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PubMed1998

Modulation of carcinoembryonic antigen release by glucosylceramide--implications for HT29 cell differentiation.

Previous work suggested that glucosylceramide (GlcCer) plays a role in the regulation of cell differentiation of HT29 human colon tumor cells. In the present study, we investigated the role of GlcCer in the cellular release of carcinoembryonic antigen (CEA), a marker for cell differentiation. This was done by modulating the intracellular level of the glycolipid, according to two different approaches. The cells were treated with D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), which resulted in a specific lowering of the cellular GlcCer pool. Alternatively, by exogenous addition of a short-chain analog of the lipid, hexanoyl(C6)-GlcCer, the cellular pool was enhanced. The results demonstrate that PDMP causes an increase in the release of CEA, while exogenous C6-GlcCer suppresses its release. Furthermore, the enhanced release of CEA in the presence of PDMP, could be completely reversed upon exogenous addition of C6-GlcCer. Control experiments reveal that a potential interference of the well-known modulator of cell physiology, ceramide (Cer), can be excluded. Long-term depletion of GlcCer resulted in a change in a morphological feature of differentiation of the cells, i.e. an increase in apical membrane surface with microvilli brush borders, accompanied by an enhanced expression of the cytoskeletal protein villin. These results, together with the observations on modulation of the differentiation marker CEA by GlcCer, provide support for the conclusion that GlcCer interferes with the differentiation of HT29 cells.

Carcinoembryonic Antigen↗
PubMed2002

Pharmacological modulation of carcinoembryonic antigen in human cancer cells: studies with staurosporine.

Preliminary studies, performed in our laboratory, showed that staurosporine (ST), a protein-kinase (PK) inhibitor, increases the expression of the carcinoembryonic antigen (CEA) in a human colon cancer cell line. The present study explores the cellular and molecular effects of ST on the CEA expression in breast cancer MCF-7 line and in a number of colon cancer cell lines characterized by the different basal levels of the antigen, including two cloned sublines (i.e. C22.20 and C6.6, expressing low and high CEA levels, respectively). In all cases, increase of the CEA expression was observed at drug concentrations devoid of marked cytostatic effects (e.g. 5 nM) and was accompanied by the enhanced CEA shedding in the supernatant. Moreover, the increase of the CEA levels both occurred in the cell membranes and in the cytosolic compartments and appeared to be the result of the enhanced CEA gene transcription. Similar results have been previously obtained with interferon-gamma. However, ST treatment, different from interferon-gamma, did not up-regulate the level of the HLA class I molecules. A preliminary investigation also showed that other PKC inhibitors did not substantially modulate the CEA expression. Therefore, the biochemical mechanism underlying the effect of ST should not be correlated with that involved in the PKC inhibition. The present study suggests that ST and, presumably, its analogs used in the cancer treatment could enhance the CEA expression on neoplastic cells in patients affected by the CEA-positive malignancies. This appears to be of potential clinical interest for the development of new immunotherapeutic or diagnostic approaches based on the pharmacological modulation of this antigenic marker.

Carcinoembryonic Antigen↗
PubMedDate not supplied

The role of cytokines in the modulation of cell surface antigens of human melanoma.

A number of different cytokines, including IL-1 alpha and beta, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IFN-alpha, -beta and gamma, TNF-alpha -beta, and TGF-beta 1, can modulate the expression of distinct cell surface antigens of normal and neoplastic cells. Both induction/increase of expression and reduction of expression can be achieved depending on the antigen and on the cytokine. Antigens subjected to the modulating activity of cytokines include distinct families of cell surface structures such as the molecules coded by the major histocompatibility complex (MHC), the superfamily of adhesion receptors that regulate cell-cell and cell-matrix interaction, receptors for cytokines and growth factors and tumor-associated antigens. The modulating activity of cytokines is a consequence of their influence on gene expression, protein synthesis, membrane expression and shedding of antigens from the cell surface. The changes of phenotype due to the action of cytokines can influence the signalling pathways dependent on the expression and function of cell surface structures. Therefore, the antigen modulating activity of cytokines can thoroughly affect the biological behavior of normal and neoplastic cells. As described here, most of the modulating effects of cytokines on different cell surface structures and the functional consequences of antigenic modulation can be verified in human malignant melanoma cells.

