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)

Monocytes (MO) cultured for > or =5 days with either macrophage-CSF (M-CSF) or granulocyte macrophage (GM)-CSF and IL-4 differentiated without concomitant proliferation into CD14+ macrophages (Mphi) or CD1a+ dendritic cells (DC), respectively. When adherent and nonadherent CD14high Mphi from M-CSF cultures were separated and cultured further in cytokine-free medium or with GM-CSF/IL-4, most cells from both fractions that were exposed to GM-CSF/IL-4 acquired CD1a expression and DC morphology and function. Conversely, GM-CSF/IL-4 withdrawal at day 5 and additional culture of sorted CD1a+ DC for 2 to 7 days in cytokine-free medium led to cells rapidly becoming adherent CD1a-CD14+ Mphi. Replacing GM-CSF/IL-4 with M-CSF hastened the conversion of DC to Mphi without increasing cell numbers. CD1a+CD14-CD83+ mature DC were induced by a > or =2-day exposure to MO-conditioned medium, LPS, or TNF-alpha/IL-1beta. Upon cytokine removal or culture with M-CSF, DC that had been pushed to maturation by conditioned medium or LPS remained stable or died in the new environment. TNF-alpha/IL-1beta-driven DC displayed heterogeneous CD83 expression and could thus be sorted into CD83high and CD83low/- cells; in cytokine-free medium or in M-CSF, most CD83low/- cells converted to Mphi, whereas most CD83high cells remained nonadherent CD1a+CD14- or died and thus appeared truly terminally differentiated. Hence, MO are precursors of Mphi as well as of DC, with each cell type having the capability to convert into the other until late in the differentiation/maturation process. Accordingly, the cytokine environment and the presence of differentiation and/or other stimulatory signals may be the "final decision-making factors" determining whether these cells will acquire DC or Mphi characteristics and function.
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PMID:Dendritic cells as the terminal stage of monocyte differentiation. 957 66

The non-major histocompatibility complex (MHC)-encoded CD1 family has recently emerged as a new antigen-presenting system that is distinct from either MHC class I or class II molecules. In the present study, we determined the genomic structure of the rat CD1 locus. It was extremely similar to mouse CD1 genes, especially to CD1D1. The 5' flanking region of the CD1 gene contained the binding motifs for two cytokine-inducible transcription factors, NF-IL2-A and NF-IL6. Some regulatory elements found in MHC class I genes (enhancer A, enhancer B, and the IFN response element) were absent. It is of interest that a tyrosine-based motif for endosomal localization found in the human CD1b cytoplasmic tail was encoded by a single short exon which was conserved in all CD1 molecules except for CD1a. Southern blot and direct sequencing analyses of inbred rat strains suggested very limited polymorphism in the 5' region where a hydrophobic ligand-binding groove is encoded; a single base substitution resulted in amino acid alteration of alanine (GCT) to valine (GTT) at codon 119. Comparison of the overall exon-intron organization of CD1 genes revealed that the length of the intron was also characteristic to each of the two classes of CD1 genes, classic CD1 and CD1D; such categorization has hitherto been made according to the sequence similarity of the coding region. This finding provides further support for the hypothesis that the two classes have different evolutionary histories. In contrast to the complete absence of the classic CD1 in rats and mice, the entire region of nonpolymorphic CD1D has been conserved through mammalian evolution. Similar functional properties of rodent CD1 and human CD1d are implied.
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PMID:Structural organization of rat CD1 typifies evolutionarily conserved CD1D class genes. 960 40

We examined the effects of different cytokine combinations and culture conditions on the expansion and modulation of cell surface antigens of CD34+ derived dendritic cells (DCs), the most efficient antigen-presenting cells capable of stimulating resting T cells in the primary immune response. Cells with a dendritic morphology and expressing HLA-DR, CD1a, S100 and CD83 were maximally expanded under serum-free conditions with the addition of SCF, GM-CSF, TNF-alpha, TGF-beta and Flt-3 ligand (fold increase of CD1a+ cells = 102 +/- 32 after 2 weeks of culture). CD34+ cells were also grown under continuous flow conditions in an artificial capillary system: after 14d of culture, the expansion in the total cell number was lower than that of the static cultures (3.3 +/- 2 v 18.9 +/- 4) but the percentage of CD1a+/CD83+/ CD80+ cells was considerably higher, whereas the CD14+ cells were significantly reduced (8.9 +/- 2 v 26 +/- 13). In continuous perfusion cultures, low levels of DC precursors and of LTC-IC were still present up to day 14. The DCs generated under flow conditions stimulated the mixed leucocyte reaction (MLR) more than the cells grown in static cultures. By electron microscopy, cells grown in the continuous flow system showed an increased number of large cells with numerous dendritic processes and abundant multilamellar complexes. The cells expanded under these conditions were sorted on the basis of their light-scatter properties into two fractions: one containing a predominance of CD1a+/S100+/ CD8 3+/CD80+/CD14- 'large cells' with great internal complexity (mature DCs); the second including 'small cells' either CD33+/CD14+, CD33+/CD15+ or CD33+/CD13-/CD14. The DCs generated and selected with this method are therefore particularly well suited for immunotherapeutic protocols.
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PMID:Expansion of dendritic cells derived from human CD34+ cells in static and continuous perfusion cultures. 960 35

