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

Representing the most potent antigen-presenting cells, dendritic cells (DC) can now be generated from human blood monocytes. We recently presented a novel protocol employing GM-CSF, IL-4, and IFN-gamma to differentiate monocyte-derived DC in vitro. Here, such cells are characterized in detail. Cells in culture exhibited both dendritic and veiled morphologies, the former being adherent and the latter suspended. Phenotypically, they were CD1a-/dim, CD11a+, CD11b++, CD11c+, CD14dim/-, CD16a-/dim, CD18+, CD32dim/-, CD33+, CD40+, CD45R0+, CD50+, CD54+, CD64-/dim, CD68+, CD71+, CD80dim, CD86+/++, MHC class I++/ , HLA-DR++/ , HLA-DP+, and HLA-DQ+. The DC stimulated a strong allogeneic T-cell response, and further evidence for their autologous antigen-specific stimulation is discussed. Although resembling a mature CD11c+ CD45R0+ blood DC subset identified earlier, their differentiation in the presence of the Th1 and Th2 cytokines IFN-gamma and IL-4 indicates that these DC may conform to mature mucosal DC.
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PMID:In-vitro differentiation of mature dendritic cells from human blood monocytes. 971 3

Dendritic cells (DC) present Ag to naive T cells and are therefore pivotal in shaping immune responses. DC may either immunize or tolerize T cells. Humans with pancreatic islet autoimmunity at high risk for insulin-dependent diabetes mellitus (IDDM) present the opportunity to investigate DC in autoimmune disease. We compared DC phenotype and function in 12 euglycemic, asymptomatic IDDM relatives with islet autoimmunity and controls matched for age, sex, and MHC class II alleles. DC were generated from adherent peripheral blood cells by culture with granulocyte/macrophage-CSF and IL-4. The yield of DC was significantly lower in IDDM relatives than in controls. While the DC phenotype, HLA-DR+CD14-, was expressed by > or =90% of the cells generated from relatives and controls, the proportion of cells that expressed CD1a and the costimulator molecules CD80 (B7-1) and CD86 (B7-2) was significantly lower in IDDM relatives. In addition, B7-1 and B7-2 expression per cell was significantly lower in IDDM relatives. These phenotypic changes were accompanied by reduced stimulation of autologous CD4 cells by DC from IDDM relatives. Similar findings were obtained in three recently diagnosed IDDM patients. These findings indicate that impairment of DC phenotype and function is a marker of islet autoimmunity and are consistent with a role for impaired DC function in the pathogenesis of autoimmune disease.
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PMID:Impaired yield, phenotype, and function of monocyte-derived dendritic cells in humans at risk for insulin-dependent diabetes. 972 65

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

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a multipotent cytokine produced by many cutaneous cell types including keratinocytes. Langerhans cells (LC) represent the major antigen-presenting cells in skin, and in vitro studies demonstrate that GM-CSF is of pivotal importance in LC. Healthy volunteers (n = 3 non-atopic, n = 3 with atopy) received recombinant human GM-CSF (0. 05 microg/mL) by intradermal injection for 3 days to the same site. Diluent was injected in a similar manner as control. Biopsies were taken 24 h after the final injection and examined immunohistochemically for LC and inflammatory cell markers. Compared with control sites, intradermal GM-CSF resulted in shortening of dendritic cell processes and redistribution of LC in the epidermis; numbers of CD1a + cells in the epidermis were significantly decreased (P < 0.005), while those in the dermis were significantly increased (P < 0.05) following intradermal GM-CSF when compared with controls. Double labelling studies on epidermal CD1a + cells indicated de novo expression of intercellular adhesion molecule (ICAM)-1 and increased expression of HLA-DR following GM-CSF (P < 0. 005, P < 0.005, respectively). Additional findings included a marked mixed inflammatory cell infiltrate in the dermis and increased expression of the endothelial cell adhesion molecules E-selectin and ICAM-1. These data indicate that in normal human skin, GM-CSF induces changes in the phenotype and distribution of CD1a + cells consistent with LC functional maturation and exit from the epidermis to the dermis. As these events are central to the initiation of cutaneous inflammation, GM-CSF may potentially play a critical role in the pathogenesis of inflammatory dermatoses.
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PMID:Effect of granulocyte macrophage-colony stimulating factor on Langerhans cells in normal and healthy atopic subjects. 976 37

