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Biomedical subjects

Z Fabry

Publications and source records attributed to Z Fabry.

17 recordsLinked to original sources
PubMed1999

The substance P receptor is necessary for a normal granulomatous response in murine schistosomiasis mansoni.

Immune cells within the granulomas of murine schistosomiasis mansoni make the neuropeptide substance P (SP) and express neurokine 1 receptor, which is the specific receptor for substance P (SPr). It was determined if mice with deletion of the SPr (SPr-/-) would develop a normal granulomatous response to schistosome ova during the course of natural infection. Mean liver granuloma size was smaller in SPr-/- mice compared with that of wild-type control animals. Although flow analysis revealed little difference in the cellular composition of the granulomas, both splenocytes and granuloma cells from SPr-/- mice produced much less IFN-gamma and IgG2a and less IgE. The expression of Th2 cytokines (IL-4/IL-5) and IgG1 was comparable to the wild-type control. The mouse with targeted disruption of its SPr had the nonmammalian gene encoding the enzyme beta-galactosidase inserted in exon 1 of the SPr gene. There was beta-galactosidase activity in many mononuclear cells scattered throughout the schistosome granulomas of SPr-/- mice. Also, a granuloma T cell line derived from this transgenic mouse produced beta-galactosidase. These results provide further evidence that in murine schistosomiasis SPr is displayed commonly on granuloma inflammatory cells and is important for granuloma development and expression of IFN-gamma circuitry in this natural infection.

Animals↗
PubMed1998

Influence of adhesion molecule expression by human brain microvessel endothelium on cancer cell adhesion.

Cultures of endothelial (En) cells derived from human brain microvessels were established in order to characterize adhesion molecule expression and to assay the adhesion properties of neoplastic cell lines to monolayers of En cells. Low constitutive expression of beta1 integrin (CD29), and ICAM-2 (CD102) was detected on human brain microvessel En cells. The beta1 chain of the VLA integrin family, ICAM-1, E-selectin (CD62E) and VCAM-1 (CD106) but not ICAM-2 and PECAM-1 (CD31) expression was upregulated by IL1-alpha, and TNF-alpha proinflammatory cytokines. High expression of PECAM-1 was found on non-activated human brain EN cells. In order to study the potential role of adhesion molecules in neoplastic cell adhesion two tumor cell lines were chosen. Adhesion of a cell line (DU145) derived from a cerebral metastasis of prostate carcinoma to human brain microvessel En cell monolayers was less pronounced compared to adhesion of a primary prostate carcinoma cell line (ND1). Adhesion of cerebral metastatic neoplastic cell line (DU145) was not significantly influenced by incubation of endothelial cells with different proinflammatory cytokines. The adhesion capability of primary prostate carcinoma line (NDI) was significantly upregulated by TNF-alpha proinflammatory cytokine. Furthermore, the adhesion of ND1 was partly inhibited using anti-E-selectin and VCAM-1 monoclonal antibodies. There was no significant effect of anti-adhesion antibodies on the adhesion characteristics of the cerebral metastatic (DU145) cell line. Our data demonstrate that different mechanisms are involved in the adhesion of neoplastic cells to cerebral En cells and turn our attention to the importance of adhesion molecule expression in the formation of metastases.

Antibodies, Monoclonal↗
PubMed1998

Murine endothelia do not express MHC class II I-Ealpha subunit and differentially regulate I-Aalpha expression along the vascular tree.

Cellular elements of the vascular wall, such as endothelium (En) and smooth muscle cells/pericytes (SM/P) possess important immunologic properties. We have previously reported that murine brain microvessel En cells and SM/P express Major Histocompatibility (MHC) class II molecules and activate syngeneic CD4+ T cells in a class II dependent way. Herein we compare MHC class II expression on brain microvessel En to aorta large vessel En cells in order to explore the mechanisms of immune responses in brain tissue versus other peripheral tissues. Interestingly, we demonstrate that En cells from brain microvessel and large aortic vessel express the I-A but not the I-E subunit of MHC class II molecules. The expression of I-A class II molecules can be upregulated on brain microvessel and aortic En cells by interferon-gamma (IFN-gamma). Similarly, the expression of I-A, but not I-E, MHC class II molecules on brain microvessel endothelial cells was upregulated in the presence of activated T cells. Interleukin-10 (IL-10) was found to inhibit IFN-gamma-mediated upregulation of I-A class II molecule expression on aortic but not on microvessel En cells. Our data may indicate that some differences in organ-specific immune responses, are defined by local parameters, such as MHC distribution and regulation.

