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)

Although T cells were previously believed to recognize only peptide antigen associated with the major histocompatibility complex (MHC), recent studies have shown that there are unique T cells specialized for recognition of lipid or glycolipid antigens bound to the MHC class I-like CD1 molecules (CD1a, b, c or d). Among these lipid-specific T cells, CD1d-restricted T cells, also referred to as natural killer (NK) T cells, are of special interest as a target of drug development, since their role in immunoregulation has been indicated in various physiological or disease conditions including autoimmunity. They are unique in their homogeneous ligand specificity for alpha-glycosylated sphingolipid and secrete large amounts of regulatory cytokines shortly after T cell receptor (TCR) engagement. The first glycolipid identified as an NKT cell ligand was alpha-galactosylceramide (alpha-GalCer) derived from marine sponges. alpha-GalCer exhibits significant immunomodulatory effects by stimulating NKT cells. However, we found that an altered analogue of alpha-GalCer with a shorter sphingosine chain (OCH), is more useful than alpha-GalCer for treatment of autoimmune disease models, because of its ability to selectively induce IL-4, a key cytokine for control of autoimmunity. As such, altered glycolipid ligands (AGL) of alpha-GalCer appear to be promising reagents for treatment of human autoimmune diseases.
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PMID:NKT cell-stimulating synthetic glycolipids as potential therapeutics for autoimmune disease. 1496 7

Especially when exposed to inflammatory stimuli, endothelial cells (EC) have been shown to promote the maturation of monocytes into dendritic cells (DC) and the long-term proliferation of CD34+ cells by constitutive cytokine production and direct cellular contact. We therefore hypothesized that cytokine-stimulated EC would induce hematopoietic progenitor cells to develop into mature dendritic cells. To test this theory, human CD34+ cells derived from cord blood or leukapheresis products were cultured with a monolayer of either interleukin (IL)-1beta, IL-4, or tumor necrosis factor (TNF)-alpha-stimulated human umbilical cord EC. The cells in suspension were analyzed weekly over a period of 6 weeks. IL-1beta supported cell expansion, whereas IL-4 had no effect on cell expansion or DC differentiation. Only TNF-alpha-stimulated EC induced the development of mature, allostimulatory DC with a high expression of CD83, HLA-DR, CD1a, and costimulatory molecules like CD80 and CD86. Acute myeloid leukemia cells from the cell line Kasumi-1 also developed DC-like features when cocultured with TNF-alpha-stimulated EC. Direct contact between endothelial and progenitor cells increased the number of developing DC. Cell cycle analysis and apoptosis studies demonstrated a reduced G2M fraction, an increased S fraction, and a decrease in TNF-alpha-dependent apoptosis of DC developing in the presence of endothelial cells. As shown by electron and confocal microscopic studies, intimate interactions between EC and DC occurred, resulting in the internalization of the developing DC within the EC monolayer and a bidirectional exchange of proteins. We conclude that, via the action of TNF-alpha, inflamed human endothelium can induce CD34+ and leukemic cells to differentiate into dendritic cells.
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PMID:Tumor necrosis factor alpha-stimulated endothelium: an inducer of dendritic cell development from hematopoietic progenitors and myeloid leukemic cells. 1499 Aug 54

Primary immune responses are initiated by dendritic cells (DC) that inform naive T helper cells about invading pathogens. DC undergo sequential events leading to irreversible maturation upon bacterial stimulation. To investigate the responses of DC during periodontal infection, we studied the effects of LPS from Porphyromonas gingivalis on DC. DC generated from human peripheral monocytes by culture with IL-4 and GM-CSF were incubated with P. gingivalis LPS (Pg LPS) or Escherichia coli LPS (Ec LPS). Flow cytometry and real-time quantitative RT-PCR analysis revealed that Pg LPS, but not Ec LPS, preferentially up-regulated CD14 and CD16 expression at protein and mRNA levels. Furthermore, Pg LPS preferentially induced the secretion of soluble CD14. CD1a, HLA-DR and CD54 were highly expressed on DC stimulated with both kinds of LPS; however, CD40, CD80, CD83 and CD86 expression on Pg LPS-stimulated DC was lower than on Ec LPS-stimulated DC. With regard to IL-6, IL-8, IL-10, IL-12 and RANTES production from DC and allogeneic T cell proliferation, Pg LPS was a weaker stimulator than Ec LPS. These results suggested that Pg LPS triggers maturation of DC with unique characteristics, which exhibited weak immunostimulatory activity and may contribute to induction of chronic inflammation at the site of periodontal infection.
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PMID:Porphyromonas gingivalis lipopolysaccharides induce maturation of dendritic cells with CD14+CD16+ phenotype. 1511 79

