Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06126 (CD1a)
 2,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a recently described serum-free culture system of purified human CD34+ progenitor cells, we show here a critical cooperation of flt3 ligand (FL) with transforming growth factor-beta1 (TGF-beta1) in the induction of in vitro dendritic cell/Langerhans cell (DC/LC) development. The addition of FL to serum-free cultures of CD34+ cells supplemented with TGF-beta1, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and stem cell factor strongly increases both percentages (mean, 36% +/- 5% v 64% +/- 4%; P = .001) and total numbers (4.4- +/- 0.8-fold) of CD1a+ dendritic cells. These in vitro-generated CD1a+ cells molecularly closely resemble a particular type of DC known as an epidermal Langerhans cell. Generation of DC under serum-free conditions was found to strictly require supplementation of culture medium with TGF-beta1. Upon omission of TGF-beta1, percentages of CD1a+ DC decreased (to mean, 10% +/- 8%; P = .001) and, in turn, percentages of granulomonocytic cells (CD1a- cells that are lysozyme [LZ+]; myeloperoxidase [MPO+]; CD14+) increased approximately threefold (P < .05). Furthermore, in the absence of TGF-beta1, FL consistently promotes generation of LZ+, MPO+, and CD14+ cells, but not of CD1a+ cells. Serum-free single-cell cultures set up under identical TGF-beta1- and FL-supplemented culture conditions showed that high percentages of CD34+ cells (mean, 18% +/- 2%; n = 4) give rise to day-10 DC colony formation. The majority of cells in these DC-containing colonies expressed the Langerhans cell/Birbeck granule specific marker molecule Lag. Without TGF-beta1 supplementation, Lag+ colony formation is minimal and formation of monocyte/macrophage-containing colonies predominates. Total cloning efficiency in the absence and presence of TGF-beta1 is virtually identical (mean, 41% +/- 6% v 41% +/- 4%). Thus, FL has the potential to strongly stimulate DC/LC generation, but has a strict requirement for TGF-beta1 to show this costimulatory effect.
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PMID:flt3 ligand in cooperation with transforming growth factor-beta1 potentiates in vitro development of Langerhans-type dendritic cells and allows single-cell dendritic cell cluster formation under serum-free conditions. 926 60

The ability to generate dendritic cells (DCs) in sizeable numbers has enormous implications for the development of clinically-effective antigen presentation procedures for cancer immunotherapy. We evaluated the generation of immunostimulatory DCs from peripheral blood CD34+ cells collected from healthy donors. CD34+ cells purified from leukapheresis product were seeded at 1 x 10(4) cells/mL in complete medium supplemented with GM-CSF, TNF alpha, IL-4, c-kit ligand, and flt3 ligand (FL). By day 14 of culture in the presence of GM-CSF + TNF alpha, the total cell number increased by 23.4 +/- 5.4-fold compared to the starting number of CD34+ cells. When the c-kit and FL were added to GM-CSF and TNF alpha, the cell number increased by 109.8 +/- 11.2-fold without affecting the immunophenotype of recovered cells. Flow cytometric analysis indicated that cells with the markers of mature dendritic cells, i.e., CD1a +CD14 -HLA-DR+, and CD80+CD86+HLA-DR+, constituted 49.0% +/- 7.5%, and 38.9% +/- 6.5%, respectively. This pattern of expression of surface antigen was unchanged whether the c-kit ligand and/or FL was added. The irradiated CD1a+HLA-DR+ cells recovered from in vitro cultures elicit a vigorous proliferation of allogeneic peripheral blood T-cells, irrespective of cytokine combinations. These findings provide advantageous tools for the large-scale generation of DCs that are potentially usable for clinical protocols of immunotherapy or vaccination in patients undergoing cancer treatment.
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PMID:Ex vivo generation of functional dendritic cells from mobilized CD34+ hematopoietic stem cells. 975 99

