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N Oppenheimer-Marks

Publications and source records attributed to N Oppenheimer-Marks.

At least 19 recordsLinked to original sources
PubMed1999

Activated T cells acquire endothelial cell surface determinants during transendothelial migration.

Activated T cells acquire endothelial cell (EC) plasma membrane constituents during transendothelial migration. This was assessed using an in vitro model system in which human peripheral blood CD4+ T cells migrated through confluent monolayers of HUVEC. Flow cytometry of migrated CD4+ T cells demonstrated that activated, but not resting, T cells acquired a variety of endothelial surface determinants, including CD31, CD49d, CD54, CD61, and CD62E. The extracellular domains of these molecules were detected on migrated T cells with mAbs, including those directed to the ligand-binding regions. A number of approaches were employed to document that the acquisition of these molecules was uniquely accomplished by activated T cells and clearly involved transfer from both resting and TNF-alpha-activated EC. Acquisition of endothelial markers by activated T cells occurred as part of the transfer of membrane components, as migrating T cells acquired EC membranes prelabeled with the lipophilic dye, 3,3'-dihexadecyloxacarbocyanine perchlorate (DiOC-16), along with EC surface proteins. Thus, during transendothelial migration, activated T cells acquire endothelial membrane components, and as a result may deliver them to perivascular sites.

Antigens, CD↗
PubMed1999

Gamma-glutamyl transpeptidase is up-regulated on memory T lymphocytes.

The ectoenzyme gamma-glutamyl transpeptidase (GGT) hydrolyzes glutathione (GSH), is required for the maintenance of normal intracellular GSH levels and modifies the activity of GSH-containing adducts. Previous data suggested that this enzyme was present on mitogen-activated T lymphocytes. However, the level of GGT protein expression on human mononuclear cell subsets has not been determined. A novel mAb to human GGT, 3A8, was developed. 3A8 was used to show that the expression of GGT is, in fact, highest on resting T cells that express markers of the memory phenotype, specifically CD45RO and decreased expression of CD45RB. The peripheral blood of patients with rheumatoid arthritis was found to have expanded numbers of T cells expressing levels of GGT up to 10-fold higher than controls. In addition, the CD4(+) T cell subset with the capacity to migrate across a human endothelial cell monolayer expresses high GGT levels. GGT expression was up-regulated on peripheral blood T cells following activation in vitro by either superantigen, phorbol ester, or IL-15, a stimulatory cytokine synthesized in rheumatoid synovium. Resting peripheral blood T cells that express GGT have higher levels of intracellular thiols than those that do not. These observations suggest that GGT may play an important role in the regulation of lymphocytes that are at a particular developmental stage.

Antibodies, Monoclonal↗
PubMed1998

Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells In vitro and in the SCID mouse-human rheumatoid arthritis model In vivo.

The capacity of endothelial cells (EC) to produce IL-15 and the capacity of IL-15 to influence transendothelial migration of T cells was examined. Human umbilical vein endothelial cells expressed both IL-15 mRNA and protein. Moreover, endothelial-derived IL-15 enhanced transendothelial migration of T cells as evidenced by the inhibition of this process by blocking monoclonal antibodies to IL-15. IL-15 enhanced transendothelial migration of T cells by activating the binding capacity of the integrin adhesion molecule LFA-1 (CD11a/CD18) and also increased T cell motility. In addition, IL-15 induced expression of the early activation molecule CD69. The importance of IL-15 in regulating migration of T cells in vivo was documented by its capacity to enhance accumulation of adoptively transferred human T cells in rheumatoid arthritis synovial tissue engrafted into immune deficient SCID mice. These results demonstrate that EC produce IL-15 and imply that endothelial IL-15 plays a critical role in stimulation of T cells to extravasate into inflammatory tissue.

Adoptive Transfer↗
PubMed1996

Enrichment of differentiated CD45RBdim,CD27- memory T cells in the peripheral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis.

