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At least 109 records · Page 6Linked to original sources
PubMed1992

Intercellular adhesion molecule-2, a second counter-receptor for CD11a/CD18 (leukocyte function-associated antigen-1), provides a costimulatory signal for T-cell receptor-initiated activation of human T cells.

Activation of T cells often requires both activation signals delivered by ligation of the TCR and those resulting from costimulatory interactions between certain T cell surface accessory molecules and their respective counter-receptors on APC. CD11a/CD18 complex on T cells modulate the activation of T cells by interacting with its counter-receptors intracellular adhesion molecule (ICAM-1) (CD54) and/or ICAM-2 on the surface of APC. The costimulatory ability of ICAM-1 has been demonstrated. Using a soluble ICAM-2 Ig fusion protein (receptor globulin, Rg) we demonstrate the costimulatory effect of ICAM-2 during the activation of CD4+ T cells. When coimmobilized with anti-TCR-1 mAb ICAM-2 Rg induced vigorous proliferative response of CD4+ T cells. This costimulatory effect of ICAM-2 was dependent on its coimmobilization with mAb directed at the CD3/TCR complex but not those directed at CD2 or CD28. Both resting as well as Ag-primed CD4+ T cells responded to the costimulatory effects of ICAM-2. The addition of mAb directed at the CD11a or CD18 molecules almost completely inhibited the responses to ICAM-2 Rg. These results are consistent with the role of CD11a/CD18 complex as a receptor for ICAM-2 mediating its costimulatory effects. Stimulation of T cells with coimmobilized anti-TCR-1 and ICAM-2 resulted in the induction of IL-2R (CD25), and anti-Tac (CD25) mAb inhibited this response suggesting the contribution of endogenously synthesized IL-2 during this stimulation. These results demonstrate that like its homologue ICAM-1, ICAM-2 also exerts a strong costimulatory effect during the TCR-initiated activation of T cells. The costimulatory effects generated by the CD11a/CD18:ICAM-2 interaction may be critical during the initiation of T cell activation by ICAM-1low APC.

Antigen-Presenting Cells↗
PubMed1992

Regulation of ICAM-1 expression and function in human dermal fibroblasts by IL-4.

ICAM-1 is found on the surface of many hematopoietic and nonhematopoietic cells and can function as an adhesive ligand for the integrin, leukocyte function-associated molecule-1 (LFA-1, CD11a/CD18). ICAM-1/leukocyte function-associated molecule-1 interaction has been shown to be of importance in many immune-mediated cell-cell adhesion reactions. In vitro, unstimulated human fibroblast cell cultures express low levels of ICAM-1. Using ELISA, cytofluorography, electron microscopy, Northern analysis, and an in vitro cell adherence assay, we demonstrate that treatment of human dermal fibroblasts with the cytokine IL-4 leads to an increase in cell surface ICAM-1 expression that is under transcriptional control as well as increased fibroblast adhesion to LFA-1-bearing T lymphocytes. The kinetics of increased ICAM-1 expression induced by IL-4 paralleled the increase in ICAM-1-dependent T lymphocyte adhesion. The increase in T cell adhesion was determined to be due to the effects of IL-4 on the fibroblasts and not the adhering T cells. Treatment of fibroblasts with IL-4 also resulted in enhanced binding of human rhinovirus, a recently reported additional ligand for ICAM-1. Virus binding was IL-4 dose dependent and could be inhibited with mAb to ICAM-1. Both the expression of ICAM-1 and the ICAM-1-dependent increase in T lymphocyte adhesion that was induced by IL-4 could be inhibited by preexposure of the fibroblasts to either IL-1 or IL-6, suggesting that multiple cytokines can have both positive and negative effects on human fibroblast ICAM-1 expression and function.

Cell Adhesion↗
PubMed1992

Deletion of antigen-specific immature thymocytes by dendritic cells requires LFA-1/ICAM interactions.