We previously showed that in chronic myeloid leukaemia (CML), it is possible to induce costimulatory molecules, CD80/CD86, on leukaemia cells by culturing adherent peripheral blood mononuclear cells from these patients with IL-4 and GM-CSF. In addition to the expression of CD80/CD86 molecules, some of the leukaemia cells also expressed the dendritic cell marker, CD1a. When these leukaemia cells were used in mixed lymphocyte leukaemia reactions, they mediated autologous T cell proliferation not seen when fresh leukaemia cells were used as the stimulator cells. In this study, we showed that reinfusion of these immunogenic leukaemia cells to the autologous hosts resulted in priming in vivo of T cells so that they could respond to subsequent rechallenge in vitro with fresh autologous leukaemia cells. Although cytotoxic T cells against leukaemia cells were not demonstrated, these T cells could proliferate and produce interferon-y when cocultured in vitro with the leukaemia cells. Our findings therefore provide further evidence for the immunogenicity of these cultured leukaemia cells in CML.
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PMID:In vitro cytokine-primed leukaemia cells induce in vivo T cell responsiveness in chronic myeloid leukaemia. 989 22

Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are required for the initiation of the immune response. DCs have been shown to be generated from hematopoietic stem cells, but relatively little is known about the regulation underlying differentiation and activation of DCs. Here, we report that recombinant human (rh)IL-13 induces functional maturation of rhGM-CSF plus rhIL-4 generated monocyte-derived immature DCs. Incubation of these immature DCs with rhIL-13 or rhTNF-alpha for 2 days resulted in increased surface expression of CD1a, CD11c, CD86 and HLA-DR. The DCs treated with rhIL-13 or rhTNF-alpha, but not rhIL-4, for 2 days were more efficient than unstimulated DCs in the primary autologous/allogeneic T-cell response whereas the antigen (Ag)-specific T-cell response was suppressed. The treatment of DCs with rhIL-13 as well as rhTNF-alpha for 4 days down-modulated endocytic capacity for FITC-dextran (FITC-DX) and lucifer yellow (LY), and induced surface expression of CD83. Morphological, phenotypical, and functional analyses revealed that the monocytes cultured with rhGM-CSF plus rhIL-13 gave rise to a DC type more mature than rhGM-CSF plus rhIL-4-induced DCs. These findings revealed a new role for rhIL-13 in regulating both the maturation and activation of DCs.
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PMID:Interleukin-13 is involved in functional maturation of human peripheral blood monocyte-derived dendritic cells. 1002 72

We examined whether priming monocytes (MO) with lipopolysaccharide (LPS) influenced their further differentiation into either macrophages (Mphi) or dendritic cells (DC). LPS-primed MO differentiated into Mphi when cultured further with Mphi colony-stimulating factor (M-CSF) but, if cultured then with granulocyte/Mphi (GM)-CSF and IL-4 (interleukin-4), only about 30% of the cells differentiated into CD1a+ CD14- DC and half became CD1a- CD14+ Mphi. Cytokines present during LPS priming could affect subsequent MO differentiation. Relative to priming with LPS alone, adding M-CSF to LPS did not modify differentiation of MO to Mphi in further culture with M-CSF, nor did it change the way of differentiation of MO into DC was altered if culture was later switched to GM-CSF/IL-4. Using GM-CSF/IL-4 plus LPS upon priming did not modify differentiation of MO to Mphi in further culture with M-CSF, as compared to priming with GM-CSF/IL-4 alone, but it counteracted the effect of LPS on the differentiation of MO to DC in further culture with GM-CSF/IL-4: about 75% of cells then became DC. Alternatively, despite activation by LPS, mature M-CSF-induced Mphi preserved the potential to differentiate into DC on subsequent culture with GM-CSF/IL-4. Thus, LPS, a bacterial product known to sustain maturation of MO/Mphi as well as of DC, may block the differentiation of MO into DC, except if signal triggering DC differentiation is delivered concomitantly, and modulate in this manner the induction of adaptive immune responses to infection.
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PMID:Lipopolysaccharide can block the potential of monocytes to differentiate into dendritic cells. 1008 6

