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Biomedical subjects

T Moll

Publications and source records attributed to T Moll.

At least 19 recordsLinked to original sources
PubMed2006

Vaccination with cell immunoglobulin mucin-1 antibodies and inactivated influenza enhances vaccine-specific lymphocyte proliferation, interferon-gamma production and cross-strain reactivity.

Influenza virus causes a contagious and potentially serious infection of the upper respiratory tract. While neutralizing antibodies are protective against infection, the problem of antigenic drift remains, requiring the constant monitoring and development of new vaccines. The magnitude of this situation is underscored by the emergence of new potentially human pathogenic influenza strains, avian H5N1 being the most recent example. We present evidence that antibodies against T cell immunoglobulin mucin-1 (TIM-1), a recently identified immunomodulatory molecule, stimulate cellular immunity against influenza viruses and cross-strain immune reactivity. To determine potential immunostimulatory properties of anti-TIM-1, mice were vaccinated with inactivated influenza virus in the presence or absence of TIM-1-specific monoclonal antibodies. Development of cellular immunity against both the influenza strain used for immunization and serotypically distinct virus strains was monitored 3 weeks after vaccination by determining antigen-specific lymphocyte proliferation and cytokine production. Results show that TIM-1 antibodies enhance antigen-specific cellular proliferation (P < 0.05) and interferon (IFN)-gamma production (P < 0.01). Using blocking anti-CD4 and CD8 antibodies, it was observed that antigen-specific cellular proliferation is CD4-dependent and that the majority of proliferating cells are CD4+. Finally, vaccination with inactivated influenza virus with TIM-1 antibody results in the significant (P < 0.001) induction of proliferation and IFN-gamma production upon stimulation with one of three serologically distinct strains. TIM-1 antibodies demonstrate an adjuvant effect promoting antigen-specific cellular proliferation and IFN-gamma production, which are important for the promotion of cell-mediated immunity. These results are the first to suggest that TIM-1 antibody may serve as a potent adjuvant in the development of new influenza virus vaccines.

Adjuvants, Immunologic↗
PubMed2001

Species-specific and conserved epitopes on mouse and human E-selectin important for leukocyte adhesion.

Selectins are C-type, cell surface lectins that are key players in leukocyte adhesion to the blood vessel wall endothelium. We describe here epitopes for a series of novel monoclonal antibodies (moAbs), UZ4-UZ7, directed against mouse E-selectin. All four antibodies specifically bind to mouse E-selectin, but not to P- or L-selectin, and all inhibit the adhesion of granulocytes, peripheral blood lymphocytes, and promyelocytic HL-60 cells to cytokine-activated mouse endothelium. Three moAbs, UZ5, UZ7, and UZ6, specifically inhibit mouse E-selectin-mediated adhesion by binding to epitopes in domains CR1 or CR2. moAb UZ4 inhibits leukocyte adhesion to both human and murine endothelium activated with IL-1 or other proinflammatory stimuli. UZ4 is the first described moAb that detects an epitope in the lectin domain which is conserved in both murine and human E-selectin (CXKKKL), but is not present in the other members of the selectin family, P- and L-selectin. Interestingly, UZ5, UZ6, and UZ7 more efficiently interfere with lymphocyte than with granulocyte adhesion to cytokine-activated endothelium, while UZ4 completely blocks adhesion of PMN, lymphocytes, and HL-60 and U937 cell lines. The data suggest that E-selectin-ligand engagement differs between lymphocytes and PMN, and that these differences may be accentuated by the CR1 and CR2 domains in the E-selectin cell adhesion molecule.

Amino Acid Sequence↗
PubMed2000

P-selectin glycoprotein ligand-1 and E-selectin ligand-1 are differentially modified by fucosyltransferases Fuc-TIV and Fuc-TVII in mouse neutrophils.

P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) are the two major selectin ligands on mouse neutrophils. Transfection experiments demonstrate that each ligand requires alpha1,3-fucosylation for selectin-binding. However, the relative contributions made by the two known myeloid alpha1, 3-fucosyltransferases Fuc-TVII or Fuc-TIV to this alpha1, 3-fucosylation are not yet clear. To address this issue, we have used mice deficient in Fuc-TIV and/or Fuc-TVII to examine how these enzymes generate selectin-binding glycoforms of PSGL-1 and ESL-1 in mouse neutrophils. Selectin binding was analyzed by affinity isolation experiments using recombinant, antibody-like forms of the respective endothelial selectins. We observe essentially normal binding of E- or P-selectin to PSGL-1 expressed by Fuc-TIV-deficient neutrophils but find that PSGL-1 expressed by Fuc-TVII-deficient neutrophils is not bound by E- or P-selectin. By contrast, E-selectin binds with normal efficiency to ESL-1 on Fuc-TVII-deficient neutrophils but exhibits an 80% reduction in its ability to bind ESL-1 isolated from Fuc-TIV-deficient neutrophils. The same specificity with which Fuc-TVII and Fuc-TIV generate selectin-binding forms of PSGL-1 and ESL-1 was found in transfection experiments with CHO-Pro(-)5 cells. In contrast, each fucosyltransferase alone could generate selectin-binding glycoforms of each of the two ligands in CHO-DUKX-B1 cells. Our data imply that in mouse neutrophils and their precursors, Fuc-TVII exclusively directs expression of PSGL-1 glycoforms bound with high affinity by P-selectin. By contrast, Fuc-TIV preferentially directs expression of ESL-1 glycoforms that exhibit high affinity for E-selectin. This substrate specificity can be mimicked in CHO-Pro(-)5 cells.

Animals↗
PubMed1999

A transcriptional repressor of the tissue factor gene in endothelial cells.