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

Epithelial Langerhans cells (LC) represent immature dendritic cells that require TGF-beta 1 stimulation for their development. Little is known about the mechanisms regulating LC generation from their precursor cells. We demonstrate here that LC development from human CD34+ hemopoietic progenitor cells in response to TGF-beta 1 costimulation (basic cytokine combination GM-CSF plus TNF-alpha, stem cell factor, and Flt3 ligand) is associated with pronounced cell cluster formation of developing LC precursor cells. This cell-clustering phenomenon requires hemopoietic progenitor cell differentiation, since it is first seen on day 4 after culture initiation of CD34+ cells. Cell cluster formation morphologically indicates progenitor cell development along the LC pathway, because parallel cultures set up in the absence of exogenous TGF-beta 1 fail to form cell clusters and predominantly give rise to monocyte, but not LC, development (CD1a-, lysozyme+, CD14+). TGF-beta 1 costimulation of CD34+ cells induces neoexpression of the homophilic adhesion molecule E-cadherin in the absence of the E-cadherin heteroligand CD103. Addition of anti-E-cadherin mAb or mAbs to any of the constitutively expressed adhesion molecule (CD99, CD31, LFA-1, or CD18) to TGF-beta 1-supplemented progenitor cell cultures inhibits LC precursor cell cluster formation, and this effect is, with the exception of anti-E-cadherin mAb, associated with inhibition of LC generation. Addition of anti-E-cadherin mAb to the culture allows cell cluster-independent generation of LC from CD34+ cells. Thus, functional E-cadherin expression and homotypic cell cluster formation represent a regular response of LC precursor cells to TGF-beta 1 stimulation, and cytoadhesive interactions may modulate LC differentiation from hemopoietic progenitor cells.
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PMID:Functional involvement of E-cadherin in TGF-beta 1-induced cell cluster formation of in vitro developing human Langerhans-type dendritic cells. 1090 41

To better characterize human dendritic cells (DCs) that originate from lymphoid progenitors, the authors examined the DC differentiation pathways from a novel CD7(+)CD45RA(+) progenitor population found among cord blood CD34(+) cells. Unlike CD7(-)CD45RA(+) and CD7(+)CD45RA(-) progenitors, this population displayed high natural killer (NK) cell differentiation capacity when cultured with stem cell factor (SCF), interleukin (IL)-2, IL-7, and IL-15, attesting to its lymphoid potential. In cultures with SCF, Flt3 ligand (FL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-alpha (standard condition), CD7(+)CD45RA(+) progenitors expanded less (37- vs 155-fold) but yielded 2-fold higher CD1a(+) DC percentages than CD7(-)CD45RA(+) or CD7(+)CD45RA(-) progenitors. As reported for CD34(+)CD1a(-) thymocytes, cloning experiments demonstrated that CD7(+)CD45RA(+) cells comprised bipotent NK/DC progenitors. DCs differentiated from CD7(-)CD45RA(+) and CD7(+)CD45RA(+) progenitors differed as to E-cadherin CD123, CD116, and CD127 expression, but none of these was really discriminant. Only CD7(+)CD45RA(+) or thymic progenitors differentiated into Lag(+)S100(+) Langerhans cells in the absence of exogenous transforming growth factor (TGF)-beta 1. Analysis of the DC differentiation pathways showed that CD7(+)CD45RA(+) progenitors generated CD1a(+)CD14(-) precursors that were macrophage-colony stimulating factor (M-CSF) resistant and CD1a(-)CD14(+) precursors that readily differentiated into DCs under the standard condition. Accordingly, CD7(+)CD45RA(+) progenitor-derived mature DCs produced 2- to 4-fold more IL-6, IL-12, and TNF-alpha on CD40 ligation and elicited 3- to 6-fold higher allogeneic T-lymphocyte reactivity than CD7(-)CD45RA(+) progenitor-derived DCs. Altogether, these findings provide evidence that the DCs that differentiate from cord blood CD34(+)CD7(+)CD45RA(+) progenitors represent an original population for their developmental pathways and function. (Blood. 2000;96:3748-3756)
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PMID:Characterization of dendritic cell differentiation pathways from cord blood CD34(+)CD7(+)CD45RA(+) hematopoietic progenitor cells. 1109 56

