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)

Presentation of cell-associated antigen to T cells is a critical event in the initiation of an anti-tumor immune response but it appears to often be deficient or limiting. Here we report an experimental system for stimulation of human T lymphocytes using autologous antigen presenting cells (APCs) and autologous tumor cells. Two types of APCs were prepared from human bone marrow: MC and DC. MC were produced by using GM-CSF and SCF. DC were obtained with the same cytokines plus IL-4. DC and MC were generated in parallel from the same patients and their phenotypes and capacities to prime T lymphocytes were analyzed and compared. MC were CD14+, CD1a-, CD33+ and HLA-DR+. Two populations of DC were defined: immature DC were uniformly CD1a-; mature DC expressed CD1a, CD80, CD86, HLA-DR, CD54 and CD58 but lacked surface CD14. Stimulation of autologous T lymphocytes was studied by measuring their proliferation and cytotoxic function. In more than 80% of our experiments the proliferation of autologous T lymphocytes cocultured with APC pulsed or not with tumor cell lysates was higher than that of T cells cultured alone. DC were more effective than MC in stimulating proliferation of lymphocytes. The capacity of a patient's autologous bone marrow-derived APC to stimulate T cells when exposed to autologous tumor cell lysates suggest that such antigen-exposed APC may be useful in specific anti-tumor immunotherapy protocols.
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PMID:In vitro immunization of patient T cells with autologous bone marrow antigen presenting cells pulsed with tumor lysates. 1107 49

We present a simple yet powerful method for the isolation and analysis of exosomes released by antigen-presenting cells (APC). Exosomes are small vesicles (40-90 nm) released by APC, and may have an immuno-regulatory function in vivo. Such exosomes originate from MHC class II peptide loading compartments and, as such, express high levels of MHC Class II. We have utilised magnetic beads, coated with monoclonal antibodies specific for HLA DP, DQ, DR for the specific isolation of exosomes from cell-free supernatants. Beads coated with exosomes are subsequently stained with conjugated antibodies, and analysed by flow cytometry. Characterisation of exosomes by this method demonstrated that exosomes derived from B-lymphocytes express abundant MHC Class I and II molecules. Other immunologically important molecules detected included the co-stimulatory molecules B7.1 (CD80) and B7.2 (CD86). The adhesion molecule ICAM-1 (CD54) was also detected. These exosomes also expressed the B cell marker CD20, and the complement inhibitory protein CD59. The expression of CD63, a lysosomal marker, was variable, and there was no detectable expression of transferrin receptor (CD71). Monocyte derived dendritic cells (cultured for 7 days in GM-CSF/IL-4), demonstrated an immature phenotype, and secreted exosomes with a similar phenotype, with abundant MHC molecules. The expression of CD63 was consistently strong, and the MHC Class I-like molecule CD1a was also present, suggesting a possible function in the presentation of lipid antigens. Again CD59 was expressed suggesting a possible role for APC exosomes in complement regulation. There was no detectable CD71, CD40, CD14, CD20 or CD83. Modification of the extraction protocol allowed a comparative analysis of exosome secretion under various conditions. Treatment of cells with calcium ionophore, or phorbol ester resulted in apparent increases in exosome release, while the phosphatidyl inositol 3-kinase inhibitor, wortmannin, reduced exosome secretion. The immuno-magnetic isolation and analysis of exosomes is a versatile and rapid tool for the analysis of APC exosomes, and may prove a valuable tool for the study of exosome biology.
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PMID:Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. 1115 May 47

Herpes simplex viruses (HSV) have developed several immunoevasive strategies. Here we demonstrate a novel mechanism by which HSV type 1 may interfere with the immune response through infection of immature dendritic cells (DC) and selective downmodulation of costimulatory molecules. In our study we show productive infection of immature monocyte-derived DC, which closely resemble sessile Langerhans cells, by sequential expression of immediate-early, early, and late viral proteins and of glycoprotein D mRNA, as well as production of infectious virus of moderate titers. Infection was cytopathic, with the progressive loss of 20 to 45% of cells from 24 to 48 h after infection, with no more than 80% of DC found to be infected. These results are in contrast to those of previous findings of nonpermissive or abortive infection of monocytes and mature monocyte-derived DC. Infection of immature DC also led to selective and asynchronous downregulation of CD1a, CD40, CD54 (ICAM-1) (12 h postinfection), CD80 (24 h postinfection), and CD86 (48 h postinfection) but not of CD11c or major histocompatibility complex class I and II molecules when compared to DC exposed to UV-inactivated virus. Thus, we propose that productive infection of epidermal Langerhans cells in vivo may lead to delayed activation of T cells, allowing more time for replication of HSV type 1 in epidermal cells.
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PMID:Immature monocyte-derived dendritic cells are productively infected with herpes simplex virus type 1. 1139 May 97