OBJECTIVE: To delineate in greater detail the phenotype of T cells that reside in the synovial tissue (ST) and synovial fluid (SF) of patients with rheumatoid arthritis (RA), in order to determine their precise differentiation status, and to determine whether the accumulation of these specific T cell subsets in these synovial compartments could be related to their capacity for transendothelial migration. METHODS: Lymphocytes from normal subjects or from the peripheral blood (PB), ST, and/or SF of RA patients were phenotypically analyzed by flow cytometry. Normal PB CD4+ T cells were also characterized using an in vitro assay of transendothelial migration. RESULTS: ST and SF were found to be enriched with memory (CD45RA-,CD45RO+,CD11abright,CD44bright and activated (CD69+) T cells. Moreover, ST and SF cells from RA patients were enriched in differentiated CD4+,CD45RBdim,CD27- T cells, a subset of mature memory T cells that develops after prolonged antigenic stimulation. In addition, PB of some RA patients contained an increased number of CD4+,CD45RBdim,CD27- T cells. The CD4+,CD11abright,CD44bright memory T cells, which included the CD45RBdim,CD27- more mature memory cells, exhibited an enhanced capacity for transendothelial migration that is likely to contribute to their enrichment in the rheumatoid synovium. CONCLUSION: RA patients manifest an increased number of mature memory T cells in the SF and ST, and some also have an increased number of these cells in PB that is likely to reflect chronic antigenic stimulation. The enrichment of these cells in the SF and ST reflects, in part, an enhanced capacity to migrate from the vascular space into inflamed tissue.

Arthritis, Rheumatoid↗
PubMed1996

Expression of the beta 7 integrin by human endothelial cells.

Integrin adhesion receptors mediate fundamental intercellular interactions of many cell types as well as cellular interactions with specific extracellular matrix molecules. To date, the beta 7 integrin has been shown to be expressed by leukocyte subsets and to mediate interactions of these cells with extracellular matrix molecules as well as with endothelial and epithelial cells. The data presented here indicate that human endothelial cells also express the beta 7 integrin both in vitro and in situ. Analysis of cDNA indicated that endothelial beta 7 was identical to that expressed by leukocytes. Cell surface expression of beta 7 was increased by exposure of the endothelium to the pro-inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1 beta. In leukocytes, beta 7 complexes with alpha 4 or alpha E integrin chains. Endothelial cells also expressed a number of alpha-integrin chains, including alpha 4, but not alpha E. The expression and utilization of beta 7, presumably complexed with alpha 4, by endothelial cells may be instrumental in the maintenance of the function or phenotype of endothelial cells.

Antigens, CD↗
PubMed1995

Phenotypic characterization of CD4+ T cells that exhibit a transendothelial migratory capacity.

The phenotype of CD4+ T cells capable of transendothelial migration was determined using an in vitro model system, in which cells migrate through a monolayer of endothelial cells (EC) on collagen gels. A specific subset of resting CD4+ memory T cells was found to migrate. T cells within this subset can be defined by the bright expression of CD11a, CD26, CD44, and CD49d. Additionally, the migratory CD4+ T cell population is largely CD58bright, CD31-, CD62L-, and is also enriched in cells that brightly express CD49c, CD49e, and CD49f. Only a minority of the cells are activated, as indicated by expression of CD69. The EC were found to play a central role in facilitating migration of this subset because selective enrichment of CD11abright, CD26bright, CD44bright, CD4+ T cells was not observed when cells migrated in the absence of EC. Activation of the T cells induced a modest degree of migration of an additional subset of CD45RA+, CD31+ naive T cells. In contrast, TNF-alpha activation of the EC increased the transendothelial migration of an additional subset of activated memory T cells that expressed CD69 and CD62L. Neither activation of the T cells, stimulation of the EC, nor the presence of macrophage inflammatory protein-1 alpha (MIP-1 alpha) or RANTES, however, altered the phenotype of the majority of the migratory CD4+ T cell population, which is characteristic of a particular stage of memory cell differentiation. These results suggest that CD4+ T cells acquire the capacity for transendothelial migration at a specific phase of maturation that is only minimally altered by the activation of either the T cell or the EC, or by the presence of specific chemokines in the subendothelial matrix.

Antigens, CD↗
PubMed1994

Phenotypic characterization of CD4-/alpha beta TCR+ and gamma delta TCR+ T cells with a transendothelial migratory capacity.

During inflammation, both CD4+ and CD4- T lymphocytes extravasate into perivascular tissues by adhering to and migrating through the vascular endothelium. These studies were undertaken to characterize the phenotype of CD4- T cells that have a capacity to migrate through endothelium. Results show that CD4- T cells exhibit a greater capacity to migrate through endothelial cells (EC) than CD4+ T cells; and that TCR-gamma delta+ T cells exhibited the greatest migratory capacity. The migrating CD8+ T cell population was enriched in CD45RO+/L-selectin-/LFA-1bright/CD29bright/CD 44bright cells. TNF-alpha-activated EC did not support increased CD4- T cell transendothelial migration and changes in the phenotype of the migrating CD8+ T cells. The migrating CD4- T cell population was enriched in VLA-2+ T cells and expressed increased densities of VLA-4, VLA-5, and VLA-6. The migrating TCR-gamma delta+ T cell population contained both CD8dim and CD8- T cells. Moreover, the migrating gamma delta T cell population was not different from the initial or nonadherent population in that it contained CD45RO+, CD45RA+, and L-selectin+ cells. Finally, migrating TCR-gamma delta+ T cells contained cells expressing V delta 2 and V gamma 9 TCR chains, but these were not enriched compared with the initial population. These studies have characterized the CD4- T cells that are capable of transendothelial migration in vitro. The results are consistent with the conclusion that unique subpopulations of CD8+ alpha beta and CD8+ and CD8- gamma delta T cells gain access to inflammatory sites by virtue of their intrinsic ability to migrate across the endothelium.