The generation of erythroid, myeloid, and lymphoid cells from human fetal liver progenitors was studied in colony-forming cell (CFC) assays. CD38(-) and CD38(+) progenitors that expressed high levels of CD34 were grown in serum-deprived medium supplemented with kit ligand, flk2/flt3 ligand, GM-CSF, c-mpl ligand, erythropoietin, and IL-15. The resulting colonies were individually analyzed by flow cytometry. CD56(+) NK cells were detected in 21.9 and 9.9% of colonies grown from CD38(-) and CD38(+) progenitors, respectively. NK cells were detected in mostly large CD14(+)/CD15(+) myeloid colonies that also, in some cases, contained red cells. NK cells were rarely detected in erythroid colonies, suggesting an early split between the erythroid and the NK cell lineages. CD1a(+) dendritic cells were also present in three-quarters of the colonies grown from CD38(-) and CD38(+) progenitors. Multilineage colonies containing erythrocytes, myeloid cells, and NK cells were present in 13.7 and 2.7% of colonies grown from CD38(-) and CD38(+) progenitors, respectively. High proliferative-potential CFCs that generated multilineage colonies were also detected among both populations of progenitors. The total number of high proliferative-potential CFCs with erythroid, myeloid, and NK cell potential was estimated to be 2-fold higher in the CD38(+) fraction compared with the CD38(-) fraction because of the higher frequency of CD38(+) cells among CD34(++) cells. The broad distribution of multipotent CFCs among CD38(-) and CD38(+) progenitors suggests that the segregation of the erythroid, myeloid, and lymphoid lineages may not always be an early event in hemopoiesis. Alternatively, some stem cells may be present among CD38(+) cells.
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PMID:Broad distribution of colony-forming cells with erythroid, myeloid, dendritic cell, and NK cell potential among CD34(++) fetal liver cells. 1167 95

Genetically modified dendritic cells (DCs) with Th1 type cytokine genes are useful for activating anti-tumor immune response. We made human interleukin (IL)-12 p70 gene-transduced DCs generated from CD34+ progenitor cells using a retrovirus system and investigated the function of IL-12-producing DCs. We used the pMX retroviral vector and made cytokine gene-containing viral vectors referred to as GFP pMX and hIL-12 pMX. Supernatants from BOSC23 cells transfected with GFP pMX and hIL-12 pMX were harvested and used for transfection of DC. Cord blood CD34+ cells were incubated with supernatants containing retrovirus for 48 h with cytokines such as IL-3, IL-6, SCF, Flt3 ligand (FL), bFGF and IGF-I. The cells were cultured for 12 days in the presence of GM-CSF, SCF, FL, IL-4 and TNF-alpha to get mature DC-enriched population. Analysis of surface marker on DCs and allogeneic MLR assay were also performed. After a 14-day culture, 60-70% of cultured CD34+ cells were DC marker (CD1a, DEC205) positive. The IL-12 p70 protein levels in supernatant of DC-GFP and DC-hIL-12 were 0.2 ng/ml and 53 ng/ml/5 x 10(5) DCs for 72 h, respectively. The addition of CH296 fibronectin fragment (FN) increased 3-fold IL-12 gene transduction efficiency into DCs. MLR assay showed that IL-12-producing DC exhibited more potent T cell growth-stimulating activity compared with GFP-DC. These results suggested that genetically modified CD34+ cell-derived DCs with human IL-12 gene are fully efficient in T cell priming, and could be a good tool for effective cancer immunotherapy.
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PMID:Retroviral-mediated IL-12 gene transduction into human CD34+ cell-derived dendritic cells. 1216 93