An in vitro assay was used for assessing the participation of various cell surface molecules and the efficacy of various cell types in the deletion of Ag-specific immature thymocytes. Thymocytes from mice expressing a transgenic TCR specific for the male Ag presented by the H-2Db class I MHC molecule were used as a target for deletion. In H-2d transgenic mice, cells bearing the transgenic TCR are not subjected to thymic selection as a consequence of the absence of the restricting H-2Db molecule but, nevertheless, express this TCR on the vast majority of immature CD4+8+ thymocytes. In this report we show that CD4+8+ thymocytes from H-2d TCR-transgenic mice are preferentially killed upon in vitro culture with male APC; DC were particularly effective in mediating in vitro deletion when compared with either B cells or T cells. Deletion of CD4+8+ thymocytes by DC was H-2b restricted and could be inhibited by mAb to either LFA-1 alpha or CD8. Partial inhibition was observed with mAb to ICAM-1, whereas mAb to CD4 and LFA-1 beta were without effect. These results are the first direct evidence of LFA-1 involvement in negative selection and provide further direct support for the participation of CD8/class I MHC interactions in this process. Like the requirements for deletion, activation of mature male-specific CD4-8+ T cells from female H-2b TCR-transgenic mice was also largely dependent on Ag presentation by DC and required both LFA-1/ICAM and CD8/class I MHC interactions; these results support the view that activation and deletion may represent maturation stage-dependent consequences of T cells encountering the same APC. Finally, our results also support the hypothesis that negative selection (deletion) does not require previous positive selection because deletion was observed under conditions where positive selection had not occurred.

Animals↗
PubMed1992

Regulation of the expression of ICAM-1 on human monocytes and monocytic tumor cell lines.

In this study we investigated the mechanisms regulating expression of ICAM-1 that plays an important role for Ag presentation, on peripheral blood monocytes, and three myelomonocytic cell lines representing different stages of monocyte maturation. ICAM-1 expression on freshly isolated monocytes was low in all donors tested. After 16- to 20-h incubation, about a 20-fold increase was observed, whereas ICAM-1 expression on lymphocytes did not change. This marked increase in Ag expression was specific for ICAM-1, because expression of other monocyte Ag remained unchanged (alpha-chain of lymphocyte function-associated Ag-1) or decreased (ICAM-2, alpha-chains of CR3 and CR4, their common beta-chain and Fc gamma RI) during overnight incubation; only HLA-DR showed a slight increase. Enhanced expression of ICAM-1 was not caused by adherence; it was also not due to trace amounts of IFN-gamma possibly present under our culture conditions. Endotoxin contamination of the medium was excluded as a cause for the enhanced expression, and neither LPS nor its antagonist polymyxin B were able to alter ICAM-1 expression. Whole blood culture almost completely prevented up-regulation of ICAM-1 expression, thus apparently mimicking the in vivo situation. Culture of monocytes together with other PBMC had no significant influence on monocyte ICAM-1 levels. From 12 different cytokines tested for their ability to modulate "spontaneous" up-regulation of ICAM-1 in culture, only IFN-gamma was found to increase expression about twofold. This effect was also observed in whole blood culture. All other cytokines had no significant effect. In contrast, ICAM-1 expression on two of the three cell lines (KG1 and HL60) was inducible by TNF-alpha to a much higher degree than by IFN-gamma, whereas the results with U937 were comparable with those obtained for normal monocytes. The protein- and RNA-synthesis inhibitors cycloheximide and actinomycin D prevented expression of ICAM-1 in a dose-dependent fashion. In Northern blot experiments no difference in the amounts of mRNA was observed between freshly isolated and cultured monocytes, indicating that "spontaneous" induction of ICAM-1 is regulated at a posttranscriptional level. In contrast, stimulation with IFN-gamma caused a significant increase of detectable RNA comparable to that observed for Ag expression. These results disclose a very special regulation of ICAM-1 expression on monocytes which could be consistent with the view that ICAM-1 is actively down-regulated in vivo until the monocyte leaves the circulation.