CD4 Antigens↗
PubMed1994

Inhibition of the transendothelial migration of human T lymphocytes by prostaglandin E2.

To determine whether part of the anti-inflammatory effects of prostaglandin E2 (PGE2) was related to inhibition of T cell interactions with endothelial cells (EC), the effects of PGE2 and other cAMP-elevating agents on the transendothelial migration of human T cells was examined. Although PGE2 did not effect T cell binding to EC, concentration-dependent inhibition of the transendothelial migration of T cells through unstimulated or IL-1-activated EC was observed. PGE2 inhibited the function of both T cells and EC, with maximal inhibition observed when both T cells and EC were treated with PGE2. However, the inhibitory action of PGE2 could not be ascribed to an effect on the adhesion receptor pair, CD11a/CD18-CD54. The inhibitory effect of PGE2 seemed to relate to its capacity to elevate cellular cAMP levels, because 3-isobutyl-1-methylxanthine enhanced PGE2 activity and dibutyryl cAMP and forskolin also inhibited transendothelial migration. The inhibitory effect of PGE2 and the other cAMP-elevating agents on the function of T cells related in part to suppression of their intrinsic locomotory behavior as random migration in the absence of EC was blocked. In EC, PGE2 and the other cAMP-elevating agents increased the barrier function of EC as evidenced by a decrease in the diffusion of [3H]mannitol through the endothelium. These results indicate that part of the anti-inflammatory action of PGE2 relates to its capacity to suppress the transendothelial migration of T cells by cAMP-mediated alterations in the function of both T cells and EC.

Bucladesine↗
PubMed1994

Virulent Treponema pallidum promotes adhesion of leukocytes to human vascular endothelial cells.

Perivasculitis and endothelial cell abnormalities are characteristic histopathologic features of syphilis, a sexually transmitted disease caused by Treponema pallidum. To extend earlier studies demonstrating that T. pallidum activates endothelial cells, we now show that virulent T. pallidum, but not heat-killed T. pallidum or nonpathogenic Treponema phagedenis, promotes increased adherence of lymphocytes and monocytes to human umbilical vein endothelial cells. Lymphocytes and monocytes are the two cell types prominent in the histopathology of syphilis. Recognition that T. pallidum can stimulate endothelial cells to bind leukocytes provides important insights into the early mechanisms of syphilis immunopathogenesis.

Cell Adhesion↗
PubMed1993

Ricin A-chain and ricin A-chain immunotoxins rapidly damage human endothelial cells: implications for vascular leak syndrome.

The results of Phase I/II clinical trials indicate that ricin A-chain-containing immunotoxins cause vascular leak syndrome, characterized by hypoalbuminemia with resultant weight gain and edema. Vascular leak syndrome may be a dose-limiting factor during treatment with ricin A-chain-containing immunotoxins. In this report, we determined the effect of ricin A-chain and ricin A-chain-containing immunotoxins on human umbilical vein endothelial cells with the aim of developing an in vitro model to study vascular leak syndrome. The major findings of our study are: (1) Human umbilical vein endothelial cells undergo rapid and dramatic changes in morphology after treatment with ricin A-chain and ricin A-chain-containing immunotoxins. These changes include rounding of the cells and, eventually, the formation of gaps between them. (2) The permeability of human umbilical vein endothelial cell monolayers to passage of molecules increases after exposure to ricin A-chain or ricin A-chain-containing immunotoxins and this is consistent with the morphologic changes. (3) Human umbilical vein endothelial cells bind 125I-rRTA in a dose-dependent manner but binding is not specific. (4) Human umbilical vein endothelial cells are moderately more sensitive to ricin A-chain-induced inhibition of protein synthesis and proliferation than simian virus-transformed mouse endothelial cells. (5) The morphologic changes are observed 1 h after exposure to the toxins, whereas inhibition of protein synthesis is not detectable until 4 h after a similar exposure. The in vitro model represents a first step in dissecting the complex events which occur in cancer patients who develop vascular leak syndrome after treatment with ricin A-chain-containing immunotoxins.

