing HLA-DR, CD1a, CD83, CD80, CD86, and potent allostimulatory activity. Therefore, normal CD34+ BM precursors can generate a post-CFU bipotential intermediate in the presence of c-kit ligand, GM-CSF, and TNF-alpha. This intermediate cell type will develop along the dendritic cell pathway when macrophages are removed and GM-CSF and TNF-alpha are provided. Alternatively, it can differentiate along a macrophage pathway when recultured with or without M-CSF.
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PMID:Dendritic cells and macrophages can mature independently from a human bone marrow-derived, post-colony-forming unit intermediate. 863 19

Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
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PMID:Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. 892 Aug 82

We describe here that lineage phenotype- negative (Lin)(-)c-kit(+) hematopoietic progenitor cells (HPCs) from day 13 postcoitus (dpc) murine fetal liver (FL) can generate dendritic cell (DC) precursors when cultured in vitro in the presence of PA6 stromal cells plus granulocyte/macrophage colony-stimulating factor (GM-CSF) + stem cell factor (SCF) + Flt3 ligand (Flt3L) for 12 to 14 days, and develop into mature DCs when stimulated with GM-CSF plus mouse tumor necrosis factor alpha (mTNFalpha) for an additional 3 to 5 days. A transwell culture system showed that the generation of DC precursors depended on the support of PA6 cell-secreted soluble factor(s). The mature DCs derived from 13 dpc FL Lin(-)c-kit(+) HPCs showed characteristic morphology and function of DCs and expressed high levels of Ia, CD86, and CD40 molecules, low levels of DEC205, E-cadherin, and F4/80 molecules, but barely detectable CD11c antigen. Once FL-derived HPCs were cultured without GM-CSF, NK1.1(+) cells developed in the presence of PA6 cells + SCF + Flt3L. These NK1.1(+) cells could develop into DC precursors at an earlier stage of differentiation by reculturing with PA6 cells + SCF + Flt3L + GM-CSF, but they would be irreversibly committed to NK cell precursors without GM-CSF after 3 days, suggesting that GM-CSF plays a critical role in controlling the transition of DC and NK cell precursors from 13 dpc FL-derived Lin(-)c-kit(+) HPCs. This study represents the first success in generating mature DCs in vitro from murine FL HPCs. (Blood. 2000;95:138-146)
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PMID:Development of dendritic cells in vitro from murine fetal liver-derived lineage phenotype-negative c-kit(+) hematopoietic progenitor cells. 1060 96

Dendritic cells (DCs) are powerful antigen-presenting cells. Because DCs are rare cells, methods to produce them in vitro are valuable ways to study their biologic properties and to generate cells for immunotherapy. This study defines the antigen-presenting properties of DCs generated in vitro from CD34+ cells of patients with breast cancer. The combination of cytokines flt3 ligand + c-kit ligand + granulocyte-macrophage colony-stimulating factor (GM-CSF) + interleukin-4 (IL-4) + tumor necrosis factor-alpha (TNF-alpha) was used to maximize the output of mature DCs in the culture of CD34+ cells while minimizing the production of monocytes. Cells grew and differentiated into DCs as measured by a time-dependent upregulation of cell surface antigens major histocompatibility complex class II, CD1a, CD80, CD86, CD40, and CD4, so that 40% +/- 9% (n = 6) of cells in culture at day 15 were CD1a+CD14-. Markers were acquired in the same sequence as on monocytes induced to differentiate with GM-CSF + IL-4. Differentiation was marked by a time-dependent increase in allostimulatory function, which, at its peak, was more potent than in cultures of DCs generated from monocytes with GM-CSF + IL-4, but was comparable on a cell-to-cell basis to that of mature monocytes cultured in flt3-ligand + c-kit-ligand + GM-CSF + IL-4 + TNF-alpha. Both CD34+ cell-derived and monocyte-derived DCs were able to process and to present tetanus toxoid and keyhole limpet hemocyanin to autologous T cells and to present major histocompatibility class I-binding peptides to CD8+ cytotoxic T lymphocytes inducing interferon-gamma production. Altogether, these results suggest that DCs generated from CD34+ cells of patients with breast cancer with flt3 ligand, c-kit ligand, GM-CSF, IL-4, and TNF-alpha are competent antigen-presenting cells, particularly for CD8+ cytotoxic T lymphocytes, and resemble mature monocyte-derived DCs in the assays described here.
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PMID:Dendritic cells generated from CD34+ progenitor cells with flt3 ligand, c-kit ligand, GM-CSF, IL-4, and TNF-alpha are functional antigen-presenting cells resembling mature monocyte-derived dendritic cells. 1068 37