Animals↗
PubMed1995

TGF-beta 2 decreases migration of lymphocytes in vitro and homing of cells into the central nervous system in vivo.

Migration of leukocytes through an in vitro, cell culture model of the blood-brain barrier (BBB) composed of murine brain microvessel endothelial (En) cells and astrocytes, and in vivo in experimental allergic encephalomyelitis (EAE), was investigated. We have recently shown that the adhesiveness of cultured murine brain microvascular endothelial cells for lymphocytes can be increased significantly by pretreatment with IL-1 beta, TNF-alpha, IFN-gamma, and LPS. In the present study, we investigated the role of TGF-beta 2 on the migration of leukocytes through the BBB. In vitro migration was assessed by measuring the percentage of 51Cr-labeled leukocytes migrating through the En/astrocyte monolayers. The basal level of migration was up-regulated significantly by treating the En/astrocyte monolayers with IL-1 alpha, IFN-gamma, TNF-alpha, and LPS. The ability of these cytokines to modulate migration was dose-dependent. Treatment of En cell/astrocyte monolayers with TGF-beta 2 down-regulated the level of leukocyte migration up-regulated by IL-1 alpha, IFN-gamma, and TNF-alpha in vitro in a dose-dependent manner. TGF-beta 2 also inhibited the migration of lymphocytes into the central nervous system (CNS) in vivo in a dose-dependent fashion. Taken together, these findings strongly suggest that TGF-beta plays an important role in the reduction of lymphocyte infiltration into the CNS in inflammatory demyelinating diseases such as EAE.

Animals↗
PubMed1995

Involvement of nitric oxide in IFN-gamma-mediated reduction of microvessel smooth muscle cell proliferation.

Previous studies in our laboratory demonstrated that murine cerebral microvessel smooth muscle cells (SMC) activate syngeneic CD4+ T-cells in vitro. These T-cells, or their culture supernatants, in turn, strongly inhibit proliferation of the SMC. The present study focuses on IFN-gamma as a mediator of inhibition of SMC proliferation, and addresses the molecular mechanism of this inhibition. IFN-gamma profoundly reduced the proliferation of murine brain microvessel smooth muscle cells in vitro. Three lines of evidence indicate that nitric oxide contributed to this effect: (1) IFN-gamma-mediated inhibition of proliferation correlated with the quantity of nitrite, a stable breakdown product of nitric oxide, in culture supernatants; (2) the addition of N(g)- monomethyl-l-arginine, and inhibitor of nitric oxide synthesis, restored proliferation to control or near control levels; and (3) the addition of hemoglobin, which has a high affinity for, and thus sequesters nitric oxide, also resulted in significant restoration of the proliferative response. However, the nitric oxide donating chemical sodium nitro-prusside, at concentrations up to 100 microM, had no direct cytostatic effect. These results suggest that nitric oxide is a necessary but insufficient component in IFN-gamma-mediated inhibition of microvessel smooth muscle cell proliferation. TNF-alpha also stimulated nitric oxide production by the smooth muscle cells, but was not as potent as IFN-gamma at inhibiting proliferation. Knowledge of the physiological effects of lymphokines on cells of the brain microvasculature will contribute towards a better understanding of inflammatory processes in diseases such as multiple sclerosis and infectious encephalitis.

Animals↗
PubMed1995

Adhesion molecule expression and lymphocyte adhesion to cerebral endothelium: effects of measles virus and herpes simplex 1 virus.

Expression of endothelial cell (EC) adhesion molecules is increased in inflammatory neurological disorders and this may regulate lymphocyte homing to the central nervous system (CNS). Viral encephalitis is characterised by lymphocytic infiltration of the CNS and one mechanism of this response may be EC adhesion molecule induction with consequent inflammatory cell/EC binding. This report characterises the effects of herpes simplex 1 (HSV1) or measles virus (MV) infection of BALB/c brain microvascular EC in vitro on adhesion of naive syngenic splenocytes and levels of ICAM-1. Adhesion was enhanced by 42% for MV-infected cells and by 73% for HSV-1-infected EC. At the multiplicities of infection employed, levels of ICAM-1 were upregulated on HSV-1-infected EC, but not on MV-infected EC. It is concluded that ICAM-1/ligand interactions do not play a role in mediation of MV enhancement of adherence, but represent one mechanism responsible for increased lymphocyte adherence to HSV-1-infected cerebral EC.