Animals↗
PubMed1993

Expression of the TAL1 proto-oncogene in cultured endothelial cells and blood vessels of the spleen.

The TAL1 proto-oncogene encodes a basic helix-loop-helix (bHLH) protein that has been implicated in the pathogenesis of T-cell acute lymphoblastic leukemia. Normal expression of TAL1 is observed in erythrocytic, megakaryocytic and mastocytic cells of the hematopoietic lineage. We now report that both RNA transcripts and polypeptide products of TAL1 are present in human umbilical vein endothelial cells cultured in vitro. Moreover, in situ hybridization revealed a restricted pattern of TAL1 expression in endothelial cells in vivo, including vessels within the white pulp and follicles of the spleen. In view of its presumptive role as a transcriptional factor, the TAL1 gene product may serve during normal development as a regulator of endothelial cell growth or differentiation.

Basic Helix-Loop-Helix Proteins↗
PubMed1992

Identification of subsets of human T cells capable of enhanced transendothelial migration.

A critical step in immunologically mediated inflammation is the migration of T cells between endothelial cells of postcapillary venules and into the tissues. To determine whether specific cells are capable of transendothelial migration, T cells that had migrated through endothelial monolayers were retrieved and analyzed. To accomplish this, human umbilical vein endothelial cells (EC) were cultured to confluence on collagen gels and incubated with human T cells. T cells that were nonadherent to the EC, those that bound to the endothelium, and cells that had migrated through the endothelial monolayer and into the collagen were individually harvested and characterized. After a 4-h incubation with EC, T cells distributed themselves such that 77 +/- 2% were nonadherent, 13 +/- 2% were bound to EC, and 10 +/- 1% had migrated into the collagen. The CD4+ T cells that had migrated into the collagen were predominantly CD29bright/CD45RObright and CD45RA-. CD8+ T cells demonstrated a greater transendothelial migratory capacity than the CD4+ T cells. The migrated CD8+ T cells were mainly CD29bright but CD45RA+. Additional phenotypic analysis of the migrating cells indicated that they contained fewer cells that expressed L-selectin. Moreover the surface expression of CD7 was less dense in the T cells that had migrated than in the nonadherent T cells. Finally the T cells that migrated were not enriched for CD45RBdim T cells. Prolonging the incubation with EC to 36 h increased the number of T cells that migrated but did not alter the predominance of CD29bright T cells in the migrated population. Stimulation of EC with IL-1 or IFN-gamma also increased the number of adherent and migrating T cells, respectively, but did not alter the phenotype of the migrating cells. These results indicate that the capacity for transendothelial migration is an intrinsic ability of certain subpopulations of T cells and is related to their stage of differentiation as identified by their surface phenotype.

Antigens, CD↗
PubMed1992

The intrinsic migratory capacity of memory T cells contributes to their accumulation in rheumatoid synovium.

OBJECTIVE: Mechanisms controlling the infiltration of T cells into rheumatoid synovium have not been fully characterized. These studies were undertaken to investigate the relationship between T cell phenotype and migratory capacity, so as to elucidate mechanisms that might contribute to the accumulation of T cells at inflammatory sites. METHODS: The characteristics of in vivo migrating cells were studied by dual-immunofluorescence FACS (fluorescence-activated cell sorter) analysis of rheumatoid synovial and peripheral blood T cells. Migratory cells were also characterized using a recently developed in vitro assay, wherein peripheral blood T lymphocytes (PBTL) with the capacity to migrate through endothelial cell monolayers were retrieved and assessed. RESULTS: Migratory CD4+ T cells from rheumatoid arthritis (RA) and normal individuals were characterized as being CD45RA-, CD29bright, CD11abright, L-selectin-, CD54+, and CD58+. Migrating RA PBTL (compared with normal PBTL), however, were significantly enriched in activated HLA-DR+ T cells. RA synovial tissue lymphocytes exhibited a similar phenotype, but with decreased surface density of CD4 and an increase in HLA-DR and VLA-1. RA synovial lymphocytes exhibited a 2-3-fold increase in migratory capacity over normal and RA PBTL: CONCLUSION: These studies demonstrate the inherent migratory proficiency of CD4+ T cells that express a memory phenotype (CD29bright, CD11abright, and CD58+). In addition, enhanced transendothelial migration was observed for CD4+ T cells that were CD54+ and L-selectin-. These studies demonstrate that the migratory patterns of circulating lymphocytes may be correlated with their surface phenotype and that the intrinsic migratory capacity of memory T cells is one component contributing to their accumulation in the rheumatoid synovium.

Adult↗