Antigens, CD↗
PubMed1992

Stimulation of human naive and memory T helper cells with bacterial superantigen. Naive CD4+45RA+ T cells require a costimulatory signal mediated through the LFA-1/ICAM-1 pathway.

The role of the accessory molecule ICAM-1 in activation of subpopulations of human T cells was examined using the bacterial superantigen staphylococcal enterotoxin A (SEA) as a MHC class II and TCR-dependent polyclonal T cell activator. Human T cells responded with different sensitivity to SEA when presented on mouse accessory cells expressing a human transfected MHC class II gene product. Mouse L cells cotransfected with both MHC class II (DR2A or DR7) and ICAM-1-stimulated T cells at 100-fold lower concentrations of SEA as compared to the single transfected cells. mAb reacting with the CD11a, CD18, or ICAM-1 molecules efficiently inhibited T cell activation with the cotransfected HLA-DR2A/ICAM-1 cell but did not influence T cell activation with the HLA-DR2A single transfected cell. Analysis of the ICAM-1 requirement on CD4+ memory (CD4+45RO+) and naive (CD4+45RA+) T cells revealed that CD4+45RA+ naive Th cells were hyporesponsive to SEA-induced activation with the HLA-DR2A single transfectant. However, cotransfection of ICAM-1 enabled these cells to respond to low doses of SEA implicating that they are more dependent on accessory molecules than the CD4+45RO+ cells. rICAM-1 immobilized on a plastic surface, was able to strongly costimulate SEA-induced T cell activation with the HLA-DR2A single transfectant, suggesting that costimulatory signals mediated to the T cells through LFA-1 can be delivered physically separated from the TCR signal. CD4+45RO+ memory and CD4+45RA+ naive Th cells apparently differ in their capacities to be activated by SEA bound to HLA-DR. Although the TCR molecule densities are similar in these two subsets, costimulation with ICAM-1 is required for activation of the CD4+45RA+, but not the CD4+45RO+ T cell subset at 1 to 10,000 ng/ml concentrations of SEA. This observation indicates different activation thresholds of naive and memory Th cells when triggering the TCR over a wide dose interval of superantigen.

Antigens, Bacterial↗
PubMed1992

Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue.

Expression of proteins associated with immune function was investigated immunohistochemically in postmortem brain and spinal cord of patients with amyotrophic lateral sclerosis (ALS). Reactive microglia/macrophages displaying high levels of leukocyte common antigen (LCA), the immunoglobulin receptor Fc gamma R1, lymphocyte function associated molecule-1 (LFA-1), the complement receptors CR3 and CR4, the class II major histocompatibility complex molecules HLA-DR, HLA-DP and HLA-DQ and common determinants of the class I HLA-A,B,C complex were abundant in affected areas in ALS. These areas included the primary motor cortex, motor nuclei of the brain stem, the anterior horn of the spinal cord, and the full extent of the corticospinal tract. A significant number of T lymphocytes of the helper/inducer (CD4+) and cytotoxic/suppressor (CD8+) subtypes were observed marginating along the walls of capillaries and venules and extending into the parenchyma of affected areas. Clusters of complement activated oligodendroglia as well as degenerating neurites positive for C3d and C4d were frequently detected in ALS-affected areas. These data provide evidence of immune-effector changes in ALS. They are consistent with an autoimmune or slow virus theory of the disorder, but may reflect only secondary changes.

Amyotrophic Lateral Sclerosis↗
PubMed1992

Cetirizine does not influence the immune response.