Dendritic cells (DCs) are the most potent antigen-presenting cells in terms of initiating primary T-cell-dependent immune responses. We devised a 2-step culture method for obtaining sufficient numbers of functional DCs from umbilical cord blood (CB) CD34+ cells. In the first step, CB CD34+ cells were expanded by stimulation with early-acting cytokines such as stem cell factor (SCF), flt3 ligand (FL), and thrombopoietin (TPO) to amplify the hematopoietic progenitor cells. In the second step, granulocyte-macrophage colony-stimulating factor and interleukin 4 were added, and incubation was continued for another 5 days to induce differentiation of the expanded cells into DCs. During the first step of culturing with TPO, SCF, and FL, the total numbers of nucleated cells gradually increased, peaking at 4 weeks (245.3-fold). During the second step, expression of CD1a, CD83, and CD86 increased. Electron microscopic findings showed that these cells had cytosolic expansion to form dendrites and major histocompatibility complex class II compartments, which are characteristic of DCs. Functional analyses revealed that these cells had phagocytic activity and were capable of stimulating allogeneic T-cells in vitro.
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PMID:In vitro generation of functional dendritic cells from human umbilical cord blood CD34+ cells by a 2-step culture method. 1554 Sep 5

Interleukin (IL)-6 plays pleiotropic roles in human hematopoiesis and immune responses by acting on not only the IL-6 receptor-alpha subunit (IL-6Ralpha)(+) but also IL-6Ralpha(-) hematopoietic progenitors via soluble IL-6R. The Notch ligand Delta-1 has been identified as an important modulator of the differentiation and proliferation of human hematopoietic progenitors. Here, it was investigated whether these actions of IL-6 are influenced by Delta-1. When CD34(+)CD38(-) hematopoietic progenitors were cultured with stem cell factor, flt3 ligand, thrombopoietin and IL-3, Delta-1, in combination with the IL-6R/IL-6 fusion protein FP6, increased the generation of glycophorin A(+) erythroid cells but counteracted the effects of IL-6 and FP6 on the generation of CD14(+) monocytic and CD15(+) granulocytic cells. Although freshly isolated CD34(+)CD38(-) cells expressed no or only low levels of IL-6Ralpha, its expression was increased in myeloid progenitors after culture but remained negative in erythroid progenitors. It was found that Delta-1 acted in synergy with FP6 to enhance the generation of erythroid cells from the IL-6Ralpha(-) erythroid progenitors. In contrast, Delta-1 antagonized the effects of IL-6 and FP6 on the development of monocytic and granulocytic cells, as well as CD14(-)CD1a(+) dendritic cells, from the IL-6Ralpha(+) myeloid progenitors. These results indicate that Delta-1 interacts differentially with gp130 activation in IL-6Ralpha(-) erythroid and IL-6Ralpha(+) myeloid progenitors. The present data suggest a divergent interaction between Delta-1 and gp130 activation in human hematopoiesis.
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PMID:Notch ligand Delta-1 differentially modulates the effects of gp130 activation on interleukin-6 receptor alpha-positive and -negative human hematopoietic progenitors. 1764 74

Increasing evidence includes Wnt proteins inside the group of master-signaling pathways that govern immune and nonimmune differentiation systems, fundamental for normal development and homeostasis. Although their precise functions in bone marrow and thymus are still controversial, numerous studies have shown that Wnt signaling is able to control the proliferation of hematopoietic stem cells and thymic progenitors and might also affect their cell-fate decisions and subsequent maturation. In the present work, we analyze the effect of transient stimulation of the canonical Wnt pathway in the differentiation potential of Lin(-)CD34(+) CD1a(-) human thymic progenitors, a multipotent and heterogeneous cell population that has the capacity to develop into T cells, NK cells, monocytes, cDC, and pDC. Our results demonstrate that giving a boost to canonical Wnt signaling, triggered by transient exposure to Wnt3a or LiCl, the differentiation capacity of thymic progenitors changes, enhancing NK cell production. On the contrary, Wnt3a- or LiCl-pretreated thymic progenitors generate a significantly lower number of myeloid lineage cells, monocytes, and cDC and exhibit a reduced capacity to differentiate into pDC lineage. As a possible mechanism for this effect, we show that Wnt3a- and LiCl-pretreated progenitors change their membrane levels of receptors for cytokines pivotal for their expansion and differentiation, such as Flt3L. Moreover, canonical Wnt pathway stimulation modifies the transcription factor profile of CD34(+)CD1(-) thymocytes, increasing Hes-1 and ID3 expression levels.
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PMID:Transient beta-catenin stabilization modifies lineage output from human thymic CD34+CD1a- progenitors. 1995 56


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