Antigens, Neoplasm↗
PubMed1989

Modulation of the major histocompatibility complex antigen and the immunogenicity of islet allografts.

Modulation of major histocompatibility complex (MHC) antigen by parenchymal cells and "passenger leukocytes" is a common feature of allograft rejection. To assess its significance we have examined the fate of antigen-presenting cell (APC)-depleted pancreatic islet allografts subsequent to increasing their expression of MHC antigens by in vitro exposure to the lymphokine interferon-gamma (gIFN). While most untreated grafts survived indefinitely, gIFN-exposed grafts were acutely rejected. Using in vitro islet cell-lymphocyte coculture assays, we attempted to dissect the underlying mechanism of enhanced islet cell immunogenicity resulting from gIFN treatment. We determined that gIFN exposure did not affect the capacity of islet cells to serve as APC for T lymphocytes, however islet cell exposure to gIFN was associated with enhanced vulnerability to allogeneic cytotoxic T lymphocyte (CTL) lysis in vitro by an CD5+ (OX-19+), CD8+ (OX-8+), CD4- (W3/25-), class I-restricted CTL. On the basis of these findings, we conclude that antigenic modulation can be a decisive factor in the survival of engrafted tissues by augmenting the interaction of the graft antigens with cytolytic effector T lymphocytes.

Animals↗
PubMed2002

Clustering of very late antigen-4 integrins modulates K(+) currents to alter Ca(2+)-mediated monocyte function.

Endothelial cell vascular cell adhesion molecule-1 (VCAM-1) activates adherent monocytes by clustering their very late antigen-4 (VLA-4) receptors, resulting in the modulation of the inwardly rectifying (I(ir)) and delayed rectifying (I(dr)) K(+) currents, hyperpolarization of the cells, and enhanced Ca(2+) influx (Colden-Stanfield M and Gallin EK. Am J Physiol Cell Physiol 275: C267-C277, 1998; Colden-Stanfield M and Scanlon M. Am J Physiol Cell Physiol 279: C488-C494, 2000). The present study was undertaken to test the hypothesis that monoclonal antibodies (MAbs) against VLA-4 (MAbVLA-4) mimic VCAM-1 to cluster VLA-4 integrins, which play a key role in signaling an increase in the secretion of the proinflammatory cytokine interleukin-8 (IL-8). Whole cell ionic currents and IL-8 secretion from THP-1 monocytes that were incubated on polystyrene, VCAM-1-immobilized MAbVLA-4 or an isotype-matched MAb against CD45 (MAbCD45) were measured. Clustering of VLA-4 integrins with a cross-linked MAbVLA-4, but not a monovalent MAbVLA-4, modulated the K(+) currents in an identical manner to incubation of cells on VCAM-1. Similarly, cross-linked MAbVLA-4 or VCAM-1 augmented Ca(2+)-mediated IL-8 secretion from THP-1 monocytes and was completely abolished by exposure to CsCl, an I(ir) blocker. Thus VLA-4 integrin clustering by cross-linked MAbVLA-4 mimics VCAM-1/VLA-4 interactions sufficiently to be associated with events leading to monocyte differentiation, enhanced Ca(2+)-mediated macrophage function, and possibly atherosclerotic plaque formation.

Antibodies, Monoclonal↗
PubMed1995

Phorbol ester (TPA)-induced differential modulation of cell surface antigens in human pluripotential leukemia (K-562) cell line: effects of protein kinase inhibitors with broad- and PKC selective inhibitory activity.

Phorbol ester (TPA)-induced increase in cell surface expression of adhesion structures, i.e. intercellular adhesion molecule-1 (ICAM-1, CD54), beta 2 integrin LFA-1 (CD11a), complement-regulatory cell membrane protein-protein (CD59) and leukocyte common antigen (CD45) in human erythroid/myeloid leukemia cell line K-562 was inhibited by staurosporine, an inhibitor with broad, non-selective protein kinase inhibitory profile, but not by CGP 41,251, a benzoylated staurosporine derivative with the selective protein kinase C (PKC) inhibitory activity. Neither staurosporine nor CGP 41,251 modulated TPA-induced down-regulation of transferrin receptor (CD71). These data suggest that phorbol ester-induced cell surface antigen modulations in K-562 cells are predominantly mediated by PKC-independent signalling pathways.