Antihistamines are frequently employed in the treatment of allergic rhinitis and urticaria-angioedema syndrome. We analyzed the in vitro effects of cetirizine on the immune response. To this end the proliferation of peripheral mononuclear cells induced by mitogen and by -CD3, -CD2, or -CD28 monoclonal antibodies has been studied. Since the plasma peak of cetirizine following ingestion of 10 mg is about 1 microgram/mL, the drug was tested in the cultures at the concentration of 0.1, 1, or 10 micrograms/mL. No influence of cetirizine on T cell proliferation was detected. We also evaluated the effect of cetirizine on the expression of the following markers expressed by T cells upon activation: lymphocyte markers ICAM-1, HLA-DR, and CD25 surface expression, alpha-1-acid glycoprotein has been also studied. There was no effect of cetirizine on the investigated immunologic parameters; these data acquire clinical relevance when related to previous reports showing a depression of the immunologic response exerted by other compounds such as ketotifen and theophylline and when related to the recent data about the modulation of ICAM-1 expression on eosinophils by cetirizine. Cetirizine does not affect ICAM-1 expression of lymphocyte membrane.

Adult↗
PubMed1992

Various cell types in human atherosclerotic lesions express ICAM-1. Further immunocytochemical and immunochemical studies employing monoclonal antibody 10F3.

The specificity of monoclonal antibody 10F3, generated to smooth muscle cells isolated from fetal human aorta, has been further explored in a series of biological, biochemical, and immunocytochemical studies. In the first assay, it was found that 10F3 could inhibit aggregation of phytohemagglutinin (PHA)-induced lymphocytes in a manner comparable to that of antibody RR1/1, an anti-intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody. In immunoprecipitation experiments followed by one-dimensional gel electrophoresis, both 10F3 and RR1/1 immunoprecipitated 90 kd proteins, with results suggesting that the two antibodies recognized different epitopes of the same molecule. A series of immunocytochemical studies on human atherosclerotic lesions was performed; using single-labeling techniques, 10F3-positive cells were found in the vessel wall and in lesions of virtually all specimens of fatty streaks and fibrous plaques. Using double-labeling techniques, 10F3-positive macrophages and 10F3-positive smooth muscle cells were found; however, there were also a significant number of non-smooth muscle, nonmacrophage 10F3-positive cells. These studies demonstrate that 10F3 identifies ICAM-1, and that this protein is expressed on a variety of cell types in human atherosclerotic lesions. ICAM-1 may represent a developmentally regulated protein that is expressed in fetal but not adult mesenchymal cells, but can be re-expressed in pathologic processes such as atherosclerosis.

Adult↗
PubMedDate not supplied

The differential reactivity of cells of the melanocytic lineage with four monoclonal antibodies against IFN-gamma inducible molecules.

The reactivity of four monoclonal antibodies (MAbs) directed against IFN-gamma inducible antigens with melanocytic cells was investigated in the course of local and systemic tumor progression of human malignant melanoma. Frozen sections of histologically defined melanocytic tissues at different stages of progression were stained with these MAbs using an indirect immunoperoxidase technique. The reactivity of MAbs Me15/B3 and Me15/F9, directed against two different epitopes of a 90-kDa molecule, was found to correlate with melanoma progression. Indeed, a significantly lower percentage of small than of advanced primary melanomas or metastases stained positively. A differential staining of nevocytic and dysplastic nevi was further observed for these two MAbs, which were also non-reactive with normal skin melanocytes. The reactivity of MAb Me14/D12, which identifies the intercellular adhesion molecule ICAM-1 and MAb Mel14/F12, directed against a 40-kDa molecule, was found to be independent of the Breslow thickness of primary melanomas. Both the latter MAbs stained a high proportion of nevocytic and dysplastic nevi. The co-expression of the surface molecules defined by MAbs Me14/D12, Me15/B3 and Me15/F9 in the course of melanoma progression was also analyzed. The frequency of this co-expression increased according to the Breslow thickness of primary melanomas. In addition, up to 100% of metastases, as opposed to 20% of dysplastic nevi, were found to be simultaneously stained by these three MAbs. It is therefore conceivable that high-risk melanocytic lesions might be identified by the use of a combination of MAbs directed against IFN-gamma regulated antigens.

Antibodies, Monoclonal↗
PubMed1992

Soluble intercellular adhesion molecule 1 is released by human melanoma cells and is associated with tumor growth in nude mice.