Whether thymic dendritic cells (DC) are phenotypically and functionally distinct from the monocyte lineage DC is an important question. Human thymic progenitors differentiate into T, NK, and DC. The latter induce clonal deletion of autoreactive thymocytes and therefore might be different from their monocyte-derived counterparts. The cytokines needed for the differentiation of DC from thymic progenitors were also questioned, particularly the need for GM-CSF. We show that various cytokine combinations with or without GM-CSF generated DC from CD34+CD1a- but not from CD34+CD1a+ thymocytes. CD34+ thymic cells generated far fewer DC than their counterparts from the cord blood. The requirement for IL-7 was strict whereas GM-CSF was dispensable but nonetheless improved the yield of DC. CD14+ monocytic intermediates were not detected in these cultures unless macrophage-CSF (M-CSF) was added. Cultures in M-CSF generated CD14-CD1a+ DC precursors but also CD14+CD1a- cells. When sorted and recultured in GM-CSF, CD14+ cells down-regulated CD14 and up-regulated CD1a. TNF-alpha accelerated the differentiation of progenitors into DC and augmented MHC class II transport to the membrane, resulting in improved capacity to induce MLR. The trafficking of MHC class II molecules was studied by metabolic labeling and immunoprecipitation. MHC class II molecules were transported to the membrane in association with invariant chain isoforms in CD14+ (monocyte)-derived and in CD1a+ thymic-derived DC but not in monocytes. Thus, thymic progenitors can differentiate into DC along a preferential CD1a+ pathway but have conserved a CD14+ maturation capacity under M-CSF. Finally, CD1a+-derived thymic DC and monocyte-derived DC share very close Ag-processing machinery.
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PMID:Functional and phenotypic analysis of thymic CD34+CD1a- progenitor-derived dendritic cells: predominance of CD1a+ differentiation pathway. 1022 16

Because dendritic cells (DC) play a major role in the initiation of T cell-mediated immunity, we studied the effects of glucocorticoids, well-known inhibitors of the immune and inflammatory response, on the differentiation and maturation of human DC. DC were differentiated from human monocytes by culture with GM-CSF and IL-4 for 7 days with and without dexamethasone (Dex). Cells treated with Dex (10-8 M) (Dex-DC) developed a characteristic dendritic morphology; however, membrane phenotype analysis demonstrated that they were not fully differentiated. Dex-DC expressed low levels of CD1a and, unlike untreated cells, high levels of CD14 and CD16. Molecules involved in Ag presentation (CD40, CD86, CD54) were also impaired. In contrast, molecules involved in Ag uptake (mannose receptor, CD32) and cell adhesion (CD11/CD18, CD54) were up-regulated. After exposure to TNF-alpha or CD40 ligand, Dex-DC expressed lower levels of CD83 and CD86 than untreated cells. Dex-DC showed a higher endocytic activity, a lower APC function, and a lower capacity to secrete cytokines than untreated cells. Overall, these results indicate that DC differentiated in the presence of Dex are at a more immature stage. Moreover, Dex also partially blocked terminal maturation of already differentiated DC. In conclusion, our data suggest that glucocorticoids may act at the very first step of the immune response by modulating DC differentiation, maturation, and function.
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PMID:Glucocorticoids affect human dendritic cell differentiation and maturation. 1035 62

Based on the relative expression of CD11c and CD1a, we have identified three fractions of dendritic cells (DCs) in human peripheral blood, including a direct precursor of Langerhans cells (LCs). The first two fractions were CD11c+ DCs, comprised of a major CD1a+/CD11c+ population (fraction 1), and a minor CD1a-/CD11c+ component (fraction 2). Both CD11c+ fractions displayed a monocyte-like morphology, endocytosed FITC-dextran, expressed CD45RO and myeloid markers such as CD13 and CD33, and possessed the receptor for GM-CSF. The third fraction was comprised of CD1a-/CD11c- DCs (fraction 3) and resembled plasmacytoid T cells. These did not uptake FITC-dextran, were negative for myeloid markers (CD13/CD33), and expressed CD45RA and a high level of IL-3Ralpha, but not GM-CSF receptors. After culture with IL-3, fraction 3 acquired the characteristics of mature DCs; however, the expression of CD62L (lymph node-homing molecules) remained unchanged, indicating that fraction 3 can be a precursor pool for previously described plasmacytoid T cells in lymphoid organs. Strikingly, the CD1a+/CD11c+ DCs (fraction 1) quickly acquired LC characteristics when cultured in the presence of GM-CSF + IL-4 + TGF-beta1. Thus, E-cadherin, Langerin, and Lag Ag were expressed within 1 day of culture, and typical Birbeck granules were observed. In contrast, neither CD1a-/CD11c+ (fraction 2) nor CD1a-/CD11c- (fraction 3) cells had the capacity to differentiate into LCs. Furthermore, CD14+ monocytes only expressed E-cadherin, but lacked the other LC markers after culture in these cytokines. Therefore, CD1a+/CD11c+ DCs are the direct precursors of LCs in peripheral blood.
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PMID:A CD1a+/CD11c+ subset of human blood dendritic cells is a direct precursor of Langerhans cells. 1041 41


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