Dendritic cells (DC) are produced continuously by a unique, long-term culture (LTC) system in which hemopoiesis is supported by a splenic stromal cell layer in the absence of added growth factors. Flow cytometric analysis reveals the production of two distinct cell subsets. The more predominant large-cell subset resembles highly endocytic DC that are large, granular, and possess membrane extensions. They also express high levels of the DC markers CD11c, CD11b, DEC-205, and CD80 on their cell surface. They do not resemble mature DC because they express low levels of MHC type II and CD86 molecules, as well as c-kit and Fc receptor (FcR). These are known characteristics of immature DC. Small cells are smaller and less granular than large cells, with negative to low expression of CD11c, DEC-205, and CD86. A majority of small cells express varying levels of CD11b and CD80. Subpopulations of small cells express low levels of c-kit, FcR, and MHC type II, and only a 20% subpopulation is weakly endocytic. Upon transfer to an irradiated stromal layer, cells within the small subset proliferate and differentiate to resemble the large cells in size, complexity, membrane extensions, and CD11c and CD86 expression. The two cell subsets produced in LTC are developmentally linked, with the heterogeneous small-cell subset containing progenitors of the larger homogeneous, immature DC subset. LTC represent a valuable model system for studying DC development from hemopoietic progenitors.
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PMID:Identification of progenitor cells in long-term spleen stromal cultures that produce immature dendritic cells. 1075 64

Dendritic cells (DCs) are crucial components of the immune system because of their unique ability as antigen-presenting cells for the initiation of a primary immune response. DCs, macrophages (Ms) and granulocytes (Gs) are believed to originate from a common myeloid progenitor cell. However, little is known about the molecular mechanisms leading to DC sublineage commitment. To establish a cell system that allows the molecular and biochemical analysis of DC differentiation and activation, we used the murine non-leukaemic, multipotential stem cell line FDCP-mix. FDCP-mix cells were cultured in various amounts of GM-colony stimulating factor (CSF) and interleukin (IL)-4 for up to 16 d and analysed for morphology, expression of CD34, c-kit, Gr-1, Mac-1, CD40, MHC-I, MHC-II and co-stimulatory molecules (CD80, CD86) using flow cytometry, and for their capacity to present foreign antigen to autologous T cells. Up to d 7, the majority of FDCP-mix cells consisted of cells differentiating along the G and M lineage. Thereafter, the number of dendritic cells increased until d 13. Differentiation along the DC lineage vs. the G and M lineage was favoured when FDCP-mix cells were cultured in high concentration GM-CSF (500 U/ml) throughout the culture and IL-4 from d 9 onwards. The dendritic cells generated from FDCP-mix cells were large, non-adherent cells with veiled processes and expressed MHC II, CD40, CD80 and CD86. After pulsing with a foreign antigen (keyhole limpet haemocyanin), FDCP-mix-derived dendritic cells stimulated [(3)H]-thymidine incorporation of naive T-cells in an autologous mixed lymphocyte reaction (MLR). Our results show that functionally mature dendritic cells are generated from the multipotential stem cell line FDCP-mix. This cell line thus provides the unique possibility of establishing multipotential transgenic cell lines capable of differentiation along the DC lineage. The experimental system described here should prove a valuable tool for studying DC differentiation and function.
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PMID:Generation of functionally mature dendritic cells from the multipotential stem cell line FDCP-mix. 1112 52