We have studied the cytokine regulation of cell surface and soluble intercellular adhesion molecule 1 (ICAM-1) expression on the human melanoma cell line A375M. Unstimulated cells express ICAM-1 on their cell surface but do not secrete significant levels of soluble ICAM-1. Interleukin 1, interleukin 6, tumor necrosis factor, and gamma-interferon all increased cell surface expression of ICAM-1. Tumor necrosis factor, interleukin 1, and gamma-interferon also caused the release of soluble ICAM-1. The serum of melanoma patients has been reported to contain elevated levels of soluble ICAM-1; however, the source of this ICAM-1 is unclear. The serum from nude mice bearing s.c. human melanoma tumors was found to contain soluble human ICAM-1. ICAM-1 levels showed a positive correlation with tumor weight. The release of ICAM-1 from melanoma tumors, in response to host-derived cytokines, may have relevance to immune recognition of the tumor.

Animals↗
PubMed1992

Heterotypic adherence between murine leukemia/lymphoma cells and marrow stromal cells involves a recognition mechanism with galactosyl and mannosyl specificities.

We have previously shown that leukemia/lymphoma (LL) cells adhere to marrow stromal cells (MSC), and MSC induce clonal growth of LL cells. Even though CD11a/18 and CD54 are important in leukocyte and endothelial cell interaction, the literature suggested that these adhesion proteins are not involved in adhesion of hematopoietic stem cells to MSC. We therefore utilized a unique ICAM-1- murine MSC line (MLT) to evaluate the mechanisms of adherence of LL cells (L5178Y and L1210) to MLT. Adherence of LL cells to extracellular matrix (ECM) proteins was also examined. L1210 cells attached to collagen types III and IV, laminin, and fibronectin, but not to collagen type I. L5178Y cells did not attach to any of the ECM proteins tested. The adherence of both L1210 and L5178Y to MSC was unaffected by rat monoclonal antibodies to murine CD11a, CD11b, and CD18. Neoglycoprotein probes, mannosyl-bovine serum albumin (BSA) and galactosyl-BSA, inhibited the adherence of L5178Y and L1210 cells to MSC by 34%-63% of controls at concentrations of 10(-3) and 5 x 10(-3) M. In contrast, fucosyl-BSA had no inhibitory effect on LL cell adherence of MLT. These data suggest that 1) LL cells may adhere to MSC by a lectin mechanism with mannosyl and galactosyl specificities; and 2) other mechanisms of adherence, not yet defined, are also important in this system.

Animals↗
PubMed1992

Inhibition of Molt-4-endothelial adherence by synthetic peptides from the sequence of ICAM-1.

Previous studies have shown that inflammatory pathologies are mediated by lymphocyte adhesion to endothelium and subsequent transmigration through the endothelial monolayer. Lymphocyte-endothelial adherence is, in part, caused by the leukocyte integrin LFA-1 binding to ICAM-1, its ligand on endothelial cells. Synthetic peptides based on specific amino acid sequences of human ICAM-1 inhibit the adherence of a lymphocytic cell line, Molt-4, to cytokine-stimulated endothelial cells. A total of 26 peptides spanning the extracellular domains of ICAM-1 were evaluated for their inhibitory activity in two cell adhesion assays. Binding of fluorescently labeled Molt-4 cells to TNF-stimulated human umbilical vein endothelial cells was inhibited reproducibly by peptides ICAM1-20, ICAM26-50, ICAM40-64, ICAM132-146, and ICAM345-375. Three overlapping sequences of the peptide ICAM40-64, KELLLPGNNRKVYELSNVQEDSQPM, were synthesized and tested as well, and the sequence KELLLPGNNRKV showed the greatest inhibition. The inhibitory activity of these peptides was confirmed using a second assay, inhibition of aggregation of the Epstein-Barr virus-transformed B-lymphoblast line JY. Polyclonal antibodies were developed in rabbits by immunization with two of the peptides and characterized for their ability to inhibit lymphocyte-endothelial adherence. These studies predict potential sites for interaction of the integrin receptor, LFA-1, with its ligand, ICAM-1. Thus lymphocyte-endothelial interaction, and resulting inflammation, may be partially mediated by the association of ICAM-1 with LFA-1 at the specific molecular locations identified in this study.