The CD14-dependent and -independent dendritic cell (DC) pathways are instituted simultaneously when CD34(+) progenitor cells are treated with granulocyte-macrophage colony-stimulating factor (GM-CSF)/tumor necrosis factor (TNF) +/- stem cell factor (SCF) (GTS). If TNF activity is neutralized within 48 hours of cytokine exposure, DC development is halted and myelogranulocytic hematopoiesis takes place. In this study, we show that disruption of TNF activity at a later time point produced a distinct alteration within the DC system. Instead of downregulating DC development, treatment of GTS cultures with antibodies to TNF (anti-TNF) on day 3 provoked the selective expansion of the CD14-dependent (monocyte) DC pathway from progenitor cell populations lacking CD14 and CD1a. After an initial decrease in proliferation, anti-TNF produced a rebound in cell growth that yielded intermediate myeloid progenitors exhibiting CD14-dependent DC differentiation potential and CD14(+)CD1a+ DC precursors. Cultures enriched in CD14-dependent DCs were more potent stimulators of a mixed leukocyte reaction, compared with control GTS cultures containing both types of DCs. The intermediate progenitors expanded in the presence of anti-TNF were CD115(+)CD33(+)DR+, long-lived, and displayed clonogenic potential in methylcellulose. When exposed to the appropriate cytokine combinations, these cells yielded granulocytes, monocytes, and CD14-dependent DCs. Antigen-presenting function was acquired only when DC maturation was induced from these myelodendritic progenitors with GM-CSF + interleukin-4 or GTS. These studies show a novel mechanism by which TNF regulates the DC system, as well as providing a strategy for the amplification of the CD14-dependent DC pathway from immature progenitors. Although TNF is required to ensure the institution of DC hematopoiesis from CD34(+) progenitor cells, its activity on a later progenitor appears to limit the development of CD14-dependent DCs.
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PMID:Neutralization of tumor necrosis factor activity shortly after the onset of dendritic cell hematopoiesis reveals a novel mechanism for the selective expansion of the CD14-dependent dendritic cell pathway. 968 Mar 40

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

Human monocyte-derived dendritic cells were differentiated in vitro for 7 days with granulocyte macrophage-colony stimulating factor and interleukin-13. These cultured dendritic cells are at an immature stage of differentiation and exhert high endocytic activity via surface mannose receptor and via fluid-phase macropinocytosis. We have investigated the modulation of endocytosis by interleukin-10 in these cells. When added during the last 24 h of the 7-day culture, interleukin-10 significantly stimulated the uptake of fluorescein-labelled dextran (39 +/- 16% increase, mean +/- SD of 6 experiments), a sugar binding to the mannose receptor. This effect was dose dependent and correlated with the length of exposure to interleukin-10, with a maximal effect (more than seven-fold increase) when the cytokine was added at the beginning of the culture (day 0). The interleukin-10-increased fluorescein-labelled-dextran endocytosis was mostly mediated via the mannose receptor, as unlabelled mannose and specific antimannose receptor monoclonal antibody inhibited most of the uptake. Moreover, interleukin-10-treated cells expressed increased levels (up to four-fold) of mannose receptor. Interleukin-10 also increased, although to a lesser extent, the fluid-phase endocytosis (macropinocytosis) of fluorescein-labelled albumin. Interleukin-10 had the opposite effect on the differentiation and functional activity of monocyte-derived dendritic cells; cells having a very low stimulatory capacity and reduced expression of MHC class II and CD1a after a 7-day exposure. Thus interleukin-10 had a strong immunosuppressive effect on the differentiation and functional activity of monocyte-derived dendritic cells and yet strongly stimulated endocytosis in these cells. We speculate that an increased endocytic activity would eventually result in a decreased availability of antigens in the external milieu, thus contributing to the immunosuppressive and tolerogenic activity of interleukin-10.
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PMID:Interleukin-10 increases mannose receptor expression and endocytic activity in monocyte-derived dendritic cells. 980 26