We tried to efficiently generate human dendritic cells (DCs) from CD34+ peripheral blood hematopoietic progenitor cells mobilized by high-dose chemotherapy and subsequent administration of granulocyte colony-stimulating factor, using a liquid suspension culture system. Among various combinations, the combination of c-kit ligand, flt-3 ligand, c-mpl ligand (TPO), and interleukin (IL)-4 most potently generated the number of CD1a+CD14- DCs in cultures containing granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha). The delayed addition of IL-4 on day 6 of culture gave rise to an additional increase in the yield of CD1a+CD14-DCs that were characterized by the expression of HLA-ABC, HLA-DR, CD80, CD86, and CD83. The majority of the sorted CD1a-CD14+ cells derived from 6-day culture of CD34+ cells gave rise to CD1a+CD14- DCs and CD1a-CD14+ macrophages on day 12 of culture in the presence and absence of IL-4, respectively. These findings suggest that IL-4 promotes the differentiation of CD1a- CD14+ cells derived from mobilized CD34+ peripheral blood hematopoietic progenitors to CD1a+ CD14- DCs. The majority of these DCs expressed CD68 but not the Langerhans-associated granule antigen, a finding that suggests they emerge through the monocyte differentiation pathway. The addition of TPO and IL-4 to cultures did not affect the potential of DCs to stimulate the primary allogeneic T-cell response. These findings demonstrated that the combination of c-kit ligand plus flt-3 ligand plus TPO with GM-CSF plus TNF-alpha, followed by IL-4, is useful for ex vivo generation of human DCs from mobilized CD34+ peripheral blood progenitors.
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PMID:Efficient ex vivo generation of human dendritic cells from mobilized CD34+ peripheral blood progenitors. 1172 65

In cultures, and in tissues as well, Hodgkin's and Reed-Sternberg (H-RS) cells and anaplastic large cell lymphoma (ALCL) cells are known to express a variety of cytokines, including IL-1, -5, -6, -8, -9, TNF-alpha, GM-CSF, M-CSF, TGF-beta, CD70, CD80, and CD86. Various numbers of H-RS/ALCL cells may express cytokine receptors (R), such as CD30, CD40, IL-2R (CD25/CD122), IL-6R (CD126), IL-7R (CD127), TNF-R (CD120), TGF-beta-R (CD 105/endoglin), M-CSF-R (CD115), and SCF-R (CD117/c-kit receptor). All of these cytokines and cytokine receptors are implicated in the growth regulation of H-RS/ALCL cells, the histopathologic alterations in tissues, and the clinical manifestations in patients with Hodgkin's disease (HD) or ALCL. Many of these cytokines or cytokine receptors also play an important role in the pathogenesis of other types of lymphomas. In this review, we describe the cytokine or cytokine-receptor expression that is diacritic for H-RS/ALCL cells. The identification of such unique cytokine-cytokine receptor interactions is likely to explain the biologic property that distinguishes HD/ALCL from other types of lymphomas. These interactions include those of CD30L-CD30, CD40L-CD40, CD70-CD27, CD80/CD86- CD28, SCF-CD117, IL-9-IL-9R, and IL-7-IL-7R. The H-RS/ALCL cells express IL-9 and two cytokine receptors, CD30 and CD117, which are observed infrequently in NHLs. Although IL-7 expression is not restricted to H-RS/ALCL cells, the expression of IL-7 in conjunction with IL-9 and/or CD117 may be regarded as unique for HD/ALCL because of an unusual combination and a synergistic activity among these cytokines. The expression of CD70 and CD80/CD86 (as cytokines) may exert a unique effect in HD because of intimate contact between H-RS cells and CD27/CD28-positive T cells. The expression of these costimulators (CD70 and CD80/CD86) and other adhesion/constimulator molecules such as CD54 and CD58, along with the secretion of soluble cytokines such as IL-1, IL-6, IL-7, or TNFs by H-RS/ALCL cells, could result in the profound T-cell proliferation often seen in lymph nodes involved by HD and some ALCL. On the other hand, the expression of CD30L and CD40L by surrounding T cells may affect the proliferation of H-RS/ALCL cells. The cytokine-cytokine receptor interaction between H-RS cells and T cells via direct cell-cell contact is bidirectional, a situation not commonly seen in NHLs. Copyright 1995 S. Karger AG, Basel
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PMID:Hodgkin's Disease and Anaplastic Large Cell Lymphoma Revisited. 1. unique cytokine and cytokine receptor profile distinguished from that of non-hodgkin's lymphomas. 1172 67