Erythema toxicum neonatorum is a benign rash of unknown etiology, present to various degrees in most term newborns and characterized by an accumulation of eosinophils in dermal lesions. The recruitment of leukocytes to tissues implicates the involvement of adhesion molecules, cytokines, and chemokines. We therefore performed immunohistochemistry on punch biopsy specimens from cutaneous lesions of ten 1-day-old infants with erythema toxicum using specific monoclonal antibodies directed against a variety of adhesion molecules, cytokines, chemokines, and cell type-specific membrane markers. Biopsy specimens of noninflamed skin from four matched newborns and four adults served as controls. The immunohistologic features of erythema toxicum in all 10 infants included a strong staining of the adhesion molecule E-selectin in the vessel wall and the presence of numerous inflammatory cells that were identified as dendritic cells (CD1a, CD83, HLA-DR, CD40, and ICAM-1 positive), eosinophils (EG2 positive), neutrophils (CD15 positive), macrophages (CD14, CD68, and Mac387 positive), and E-selectin-expressing cells. Furthermore, the lesions showed a high incidence of the proinflammatory cytokines interleukin (IL)-1alpha and IL-1beta and of the chemokines IL-8 and eotaxin. This immunologic activity was reduced or absent in noninflamed skin from newborn controls and adults. We conclude that there is an accumulation and activation of immune cells in the lesions of erythema toxicum, also present in noninflamed skin of 1-day-old infants, but to a lower level. The physiologic significance of the rash remains to be elucidated.
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PMID:Erythema toxicum neonatorum: an immunohistochemical analysis. 1143 96

Tumour-derived factors suppress differentiation and function of in vitro generated DC. Here, we investigate the effect of two melanoma clones differing in their invasive and metastatic properties on the generation and/or functional maturation of human epidermal LC. LC were generated from CD34(+) cord blood progenitors under GM-CSF/TNF-alpha/TGF-beta 1. CD34(+) cells were co-cultured with or without melanoma cells using Transwell dishes. After 11 days of co-culture, CD34(+)-derived cells display a non-adherent undifferentiated morphology, a high level of monocytic CD14 marker, a down-regulated expression of LC markers (CD1a, E-cadherin) and DC markers (CD40, CD80, CD54, CD58, CD83, CD86, HLA-DR, HLA-class I). These cells were less potent than control LC in inducing allogeneic T cell proliferation. The generation of the CD14(+) population was correlated with a decrease in the CD1a(+) population, without any statistical differences between the two clones. Melanoma cells diverted the differentiation of CD34(+) cells towards a dominant CD14(+) population only if the progenitors were in an early growth phase. IL-10, TGF-beta 1 and VEGF were not responsible for these effects, as assessed by using blocking antibodies. By contrast, co-culture of fresh epidermal LC with melanoma cells did not affect their phenotype and function. Our data demonstrate that melanoma cells inhibit the earliest steps of LC differentiation, but failed to affect the functional maturation of epidermal LC. This suggests that melanoma cells participate in their own escape from immunosurveillance by preventing LC generation in the local cutaneous microenvironment.
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PMID:Human melanoma cells inhibit the earliest differentiation steps of human Langerhans cell precursors but failed to affect the functional maturation of epidermal Langerhans cells. 1174 38

Langerhans cells can originate in vitro from immature precursors stimulated with granulocyte macrophage-colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF)-alpha and stem cell factor (SCF). We asked whether these cytokines also control the differentiation state of Langerhans cells within the epidermis and upon leaving this tissue. We harvested sheets of human epidermis by controlled dispase hydrolysis of keratomes, cultured them in RPMI and 10% fetal calf serum for 48 h and analysed the sheets and the cells migrated spontaneously into the medium, most of which were Langerhans cells containing Birbeck granules. By flow cytometry, the intensity of CD1a expression was reduced quite evenly among Langerhans cells migrated from sheets within 48 h. The cells in the sheets underwent loss of dendrites, with a significant reduction in the cell perimeter that was prevented by GM-CSF and TNF-alpha together. Either of these cytokines induced expression of CD18 by cells in the sheets and those in the medium. Moreover, TNF-alpha induced expression of CD54 by cells in the medium, but not by those retained in the sheets, whereas human SCF induced, dose dependently, expression of CD54 by cells in the sheets, but not from those in the medium. The proliferation of allogeneic lymphocytes was much higher when stimulating Langerhans cells were harvested from cultures with any cytokine, rather than from cultures without cytokines. We conclude the following: (i) GM-CSF and TNF-alpha help to maintain full differentiation of Langerhans cells within the epidermis; (ii) cytokine influence on Langerhans cells adhesiveness is in part context dependent; and (iii) pretreatment with cytokines influences positively the number or accessory activity of Langerhans cells on lymphocytes during subsequent mixed leucocyte reaction.
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PMID:Control of the differentiation state and function of human epidermal Langerhans cells by cytokines in vitro. 1176 77

Decoy receptor 3 (DcR3), a soluble receptor belonging to the TNFR superfamily, is a receptor for both Fas ligand (FasL) and LIGHT. It has been demonstrated that DcR3 is up-regulated in lung and colon cancers, thus promoting tumor growth by neutralizing the cytotoxic effects of FasL and LIGHT. In this study, we found that DcR3.Fc profoundly modulated dendritic cell differentiation and maturation from CD14(+) monocytes, including the up-regulation of CD86/B7.2, and the down-regulation of CD40, CD54/ICAM-1, CD80/B7.1, CD1a, and HLA-DR. Moreover, DcR3-treated dendritic cells suppressed CD4(+) T cell proliferation in an allogeneic MLR and up-regulated IL-4 secretion of CD4(+)CD45RA(+) T cells. This suggests that DcR3.Fc may act not only as a decoy receptor to FasL and LIGHT, but also as an effector molecule to skew T cell response to the Th2 phenotype.
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PMID:Modulation of dendritic cell differentiation and maturation by decoy receptor 3. 1199 33