Ultraviolet (UV) irradiation of the skin induces complex local and systemic immunomodulatory reactions. The biological effects of UV irradiation on human skin derived afferent lymph however are unknown. The aim of this study was to examine the effects of a single combined UV-A and UV-B irradiation with 1 minimal erythema dose (MED) on human skin derived lymph in vivo. After cannulation of a superficial lymph vessel on the lower leg, lymph flow and cell output per hour were determined before and for 6 days after UV irradiation of the lymph draining skin area in 5 volunteers. Furthermore, expression of CD1a, CD4, CD8, CD28, CD54, CD80, CD86 and HLA-DR on migrating lymph cells and cytokine levels (IL-1alpha, IL-1beta, IL-2, IL-6, IL-8, IL-10, IL-13, TNF-alpha and IFN-gamma) in the afferent lymph were analyzed by cytofluorometry and ELISA. After UV irradiation a small initial enhancement in the daily lymph flow per hour was noticed in correlation with the slight erythematous skin reaction. Following resolution of the skin reaction, a delayed increase in cell output in correlation with an additional peak in the lymph flow was found between the 4th and 6th day after UV irradiation. However, no changes in the expression of CD1a, CD4, CD8, CD28, CD54, CD80, CD86 and HLA-DR on migrating lymph cells were detectable. Interestingly, in parallel to the increased lymph flow and cell output, only elevated IL-8 protein levels were reproducibly detected in the afferent lymph after UV irradiation. Furthermore, using immunohistochemistry positive staining for IL-8 was found on migrating mononuclear lymph cells. In conclusion, our data demonstrate that a single UV irradiation of the skin with 1 minimal erythema dose leads to a delayed enhancement of lymph flow, number of migrating lymph cells and cytokine levels of IL-8. Moreover, we provide evidence that migrating lymph cells, besides resident epidermal and dermal cells, may contribute to the detected levels of IL-8 in the afferent lymph.
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PMID:Effects of UV irradiation with one minimal erythema dose on human afferent skin lymph in vivo. 985 39

It is generally accepted that TCR alphabeta+ CD8+ T cells recognize immunogenic peptides bound to MHC-encoded class I molecules. This recognition is a major component of the cellular response mediating immune protection and recovery from viral infections and from certain intracellular bacterial infections. Here, we report two human CD8+ TCR alphabeta+ T cell lines specific for Mycobacterium tuberculosis Ags presented in the context of CD1a or CD1c Ag-presenting molecules. These T cells recognize lipid Ags and display cytotoxicity as well as strong Th cell type I cytokine responses. By extending presentation by the CD1 system to the major TCR alphabeta+ CD8+ T cell pool, this system gains wider applicability beyond the double negative subset of T cells previously shown to have this reactivity. This implies that previous assumptions about the role of CD8+ T cells in microbial immunity may require revision as the relative proportions of CD1-restricted and MHC class I-restricted CD8+ T cells are further defined.
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PMID:CD1-restricted microbial lipid antigen-specific recognition found in the CD8+ alpha beta T cell pool. 988 8

Dendritic cells (DCs) are pivotal for antigen presentation, T-cell priming and B-cell functions. Few studies have been carried out on DCs in human diseases, partly because the current procedures used for DC preparation include elaborate negative selection with monoclonal antibodies (MoAb) and prolonged culture in cytokine-enriched milieu, which may influence DC functions. Using physical density and their adherent properties, DCs were prepared from the blood of healthy subjects. Approximately 2% of human blood mononuclear cells (MNC) were shown to consist of DCs, yielding DCs of 80-90% purity. They expressed markers related to DCs (CD1a, CD11c, CD32 and CD83), costimulatory molecules (CD40, CD80, CD86), human leucocyte antigen (HLA) class I and II molecules and inducible nitric oxide (NO) synthase (NOS2), and lacked lymphocyte and monocyte markers (CD3, CD19, CD20, CD56 and CD14). Compared with blood MNC and T cells, DCs showed a high level of spontaneous proliferation and nitric oxide production, as well as strong proliferative responses in mixed leucocyte reactions. Enzyme-linked immunospot (ELISPOT) assays revealed higher levels of interleukin (IL)-4-, IL-10- and interferon-gamma (IFN-gamma)-secreting cells among DCs than among MNC or T cells obtained from the same blood specimens, while levels of tumour necrosis factor-alpha (TNF-alpha)- and IL-6-secreting cells did not differ. The results demonstrate that the method used is fast, effective and competitively priced, and should be useful for studies of DCs in disease states.
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PMID:Phenotypic and functional properties of dendritic cells isolated from human peripheral blood in comparison with mononuclear cells and T cells. 1007 22


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