Alkaloids↗
PubMed2002

Oral delivery of antigens in liposomes with some lipid compositions modulates oral tolerance to the antigens.

Several liposomes containing ovalbumin (OVA), a model antigen, with different lipid compositions were prepared in order to evaluate their ability to induce oral tolerance. Oral administration of these liposomal OVAs induced suppression of the proliferative responses of popliteal lymph node cells from the treated mice to OVA, suggesting that these treated mice were tolerized. The efficiency of the induction of oral tolerance was affected by the liposome composition. OVA entrapment in these liposomes could modulate the tolerizing dose of OVA itself. These results suggest that some liposomes can be suitable antigen-delivery systems for modulated and/or effective induction of oral tolerance.

Administration, Oral↗
PubMed1991

Studies of the modulation of MHC antigen and cell adhesion molecule expression on human dermal microvascular endothelial cells.

Interactions between leukocytes and endothelial cells, particularly in the microvasculature, are important for the initiation and regulation of tissue inflammation. These interactions are regulated by the recognition of specific cell adhesion molecules (CAM) on both leukocytes and endothelial cells. In this study, we examined the modulation of cell surface expression of MHC antigens and the CAM intercellular adhesion molecule 1 (ICAM-1), lymphocyte function antigen 3 (LFA-3), and CD44 on human dermal microvascular endothelial cells (HDMEC) both grown in monolayers and differentiated into capillary-like structures on the basement membrane-like substrate matrigel. HDMEC grown in monolayers or differentiated on matrigel express comparable cell surface MHC class I, LFA-3, CD44, and ICAM-1. ICAM-1, but not LFA-3 or CD44, was increased in expression in a dose- and time-dependent manner by interleukin 1 (IL-1) alpha, tumor necrosis factor (TNF) alpha, lipopolysaccharide (LPS), or interferon (IFN) gamma. Comparable upregulation was observed both in cells grown in monolayers and cells differentiated on matrigel. IL-1 alpha, TNF alpha, and LPS increased ICAM-1 expression on average 100-200% whereas IFN gamma was somewhat less potent. Comparative studies with human umbilical vein endothelial cells (HUVEC) demonstrated consistently lower levels of ICAM-1 expression on HUVEC, but greater increases after cytokine stimulation. Pretreatment with dexamethasone or transforming growth factor (TGF) beta did not affect baseline expression of ICAM-1 or inhibit upregulation of ICAM-1 on HDMEC by IL-1 alpha, TNF alpha, LPS, or IFN gamma. Both IFN gamma and TNF alpha, but not IL-1 alpha increased MHC class I expression, whereas only IFN gamma induced the expression of HLA-DR on HDMEC. The effect of IL-1 alpha, TNF alpha, or IFN gamma was inhibited by antibody to the specific cytokine, but was unaffected by antibody to other cytokines. Additionally, IFN alpha or beta inhibited upregulation of HLA-DR by IFN gamma, but had no effect on the increased MHC class I or ICAM-1 expression mediated by this cytokine. These data demonstrate that the expression of CAM and MHC antigens on small vessel-derived endothelial cells is different from that observed on large-vessel HUVEC, is regulated by the presence of multiple cytokines operating via distinct pathways, and the expression and regulation of these proteins appear to be similar on cells that have been grown in monolayers to those morphologically differentiated into blood vessel-like structures.

Cell Adhesion Molecules↗
PubMed1988

Induction of carcinoembryonic antigen secretion and modulation of protein secretion/expression and fibronectin/laminin expression in human colon carcinoma cells by transforming growth factor-beta.