Antigen-driven interaction of dendritic cells (DC) with CD4(+) T(h) cells results in the exchange of bidirectional activating signals. Cross-linking of TCR by MHC class II-bound antigen activates T(h) cells, resulting in their up-regulation of CD40 ligand. Here we show that MHC class II molecules, in addition to their passive role in DC-T(h) cell interaction, can also actively induce DC maturation. Cross-linking of MHC class II molecules on human monocyte-derived DC results in the up-regulation of the surface expression of CD83, CD80, CD86, CD54, CD1a and CD40 molecules, the typical DC maturation-associated markers. It also promotes a rapid homotypic aggregation of DC paralleled by the up-regulation of such adhesion molecules as VLA-4, tissue transglutaminase, CD54 and CD11c. The impact of MHC class II cross-linking upon DC was context dependent. The outcome of MHC class II signaling depends on the maturation status of DC. While the cross-linking of MHC class II on immature DC promoted their maturation, the dominant effect upon the DC that were previously matured was the induction of DC apoptosis. Our current observations indicate that, in addition to the previously reported negative impact of MHC class II-mediated signaling on DC function, it also promotes DC maturation, participating in the enhancement of DC stimulatory function. Importantly, MHC class II-induced DC maturation and apoptosis are mediated by different signaling pathways, sensitive to different sets of inhibitors. This opens the possibility of differential regulation of each of these events in immunotherapy.
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PMID:Differential regulation of maturation and apoptosis of human monocyte-derived dendritic cells mediated by MHC class II. 1220

Dendritic cells are professional antigen presenting cells which are being used as adjuvants in tumor vaccination trials. Most clinical protocols currently include 4 to 10 weekly infusions of doses > 10(6) cells, each inoculum coming from a simple culture of blood monocytes. In the present study, several millions of dendritic cells from a single leukapheresis were produced; monocytes were isolated by elutriation and then cultured in Teflon bags in presence of 800 U/ml GM-CSF + 100 micro g/ml IL-13 + 10% fetal calf serum (FCS). The dendritic cells from this single batch were aliquoted in many doses for potential multiple infusions and cryopreserved in 10% DMSO + 2% human albumin in Teflon-kapton Fresenius bags either at -1 degrees C/min using a controlled rate freezer, or putting the bags directly in a -80 degrees C mechanical freezer without controlling the temperature rate. Six experiments were carried out. After one month of cryopreservation, the cells were thawed in a 40 degrees C water bath. Before and after freezing, cells were evaluated for immunophenotype (CD1a, CD14, CD40, CD80, CD83, CD86, CD54, CD58, CD16, CD32, CD64 and HLA-DR) and for their capacity to stimulate allogenic (MLR) or autologous (antigen presentation tests) lymphocytes. The results demonstrated that the mean recovery rates after freezing in liquid nitrogen or at -80 degrees C were (67 +/- 14)% and (71 +/- 13)% respectively, without any significant difference between the two techniques. The immunophenotype was not modified by the freezing-thawing procedure, as well as the lymphocyte stimulating capacities. In conclusion, our study showed that substantial numbers of functional DCs can be derived from peripheral blood monocytes using Teflon bags. DCs can be cryopreserved in a good laboratory practice setting for further clinical trials with an acceptable loss of cells and without modification of their functions.
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PMID:Cryopreservation of Dendritic Cells Grown in Vitro from Monocytes for Their Future Clinical Use. 1257 59

The purpose of this study was to investigate the function of dendritic cells derived from chronic myeloid leukemia (CML-DC). Mononuclear cells were prepared from bone marrow and peripheral blood of 24 patients with CML, and the DCs were obtained by incubation of MNCs with media containing GM-CSF, IL-4 and TNF-alpha. The phenotype of CML-DCs was identified by flow cytometry. FITC-dextran uptake, (3)H-TdR incorporation or MTT assay and lactate dehydrogenase release assay were used to detect uptake of exogenous antigen in immature DCs, the antigen presenting ability in mature DCs and specific cytotoxicity of CTL to leukemic cells, respectively. The DCs with high expression of CD1a, CD86, CD80, HLA-DR, CD54 and CD4 were obtained from marrow and blood of patients with CML. The uptake of FITC-DX was observed in early DCs. There was a potent stimulation to allo-MLR in DCs cultured for 7 - 10 days, and a lightly lower stimulation to auto-MLR. CML-DCs can induce the generation of specific cytotoxic T cells. These results suggest that CML-DCs are functional DCs with the ability to induce anti-leukemia effect.
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PMID:[The Function of Dendritic Cells Derived from Chronic Myeloid Leukemia] 1257 75


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