Animals↗
PubMed1995

CNS antigen presentation.

Presentation of antigens for the CNS follows the same general rules as for other tissues. However, the presence of special CNS cells with immune functions plus the blood-brain barrier (BBB) suggests that differences in the way that the immune system functions in the CNS might help to explain why some autoimmune diseases are unique to the CNS. Irrespective of whether CNS antigen presentation takes place inside or outside the CNS (or both), the BBB clearly plays a major role in CNS immune function. The BBB governs the quantity and type of lymphocytes that enter the CNS by way of specific adhesion-molecule binding between lymphocytes and endothelium and possibly by selecting for antigen-specific lymphocytes in antigen-recognition events.

Animals↗
PubMed1994

Nervous tissue as an immune compartment: the dialect of the immune response in the CNS.

Here, Zsuzsa Fabry and colleagues address the question of whether the unique cellular environment of the central nervous system (CNS) contributes to the observed differences in immunological functions between the CNS and other organs. In particular, they discuss the significance within the CNS of the blood-brain barrier, the nonconstitutive expression of major histocompatibility complex (MHC) molecules, the unusual set of potential antigen-presenting and effector cells, and the production of immune or neuromediators from various cellular sources.

Animals↗
PubMed1993

Differential activation of Th1 and Th2 CD4+ cells by murine brain microvessel endothelial cells and smooth muscle/pericytes.

CD4+ Th cell infiltration into the brain and the activation by cellular elements of the central nervous system (CNS) are thought to be important steps in the initiation of CNS autoimmune diseases. T cell activation requires Ag-specific stimulation and additional costimulatory signals provided by the APC. Here we describe how murine brain microvessel endothelial (En) cells and smooth muscle/pericytes (SM/P) selectively induce the Ag-specific activation of different Th1 and Th2 CD4+ T cell clones. Th1 and Th2 cell clones were used that were specific for the same peptide Ag in the context of the same class II allotype. SM/P preferentially activated Th1 cell clones, whereas En cells activated Th2 cell clones better, as reflected by cell proliferation and production of IL-2 by SM/P-activated Th1 clones and IL-4 by Th2 clones. There was no difference in the level of expression of CD4, CD2, or LFA-1 molecules between these Th cell clones, and anti-CD4, CD2, LFA-1 or ICAM-1 mAb did not differentially affect Ag-induced proliferation among the clones. Moreover, antibody to CD28 did not influence Ag presentation by brain microvessel En or SM/P cells to Ag-specific Th1 and Th2 clones. These results suggest that: 1) different The subsets might require different signals for their activation; 2) different APC might provide different costimulatory signals for Th cell subsets; and 3) brain microvessel En and SM/P might play a differential role in induction of autoreactive T cell responses in the CNS.

Animals↗
PubMed1993

Production of the cytokines interleukin 1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes.

Murine brain microvessel endothelial cells and smooth muscle/pericytes (SM/P) cells were cultured from newborn BALB/c (normal strain) and SJL/j (autoimmune-prone strain) mice. These cells were evaluated for their ability to produce interleukin (IL)-1 and IL-6 cytokines. The expression of mRNA for IL-1 and IL-6 was shown in highly purified BALB/c endothelial cells and SM/P cells using polymerase chain reaction with specific primers for IL-1 alpha, IL-1 beta and IL-6. IL-6 but not IL-1 mRNA was detected in unstimulated SJL/j brain microvessel cells. The presence of IL-1 and IL-6 mRNA in the BALB/c brain microvessel endothelial cells and SM/P was confirmed by in situ hybridization. By D10.G4.1 assay, unstimulated BALB/c endothelial cells were shown to produce active IL-1 to a higher degree than SM/P. By B9 bioassay, a low amount of active IL-6 was detected in the supernatant of endothelial cells and SM/P. The production of IL-1 and IL-6 in the bioassays was upregulated by lipopolysaccharide (LPS) activation of the cells in a time- and dose-dependent way. IL-6 production was also shown to be upregulated by IL-1 beta activation of the cells. Brain microvessel endothelial cells of SJL/j origin released equivalent amounts of IL-6 compared to endothelial cells of BALB/c origin. However, the production of IL-6 was markedly higher in SM/P of SJL/j origin than in those of BALB/c origin. These observations, together with our previous data showing that brain microvessel SM/P cells produce GM-CSF, emphasize the possibility for active participation of brain microvasculature SM/P as well as endothelium in inflammatory reactions of the central nervous system.