We have recently reported that TGF-beta induces a response similar to that of planar polar differentiation promoters in human colon carcinoma MOSER cells. N,N-Dimethylformamide and TGF-beta had similar effects on MOSER cells with respect to reversible inhibition of growth (both in monolayer culture and semisolid medium), induction of fibronectin expression and the induction of morphological alterations (Cancer Res., 47:2950-2954, 1987). Since the expression of carcinoembryonic antigen (CEA) has been reported to be modulated by planar polar compounds that promote differentiation in colon carcinomas, we addressed the issue of whether the differentiation-like effects of TGF-beta on these cells would also encompass modulation of CEA expression in the MOSER cells. The biological modulating effects of TGF-beta on extracellular matrix glycoprotein expression and the expression and secretion of cellular proteins were also studied in view of the reported modulating effects of this growth factor on untransformed, noncolonic cells. In this communication we report that TGF-beta induced the synthesis of fibronectin and laminin but not collagen IV. TGF-beta also induced CEA secretion in a dose-dependent manner. Elevated CEA secretion was detected following 48 h of TGF-beta treatment and a 16-fold increase in CEA secretion was observed following 7 days of treatment. The cells were committed to secrete CEA following one dose of TGF-beta treatment. The enhanced expression of four cellular proteins (Mr 42,000, Mr 48,000, Mr 52,000, and Mr 55,000) and the enhanced secretion of three proteins (Mr 66,000, Mr 200,000, and Mr 400,000) were also induced. Some of these protein alterations were detected as early as 6-24 h following TGF-beta treatment. It is concluded that TGF-beta modulated the production and secretion of CEA, the synthesis of fibronectin and laminin, and the expression and secretion of several cellular proteins in the colon carcinoma MOSER cells. To our knowledge, this is the first report on the modulation of CEA and laminin by TGF-beta in tissue-cultured cells, and is the first report on the modulation of cellular proteins by this growth factor in human colon carcinoma cells.

Carcinoembryonic Antigen↗
PubMed1992

Utilization of fractionated soluble egg antigens reveals selectively modulated granulomatous and lymphokine responses during murine schistosomiasis mansoni.

Worm eggs deposited in the livers and intestines of Schistosoma mansoni-infected mice secrete soluble egg antigens (SEA) and induce T cell-mediated circumoval granulomas. In the present study, we fractionated crude SEA by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and tested the fractions for granuloma elicitation and lymphokine production at different stages of the infection. SEA fraction-coupled beads were used to elicit artificial pulmonary granulomas. Acutely infected mice responded with granulomas to seven fractions (less than 21-, 25- to 30-, 32- to 38-, 60- to 66-, 70- to 90-, 93- to 125-, and greater than 200-kDa fractions) of SEA, whereas chronically infected mice responded to four fractions (60- to 66-, 70- to 90-, 93- to 125-, and greater than 200-kDa fractions). In response to both crude and fractionated SEA, granuloma T cells produced high levels of gamma interferon at the preacute (6-week) stage of infection, but production subsequently diminished. Interleukin-2 (IL-2) and IL-4 production peaked at the acute (8-week) stage of infection and concurrently decreased at the chronic (20-week) stage. At the acute stage of the infection, the granulomagenic SEA fractions also elicited IL-2 and IL-4 production; at the chronic stage, IL-2 production and, to a lesser degree, IL-4 production corresponded to SEA fractions that elicited granulomas. Isolated SEA proteins from the 32- to 38-kDa fraction demonstrated differential lymphokine responses: predominant gamma interferon and IL-2 production was elicited by the 32-kDa fraction, whereas the 35- and 38-kDa proteins elicited predominant gamma interferon and IL-4 production. However, all three proteins elicited granuloma formation. The present study reveals changes in granulomatous responses to SEA fractions during the acute and chronic stages of the infection as well as distinct phases of gamma interferon, IL-2, and IL-4 lymphokine production throughout the infection. Based on these results, it is concluded that granuloma formation and IL-2 and IL-4 production are interrelated.

Animals↗
PubMed1977

Modulation of antigen-induced histamine release from bovine granulocytes by several anti-allergic agents.

Sensitised bovine granulocytes release histamine when exposed to antigen. Several anti-allergic agents, some previously shown to be active in cattle, were tested to investigate their modulation of this histamine release process. Diethylcarbamazine citrate potentiated release at low concentrations and inhibited at high concentrations. Sodium meclofenamate and PR-D-92-EA were potent inhibitors. Acetylsalicylic acid and ICI 74,917 inhibited at high concentrations. Disodium cromoglycate was relatively ineffective, although it potentiated histamine release at low concentrations.

Animals↗
PubMed2005

Phagosomal processing of Mycobacterium tuberculosis antigen 85B is modulated independently of mycobacterial viability and phagosome maturation.