Amino Acid Sequence↗
PubMed1992

Regulation of locomotion and cell-cell contact area by the LFA-1 and ICAM-1 adhesion receptors.

We demonstrate complementary differences in the behavior of B lymphoblastoid cells adhering to LFA-1 or its counter-receptor ICAM-1. The interaction of B lymphoblastoid cells with glass-supported planar bilayers bearing LFA-1 or ICAM-1 was observed by time-lapse video microscopy, and the distribution of adhesion receptors on cells interacting with the planar bilayers was studied by immunofluorescence microscopy. B lymphoblasts formed a large contact area and crawled rapidly (up to 25 microns/min) on planar bilayers bearing ICAM-1. In contrast, these cells attached to planar bilayers bearing LFA-1 through a fixed point about which the cells actively pivoted, using a single stalk-like projection. Phorbol ester-stimulated lymphoblasts, which adhere more strongly to ICAM-1-bearing substrates than unstimulated lymphoblasts, were still capable of locomotion on ICAM-1. Phorbol ester stimulation of B lymphoblasts on planar bilayers bearing LFA-1 promoted a rapid conversion from "stalk" attachment to symmetrical spreading of the cell on the substrate. Cellular LFA-1 remained uniformly distributed on the cell surface during interaction with bilayers bearing purified ICAM-1 as determined by immunofluorescence. In contrast, ICAM-1 was concentrated in the stalk-like structure through which the unstimulated B lymphoblasts adhered to LFA-1 in planar bilayers, but ICAM-1 immunofluorescence became more uniformly distributed over the cell surface within minutes of phorbol ester addition. Neither LFA-1 or ICAM-1 colocalized with the prominent staining of filamentous actin in the ruffling membrane regions. Interaction through cell surface LFA-1 and ICAM-1, 2, or 3 promotes different cellular morphologies and behaviors, the correlation of which with previously observed patterns of lymphocyte interaction with different cell types is discussed.

B-Lymphocytes↗
PubMed1992

Ganglioside, adhesion molecule, and HLA antigen expression in basal cell carcinoma lesions.

The antigenic profile of basal cell carcinoma (BCC) cells was analyzed by immunoperoxidase staining of 27 surgically removed BCC lesions with antiganglioside, antiadhesion molecule, and antihistocompatibility locus antigen (HLA) monoclonal antibodies (MoAb). The large majority of BCC lesions were stained by antiganglioside MoAb; among the latter the anti-GD3 ganglioside MoAb R24 displayed the broadest reactivity. The GD3 ganglioside expression by BCC cells, which was corroborated by thin layer chromatography immunostaining with MoAb R24, appears to be a proliferation dependent phenomenon. Among the adhesion molecules tested vitronectin receptor and CDw44 were found in up to 70% of the lesions tested, while intercellular adhesion molecule 1 (ICAM-1) was detected in only a low percentage of BCC cells in one lesion. ICAM-1 was not induced on BCC cells in five and three lesions removed 24 and 48 h, respectively, following the intralesional injection of gamma-interferon. The latter enhanced HLA Class I antigen expression and induced ICAM-1 expression by the surrounding keratinocytes; furthermore gamma-interferon induced HLA Class II antigen expression by a small percentage of BCC cells in three lesions. These results suggest that malignant transformation of keratinocytes is associated with a selective loss of susceptibility to induction by cytokines of ICAM-1 expression. Besides confirming the low HLA Class I and Class II antigen expression by BCC cells, the present investigation has shown a differential expression of distinct monomorphic determinants of HLA Class I antigens and a lower expression of HLA-A antigens than of HLA-B antigens by BCC cells. Furthermore, the present study has shown that HLA Class II antigens can be induced on BCC cells by cytokines.

Aged↗