Animals↗
PubMed1992

Adhesion molecules on murine brain microvascular endothelial cells: expression and regulation of ICAM-1 and Lgp 55.

The mechanisms for the initiation of immune reactions in the central nervous system are poorly understood. In this report, we describe the presence of intercellular adhesion molecule-1 (ICAM-1) and Lgp 55 (suggested mouse homologue of human intercellular adhesion molecule-2, ICAM-2) on the surface of brain microvessel endothelium (EN) cells and show in vitro induction of ICAM-1 molecules on EN cells with pro-inflammatory cytokines. ICAM-1 expression was detected using flow cytometry analysis with biotinylated anti-ICAM-1 antibody (YN1/1.7.4). Lgp 55 expression was characterized using PA3 monoclonal antibody. According to our results, 30-40% of the non-activated brain EN cells expressed ICAM-1 and 15-20% expressed Lgp 55 molecules. The ICAM-1 molecule expression was increased after the activation of the cells with recombinant murine gamma interferon (IFN-gamma), tumor necrosis factor (TNF-alpha), and interleukin-1 alpha (IL1-alpha) in a dose-dependent manner. The increased ICAM-1 expression was detected as early as 2 h following the cytokine treatment and reached its maximum after 24 h. Transforming growth factor-beta (TGF-beta) did not influence the expression of ICAM-1 molecule. Lgp 55 molecule does not seem to be regulated by pro-inflammatory cytokines. ICAM-1 and Lgp 55 expression was found to be polarized on the luminal surface of EN by confocal laser microscopy suggesting accessibility for leukocytes. Inducible ICAM-1 expression may play a critical role in formation of inflammatory reactions inside the central nervous system.

Animals↗
PubMed1992

Brain microvascular smooth muscle and endothelial cells produce granulocyte macrophage colony-stimulating factor and support colony formation of granulocyte-macrophage-like cells.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent stimulator of macrophages and neutrophils and plays a role in inflammatory diseases. In this article, we report that mouse brain-derived microvascular smooth muscle cells (SM) and endothelial cells (En) in coculture with splenocytes support the colony proliferation of immature granulocyte-macrophage-like (GM) cells. Unstimulated SM and En cells release GM-CSF as shown by ELISA assay and SM expresses mRNA for GM-CSF by polymerase chain reaction (PCR). Stimulation of SM and En by a nonspecific activator (lipopolysaccharide) results in upregulation of GM-CSF production. GM colonies cannot be grown on cultured astrocytes or on extracellular matrix alone prepared from smooth muscle or endothelium. However, colonies form on the extracellular matrix and on astrocytes, either in the presence of SM- or En-conditioned medium or after the addition of recombinant GM-CSF. The GM cells are positive for nonspecific esterase, peroxidase, and MAC-1 markers but are negative for FC gamma receptors and for Thy 1.2, CD8, CD4, MHC class II, and Asialo GM1 markers. These observations emphasize the possibility for active participation of brain microvasculature SM and En in acute inflammatory reactions of the central nervous system.

Amino Acid Sequence↗
PubMed1991

Adhesion of splenocytes to brain microvascular endothelium in the BALB/c and SJL/j mouse systems.