Control of Mycobacterium tuberculosis infection requires CD4 T-cell responses and major histocompatibility complex class II (MHC-II) processing of M. tuberculosis antigens (Ags). We have previously demonstrated that macrophages process heat-killed (HK) M. tuberculosis more efficiently than live M. tuberculosis. These observations suggested that live M. tuberculosis may inhibit Ag processing by inhibiting phagosome maturation or that HK M. tuberculosis may be less resistant to Ag processing. In the present study we examined the correlation between M. tuberculosis viability and phagosome maturation and efficiency of Ag processing. Since heat treatment could render M. tuberculosis Ags more accessible to proteolysis, M. tuberculosis was additionally killed by antibiotic treatment and radiation. Processing of HK, live, radiation-killed (RadK), or rifampin-killed (RifK) M. tuberculosis in activated murine bone marrow macrophages was examined by using an I-A(b)-restricted T-cell hybridoma cell line (BB7) that recognizes an epitope derived from Ag 85B. Macrophages processed HK M. tuberculosis more rapidly and efficiently than they processed live, RadK, or RifK M. tuberculosis. Live, RadK, and RifK M. tuberculosis cells were processed with similar efficiencies for presentation to BB7 T hybridoma cells. Furthermore, phagosomes containing live or RadK M. tuberculosis expressed fewer M. tuberculosis peptide-MHC-II complexes than phagosomes containing HK M. tuberculosis expressed. Since only live M. tuberculosis was able to prevent acidification of the phagosome, our results suggest that regulation of phagosome maturation does not explain the differences in processing of different forms of M. tuberculosis. These findings suggest that the mechanisms used by M. tuberculosis to inhibit phagosomal maturation differ from the mechanisms involved in modulating phagosome Ag processing.

Acyltransferases↗
PubMed1984

Modulation induction of the T3 antigen by OKT3 antibody is monocyte dependent.

We investigated the influence of monocytes on the susceptibility of the T3 antigen on human T cells to modulation induction by OKT3 antibody. In the absence of monocytes, the T3 antigen was only minimally susceptible to modulation. After the addition of 20% monocytes to the culture, however, complete modulation was readily observed. Furthermore, we found that even in the absence of OKT3 antibody, monocytes were able to down-regulate the expression of the T3 antigen, although to a lesser extent. The ability of monocytes to enhance antigenic modulation proved to be a more general phenomenon. Each individual T cell antigen, however, differed in its susceptibility to modulation by antibody, monocytes, or both, thereby establishing its own characteristic pattern. In addition, after complete modulation of the T3 antigen, the addition of monocytes to the culture thereafter had a distinct inhibitory effect on the reexpression of the T3 antigen. Monocyte enhancement of T3 modulation is significantly reduced when using the OKT3 F(ab')2 fragment, as is OKT3 mitogenesis. After pulsing the monocytes with OKT3 antibody before adding them to the culture, T3 modulation became nearly complete even in the absence of added OKT3 antibody. Monocyte-induced modulation proved not to be MHC restricted, thus allowing for comparative analysis of this effect between monocytes and other cell types. A moderate, however, incomplete modulation enhancement was observed with the human monocyte cell line U937 and with Daudi cells. This finding proved to coincide with the distinct ability of these cell lines to bind OKT3 antibody by their Fc receptors, as was the case with monocytes. In contrast, neither Fc receptor binding nor T3 modulation enhancement was observed with the cell lines Cess and G7. In addition, no effective T3 modulation was observed with glutaraldehyde-fixed monocytes. The overall results seem to indicate that effective modulation of the T3 antigen by OKT3 antibody requires the active participation of Fc receptors on monocytes.

Adjuvants, Immunologic↗
PubMed1998

Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns.

Current thinking attributes the balance between T helper 1 (Th1) and Th2 cytokine response patterns in immune responses to the nature of the antigen, the genetic composition of the host, and the cytokines involved in the early interaction between T cells and antigen-presenting cells. Here we introduce glutathione, a tripeptide that regulates intracellular redox and other aspects of cell physiology, as a key regulatory element in this process. By using three different methods to deplete glutathione from T cell receptor transgenic and conventional mice and studying in vivo and/or in vitro responses to three distinct antigens, we show that glutathione levels in antigen-presenting cells determine whether Th1 or Th2 response patterns predominate. These findings present new insights into immune response alterations in HIV and other diseases. Further, they potentially offer an explanation for the well known differences in immune responses in "Th1" and "Th2" mouse strains.