The true identity of Hodgkin's mononuclear cells and Reed-Sternberg (H-RS) cells has been a subject of controversy for decades. Those who believe that Hodgkin's disease (HD) is a heterogeneous disease may consider it to constitute lymphomas of various origins. However, this theory seems incompatible with the finding of similar phenotypic, biologic, and immunologic properties among most HD. We believe that, in the majority of cases, HD, except for LP and some LD-type HD, is a homogeneous disease despite differences in the degree of fibrosis and/or cellular reaction. The heterogeneity in cellular reactions is a result of secretion of various cytokines by H-RS cells, which may or may not be influenced by the presence of EBV. H-RS cells, and anaplastic large cell lymphoma (ALCL) cells as well, can express a combination of cytokines and cytokine receptors that is not seen in other types of lymphomas. The unique cytokine/receptor profile (e.g. the expression of c-kit-R/CD117), along with various properties associated with H-RS/ALCL cells, leads to a hypothesis that H-RS/ALCL cells are related to similar lymphohematopoietic progenitor cells with different etiologies and somewhat limited differentiation capacity. A number of H-RS cells may differentiate with limited capacity along the B-cell pathway and may be infected by EBV, which further complicates the biologic and immunologic properties of these cells. The majority of H-RS cells may also, however, differentiate along the antigen-presenting dendritic cell pathway, as indicated by the abundant expression of restin, CD15, CD40, CD54, CD58, CD80, and CD86. The majority of ALCL cells clearly differentiate to T cells, but some may acquire B-cell or histiocyte phenotypes. The progenitor cell hypothesis may explain (1) the variable expression of CD117, CD43, and CD34 as well as the absence of CD27, CD45 and CD45RA in H-RS cells; (2) the inconsistent and irregular patterns of phenotype and genotype and the various, often very limited, degrees of differentiation among these two types of lymphoma cells; (3) the existence of secondary HD or ALCL associated with rare types of lymphomas or leukemias, or vice versa; (4) the absence of recombinase and of the B-specific transcription factors BSAP; and (5) the frequent expression of IL-7 and IL-9 in H-RS cells. Copyright 1996 S. Karger AG, Basel
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PMID:Hodgkin's Disease and Anaplastic Large Cell Lymphoma Revisited. ii. from cytokines to cell lineage. 1172 77

Bone marrow contains a population of rare progenitor cells capable of differentiating into osteoblasts, chondrocytes, adipocytes, myoblasts, and hematopoiesis-supporting stromal cells. These cells, referred to as mesenchymal progenitor cells (MPCs), can be purified and culture-expanded from animals and humans. Using bone-marrow-conditioned medium combined with basic fibroblast growth factor, we cultured a relatively homogeneous population of MPCs from murine bone marrow, which uniformly expressed stem cell antigen-1, CD29, CD44, c-kit, and CD105, while being negative for expression of CD45, CD31, and CD34. In vitro differentiation assays showed the tripotential differentiation capacities of these cells toward adipogenic, osteogenic, and chondrogenic lineages. Most importantly, immunophenotypic analyses demonstrated that MPCs did not express major histocompatibility complex class II molecules or the T-cell costimulatory molecules CD80 and CD86, consistent with further investigation showing that MPCs failed to elicit a proliferative response from allogeneic lymphocytes. Moreover, when allogeneic or third-party MPCs were added to T cells stimulated by allogeneic lymphocytes or the potent T-cell mitogen concanavalin-A, a significant reduction in T-cell proliferation was observed. In conclusion, our data demonstrate that we successfully isolated and culture-expanded a relatively homogeneous population of MPCs from adult murine bone marrow. Additionally, these primary cells could suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. This immunoregulatory feature of MPCs strongly implies that they may have potential applications in allograft transplantation.
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PMID:Isolation of mouse marrow mesenchymal progenitors by a novel and reliable method. 1296 7


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