Adhesion of hematopoietic cells to endothelial (En) cells plays an important role in their migration into extravascular tissue. This report characterizes the adhesion properties of naive splenocytes to syngeneic and allogeneic mouse brain microvascular endothelium isolated from the BALB/c or SJL/j mouse strains. Syngeneic adhesion reaches maximum levels by 60 min at 37 degrees C, but is more pronounced in the BALB/c system (mean adhesion = 10.7% +/- 1.0) compared to adhesion seen in the SJL/j (mean adhesion = 4.3% +/- 0.6). BALB/c, but not SJL/j adhesion, seems to be mediated, at least in part, by the interaction of CD11a/CD18 (lymphocyte function-associated antigen 1 (LFA-1] with one of its ligands, because BALB/c adhesion is partially inhibited when the assay is carried out either in the presence of chelating agents or with antibodies to the CD11a/CD18 molecule. Activation of the endothelium with recombinant interferon-gamma (rIFN-gamma), recombinant interleukin-1 alpha (rIL-1 alpha), and recombinant tumor necrosis factor-alpha (rTNF-alpha), enhances adhesion in both BALB/c and SJL/j. IFN-gamma and IL-1 alpha mediated adhesion enhancement is abrogated by antibodies to the CD11a/CD18 molecules in the BALB/c but not in the SJL/j system. The adhesion of splenocytes to mouse brain En clearly has unique properties, and whether or not the differences seen in the SJL/j system in any way influences its susceptibility to the autoimmune demyelinating disease, experimental autoimmune encephalitis, remains to be determined.

Animals↗
PubMed1990

Activation of CD4+ lymphocytes by syngeneic brain microvascular smooth muscle cells.

Splenocyte proliferation as measured by [3H]thymidine incorporation was detected when brain microvessel smooth muscle cells (SM) were cocultured with syngeneic spleen cells. This report focuses on the role of different lymphocyte populations in this activation. The central role of CD4+ T cells in the proliferation response has been established by different sets of experiments. The phenotypic characterization of splenic lymphocytes before and after the co-culture showed that the only cell type present in higher number after the co-culture than before is the CD4+ T cell. When CD4+ cells were purified by flow microfluorimetry and co-cultured with SM a strong proliferative response was detected. In contrast, purified CD8+ cells in co-culture with SM cells did not proliferate. The activation of CD4+ cells by SM required direct cell-to-cell contact and could be detected on the fourth day, reaching maximal levels at the 6th and 7th days of the co-culture. The activation is more pronounced in the syngeneic system than under allogeneic conditions and is inhibited by anti-MHC II mAb, but not by anti-MHC II mAb. The finding that vascular smooth muscle cells can activate syngeneic T cells may have important implications concerning the mechanism of induction of vasculitis.

Animals↗
PubMed1990

Antigen presentation by brain microvessel smooth muscle and endothelium.

It has been previously reported that cultured brain microvessel smooth muscle cells (SM) express major histocompatibility complex (MHC) class II antigen. Here we report that SM is able to present ovalbumin (OVA) antigen to an OVA-specific T cell hybridoma (A2.2E10) and also presents keyhole limpet hemocyanin (KLH) to a KLH-specific T cell clone (HDK-1). Both the class II expression and the antigen-presenting capacity of SM cells is increased by interferon-gamma stimulation. Antigen presentation by SM is also MHC restricted as it is blocked by anti-Ia monoclonal antibodies. In contrast to SM, brain endothelium (En) presents whole OVA, digested OVA and KLH poorly, to a much lesser degree than SM, to the same antigen-specific T cells.

Animals↗
PubMed1989

Purification of murine endothelial cell cultures by flow cytometry using fluorescein-labeled griffonia simplicifolia agglutinin.

Griffonia simplicifolia agglutinin (GSA) is a valuable histochemical tool in the identification of endothelium. In this study GSA labeled with fluorescein isothiocyanate (GSA-FITC) was used to purify cultures of murine cerebral microvascular endothelium. Cultures were stained with GSA-FITC, then sorted using a fluorescence-activated cell sorter (FACS). GSA-positive endothelial cells were collected, re-cultured, and subsequently re-analyzed by FACS using GSA-FITC. Cultures that initially contained 80 +/- 3 to 89 +/- 3% (X +/- SE) GSA-positive cells were purified to 98 +/- 1% positivity. Immunohistochemistry with an anti-muscle-action antibody confirmed that FACS sorting of GSA-FITC-stained cells effectively removed contaminating smooth muscle cells from endothelial cell cultures. Viability, proliferation, and prostaglandin production of the cells was unaltered by lectin staining and FACS sorting. Thus, GSA-FITC can be used in conjunction with flow cytometry to enhance the purity of murine endothelial cell cultures without adversely affecting cell viability, growth, or metabolism.

Actins↗