In the present study, we analyzed the phenotypic alterations induced by several allergens on immature dendritic cells (DC), with the aim to develop a potential in vitro alternative for predicting the sensitizing potential of chemicals. DC were generated from human monocytes cultured in the presence of GM-CSF, IL-4 and TGF-beta1 and treated for 2 or 4 days with different chemicals. Surface marker expression (HLA-DR, CD1a, CD40, CD54, CD83, CD86, CCR7 and E-cadherin) was analyzed by flow cytometry. Results showed that a 2-day treatment with the representative allergens DNCB and NiSO(4) induced significant changes of most antigens while other chemicals such as balm of Peru (strong allergen), kathon (moderate allergen), cinnamic aldehyde (mild allergen) or the irritant SLS had no significant effect. In contrast, the 4-day treatment with allergens substantially improved the results. Indeed, despite a large variability according to the donors, the number of modified antigens was significantly higher with all the tested chemicals, except kathon, as compared to that observed with the irritant SLS. The present study indicates that, in this model, the screening of mild or moderate allergens requires both the consideration of many antigens and a prolonged time of incubation with the chemicals.
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PMID:Moderate skin sensitizers can induce phenotypic changes on in vitro generated dendritic cells. 1513 Jun 7

The aim of this work was to study the influence of nitric oxide (NO) in the differentiation of human monocytes to dendritic cells. Human monocytes from healthy donors were differentiated to immature dendritic cells in presence of GM-CSF and IL-4. Maturation of dendritic cells was achieved with GM-CSF and TNF-alpha. Nitric oxide donors (SIN-1, DEA-NO or DETA-NO) were added during differentiation of monocytes to dendritic cells and also during dendritic cells maturation. Immature dendritic cells showed a characteristic phenotype CD80+ CD1a+ HLA-DR+ CD86+ CD40+ CD14(low/-), different from adherent monocytes CD80- CD1a- HLA-DR+ CD86+ CD40- CD14++. The addition of SIN-1 the first day of monocyte differentiation reduced cell viability and increased the percentage of apoptotic immature dendritic cells. Peroxynitrite donor, SIN-1, produced more toxic effects than DEA-NO or DETA-NO. An increase in the subpopulation CD1a+ CD80+ HLADR+ of immature dendritic cells was observed when SIN-1 or DEA-NO, but not DETA-NO, was added at the beginning of monocyte culture. There was a significant reduction in the expression of TNF-alpha receptor of mature dendritic cells when SIN-1 and DEA-NO were added together GM-CSF and TNF-alpha at the beginning of maturation. The presence of SIN-1, DEA-NO or DETA-NO in maturation induced an increase of CD83+ cells. These results suggest that nitric oxide affects differentiation and maturation of dendritic cells and this effect depends on the nitric oxide donor used.
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PMID:Effect of nitric oxide in the differentiation of human monocytes to dendritic cells. 1513 4

This paper presents an improved method of isolating, culturing and cryopreserving human monocytes in large quantity with high purity using standard laboratory centrifuges. Monocytes were isolated from 300 to 360 ml of heparinized human blood using a Double Density technique employing Ficoll Isopaque and 46% iso-osmotic Percoll. Yields of monocytes ranged from 75 to 205 million (from 300 to 360 ml of blood) with an average purity of 90.6%. The ability of fresh or frozen monocytes to adhere to endothelial cells in the presence of oxidized L-alpha-1-palmitoyl-2-arachidonosyl-sn-glycero-3-phosphocholine (oxPAPC) or lipopolysaccharide (LPS) did not differ and no significant difference in response to the chemotactic stimulant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) was observed. We define a useful method for the culture and differentiation of fresh or frozen monocytes isolated by this method, into macrophages as judged by morphology, expression of the macrophage marker SRA-1 and induction of inflammatory genes TNF-alpha, IL-6 and COX-2. Also, fresh or frozen Double Density isolated cells can be successfully differentiated into dendritic cells in the presence of GM-CSF and IL-4 as judged by the expression of the hallmark surface proteins CD1a and DC-sign and the absence of CD14. This method also yields a pure population of lymphocytes.
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PMID:Method for large scale isolation, culture and cryopreservation of human monocytes suitable for chemotaxis, cellular adhesion assays, macrophage and dendritic cell differentiation. 1518 91

Myeloid dendritic cells (DCs) are conventionally generated by culturing human peripheral blood monocytes in the presence of GM-CSF and IL-4. Here we report that IL-4 alone, in the absence of detectable endogenous GM-CSF, transforms human peripheral blood monocytes to a CD1a(dim) DC subset that could be matured to CD83(+) DCs. Absence of endogenous GM-CSF in IL-4-DC was demonstrated by RT-PCR and flow cytometry. With the exception of CD1a expression, surface marker, morphology and phagocytic activity of these DCs (IL-4-DC) were similar to myeloid DCs (GM-IL-4-DC) conventionally generated in the presence of GM-CSF and IL-4. Conventional GM-IL-4-DC produced less IL-12 compared with IL-4-DC after stimulation with anti-CD40 monoclonal antibody, or LPS plus IFN-gamma, although the difference was more prominent when LPS plus IFN-gamma was used as the stimulus. The GM-IL-4-DC also induced less frequent IFN-gamma(+) T cells in a mixed leukocyte reaction (MLR) than that of IL-4-DC. Yields of IL-4-DCs were marginally lower than that of GM-IL-4-DCs. Our data indicate that peripheral blood monocytes can be transformed to CD1a-deficient myeloid DCs solely by IL-4, and these IL-4-DCs are likely to induce a stronger Th1 response than conventional GM-IL-4-DCs.
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PMID:IL-4 alone without the involvement of GM-CSF transforms human peripheral blood monocytes to a CD1a(dim), CD83(+) myeloid dendritic cell subset. 1521 52