Animals↗
PubMed2004

Prophylaxis of autoimmune diabetes by antigen based immune modulation: are we there yet?

Autoimmune type 1 diabetes (early onset/juvenile and slow onset T1D) is a disease mediated by autoreactive T cells accompanied by autoantibodies against islet associated antigens. The genetic predisposition, the association with certain HLA alleles (DR4 and DQ8) as well as the possibility to identify high-risk subjects by autoantibody measurement, fueled hope in regards to potential prophylaxis by vaccination. Numerous preclinical studies along with accumulating evidence for the role of certain autoantigens and putative dominant epitopes created the premises of clinical trials addressing this objective. However, the disappointing outcomes of many of such trials made it clear that significant challenges to clinical application of this concept must be addressed: we do not know at this point, how to choose the most appropriate set of autoantigens, how to optimally use them as a vaccine, whether to define and enroll only a subset of recipients, how to monitor their T cell responses to the vaccine and lastly, which the end-points of clinical T1D trials from an immunologic or metabolic perspective should be? Herein, we will approach some of the opportunities and obstacles associated with this intriguing strategy to fight autoimmune diabetes based on promising novel insight gained form studies with animal models.

Autoantigens↗
PubMed2004

Down-modulation of the antigen receptor by a superantigen for human B cells.

B cell superantigens (SAgs) have been implicated in human diseases by demonstrating non-clonotypic expansion of B cells bearing certain immunoglobulin variable region genes. One possibility is that, during infection with microorganisms secreting SAgs, these potent molecules might modulate BcR expression. To test this hypothesis, we investigated the potential effects of a SAg, protein L from Peptostreptococcus magnus, on antigen B cell receptor (BcR) surface expression in vitro. Using fluorescence microscopy, we found that this SAg induced down-regulation of BcR expression. This effect was time-, dose-, and temperature-dependent, and shedding of cell surface IgM molecules into the culture supernatant was not detected. These data demonstrate that SAg-mediated down-regulation of the BcR expression occurs primarily as a result of BcR internalization. In addition, two specific inhibitors of protein tyrosine kinases were found to retard the BcR modulation on the cell surface and inhibit SAg-induced receptor internalization, showing that tyrosine phosphorylation is required for subsequent internalization of mIg-ligand complexes. The down-modulation of BcR expression may have pathological consequences in patients infected with microorganisms secreting SAgs.

B-Lymphocytes↗
PubMed1990

Modulation of the antigenic phenotype of early-passage human melanoma cells derived from multiple autologous metastases by recombinant human leukocyte, fibroblast and immune interferon.

We have investigated the relationship between in vitro cultivation of autologous melanoma metastases derived from different patients and their levels of expression of class-I and -II major histocompatibility complex (MHC) antigens and melanoma-associated antigens (MAAs). Cell cultures were established from 23 individual metastatic melanoma lesions from 10 patients and were tested early after isolation (between 3rd and 10th passages) for both constitutive expression and modulation by recombinant human leukocyte (IFN-alpha), fibroblast (IFN-beta) or immune (IFN-gamma) interferon of MHC antigens and MAA. All of the melanoma cell lines displayed altered antigen expression following IFN treatment. While in vitro cultures derived from different individuals varied in both constitutive and IFN-modified antigenic expression, cultures of autologous metastases derived from the same patient were very similar. In addition, differences in antigenic profile were apparent when early-passage in vitro cultures were compared with the same melanoma lesion, not established in culture, from which they were derived. The unique de novo and IFN-modified antigenic phenotype of cultures derived from different patients indicates that the antigenic phenotype displayed by melanoma cultures grown in vitro is genetically determined. The differences found between in vitro cultures and their corresponding in vivo lesions, as well as the antigenic heterogeneity displayed by multiple autologous melanoma lesions in vivo, suggest that the in vivo antigenic phenotype may be determined, at least in part, at an epigenetic level.

Antigens, Neoplasm↗