Human monocytes can differentiate into dendritic cells (DCs) according to the nature of environmental signals. We tested here whether the infection with the live tuberculosis vaccine bacillus Calmette-Guerin (BCG), which is known to be limited in preventing pulmonary tuberculosis, modulates monocyte and DC differentiation. We found that monocytes infected with BCG differentiate into CD1a- DCs (BCG-DCs) in the presence of granulocyte macrophage-colony stimulating factor and interleukin (IL)-4 and acquired a mature phenotype in the absence of maturation stimuli. In addition, BCG-DCs produced proinflammatory cytokines (tumor necrosis factor alpha, IL-1beta, IL-6) and IL-10 but not IL-12. BCG-DCs were able to stimulate allogeneic T lymphocytes to a similar degree as DCs generated in the absence of infection. However, BCG-DCs induced IL-4 production when cocultured with human cord-blood mononuclear cells. The induction of IL-4 production by DCs generated by BCG-infected monocytes could explain the failure of the BCG vaccine to prevent pulmonary tuberculosis.
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PMID:Dendritic cells derived from BCG-infected precursors induce Th2-like immune response. 1524 Jul 55

Acute and chronic Plasmodium falciparum malaria are accompanied by severe immunodepression possibly related to subversion of dendritic cells (DC) functionality. Phagocytosed hemozoin (malarial pigment) was shown to inhibit monocyte functions related to immunity. Hemozoin-loaded monocytes, frequently found in circulation and adherent to endothelia in malaria, may interfere with DC development and play a role in immunodepression. Hemozoin-loaded and unloaded human monocytes were differentiated in vitro to immature DC (iDC) by treatment with GM-CSF and IL-4, and to mature DC (mDC) by LPS challenge. In a second setting, hemozoin was fed to iDC further cultured to give mDC. In both settings, cells ingested large amounts of hemozoin undegraded during DC maturation. Hemozoin-fed monocytes did not apoptose but their differentiation and maturation to DC was severely impaired as shown by blunted expression of MHC class II and costimulatory molecules CD83, CD80, CD54, CD40, CD1a, and lower levels of CD83-specific mRNA in hemozoin-loaded iDC and mDC compared with unfed or latex-loaded DC. Further studies indicated activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in hemozoin-loaded iDC and mDC, associated with increased expression of PPAR-gamma mRNA, without apparent involvement of NF-kappaB. Moreover, expression of PPAR-gamma was induced and up-regulation of CD83 was inhibited by supplementing iDC and mDC with plausible concentrations of 15(S)-hydroxyeicosatetraenoic acid, a PPAR-gamma ligand abundantly produced by hemozoin via heme-catalyzed lipoperoxidation.
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PMID:Hemozoin (malarial pigment) inhibits differentiation and maturation of human monocyte-derived dendritic cells: a peroxisome proliferator-activated receptor-gamma-mediated effect. 1535 56

Interferon beta (IFN beta) has complex immune regulatory properties that contribute to its treatment effect on multiple sclerosis (MS). In this study, we investigated the role of IFN beta in differentiation and functional properties of monocytes and monocyte-derived dendritic cells that are critical to the inflammatory process in MS. The results revealed that IFN beta inhibited intracellular production of interleukin (IL)-1b (P<0.01) in both monocytes exposed to in vitro treatment of IFN beta and monocytes analysed ex vivo from MS patients treated with IFN beta. IFN beta was shown to modulate differentiation of monocytes into dendritic cells in the presence of IL-4 and GM-CSF, which resulted in a delayed differentiation process. Furthermore, it characteristically altered the phenotypic features of differentiated dendritic cells by inhibiting the expression of CD1a, CD11b, CD11c, CD123 and CD209 while upregulating costimulatory molecules, such as CD86. The selective regulatory properties of IFN beta appeared to render the function of differentiated dendritic cells to produce an increased amount (P<0.01) while their ability to secrete proinflammatory IL-12 and TGF beta was significantly reduced. The observed collective effects of IFN beta seemed to correlate with Th2 immune deviation. The study has provided new insights into the regulatory mechanisms of IFN beta in the treatment of MS.
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PMID:Regulation of differentiation and functional properties of monocytes and monocyte-derived dendritic cells by interferon beta in multiple sclerosis. 1547 64


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