Tissue factor, the high-affinity receptor and cofactor for the plasma serine protease VII/VIIa, is the primary cellular initiator of the blood coagulation cascade. Inside the vasculature, expression of the tissue factor gene must be tightly controlled. Whereas the endothelium normally does not express tissue factor, on stimulation with inflammatory cytokines or endotoxin the gene is transcriptionally upregulated leading to a procoagulant state. We have now detected a repressive cis-acting element in the tissue factor promoter that downmodulates tissue factor transcription in endothelial cells. In reporter gene assays, deletion of this element leads to an increase of tissue factor transcription and insertion of a trimerized site reduces transcription. Specific protein/DNA complexes are formed on the element with nuclear extracts in electrophoretic mobility shift assays and cross-linking of the proteins followed by SDS-PAGE detects the presence of at least 2 subunits of approximately 40 and 60 kDa, respectively. After transfection of different cell types with the reporter genes, the suppressive effect of the element can only be revealed in endothelial cells. These data suggest that this element represents a novel transcription factor target sequence that functions to suppress expression of the tissue factor gene, preferentially in endothelial cells thereby supporting a noncoagulant state.

Animals↗
PubMed1998

In vitro degradation of endothelial catenins by a neutrophil protease.

It has been recently proposed that adhesion of polymorphonuclear cells (PMNs) to human umbilical vein endothelial cells leads to the disorganization of the vascular endothelial cadherin-dependent endothelial adherens junctions. Combined immunofluorescence and biochemical data suggested that after adhesion of PMNs to the endothelial cell surface, beta-catenin, as well as plakoglobin was lost from the cadherin/catenin complex and from total cell lysates. In this study we present data that strongly suggest that the adhesion-dependent disappearance of endothelial catenins is not mediated by a leukocyte to endothelium signaling event, but is due to the activity of a neutrophil protease that is released upon detergent lysis of the cells.

Cadherins↗
PubMed1998

Stimulation of P-selectin glycoprotein ligand-1 on mouse neutrophils activates beta 2-integrin mediated cell attachment to ICAM-1.

The entry of neutrophils into inflamed tissues is initiated by cell rolling on the blood vessel wall followed by arrest and transendothelial migration. Rolling is mediated by the selectins, while the two subsequent steps require activated beta 2-integrins. We have investigated whether the binding of P-selectin to mouse neutrophils could trigger the activation of beta 2-integrins. We show that cross-linking of P-selectin glycoprotein ligand-1 (PSGL-1) on mouse neutrophils with an antibody-like recombinant form of P-selectin or with monoclonal antibodies stimulated the production of reactive oxygen intermediates and enhanced neutrophil attachment to intercellular adhesion molecule 1 (ICAM-1)-expressing CHO cells. This effect was independent of whether complete antibodies or F(ab')2 fragments were used. The adhesion-stimulating effect of P-selectin could be blocked by monoclonal antibodies against PSGL-1. Increase of cell attachment was dependent on lymphocyte function-associated antigen 1 (LFA-1) and on Mac-1, since it could be blocked with antibodies against both respective integrin alpha-chains. Moreover, cell surface expression of Mac-1 increased upon cross-linking of PSGL-1. In agreement with published data, treatment of human neutrophils with P-selectin-IgG did not enhance attachment to ICAM-1. Our data suggest that ligation of PSGL-1 on mouse neutrophils, but not on human neutrophils, activates beta 2-integrin mediated cell attachment to ICAM-1.

Animals↗
PubMed1997

The P-selectin glycoprotein ligand-1 is important for recruitment of neutrophils into inflamed mouse peritoneum.

The P-selectin glycoprotein ligand-1 (PSGL-1) is a high-affinity ligand of P-selectin on myeloid cells and certain subsets of lymphoid cells. We generated the rat monoclonal antibody (MoAb) 2PH1 that recognizes an epitope within the first 19 amino acids at the N-terminus of the processed form of mouse PSGL-1. This antibody blocks attachment of mouse myeloid cells to P-selectin under both static and flow conditions. Intravenous administration of saturating amounts of 2PH1 reduced the number of rolling leukocytes in venules of the acutely exposed mouse cremaster muscle by 79% (+/-5.7%), whereas an anti-P-selectin MoAb reduced it completely. Examining the effect of the MoAb 2PH1 on the recruitment of neutrophils into chemically inflamed mouse peritoneum showed that blocking PSGL-1 inhibited neutrophil accumulation in the peritoneum by 82% (+/-7%) at 2 hours and by 59% (+/-7.9%) at 4 hours after stimulation. A similar effect was seen with the MoAb against P-selectin. Simultaneous administration of both antibodies at the 4-hour time point blocked neutrophil accumulation by 86% (+/-4.2%), arguing for an additional partner molecule for PSGL-1 besides P-selectin. This is the first demonstration of the importance of PSGL-1 in the recruitment of mouse neutrophils into inflamed tissue.

Animals↗
PubMed1997

P-selectin glycoprotein ligand-1 (PSGL-1) on T helper 1 but not on T helper 2 cells binds to P-selectin and supports migration into inflamed skin.

We have shown recently that mouse Th1 cells but not Th2 cells are selectively recruited into inflamed sites of a delayed-type hypersensitivity (DTH) reaction of the skin. This migration was blocked by monoclonal antibodies (mAb) against P- and E-selectin. Here we show that Th1 cells bind to P-selectin via the P-selectin glycoprotein ligand-1 (PSGL-1). This is the only glycoprotein ligand that was detectable by affinity isolation with a P-selectin-Ig fusion protein. Binding of Th1 cells to P-selectin, as analyzed by flow cytometry and in cell adhesion assays, was completely blocked by antibodies against PSGL-1. The same antibodies blocked partially the migration of Th1 cells into cutaneous DTH reactions. This blocking activity, in combination with that of a mAb against E-selectin, was additive. PSGL-1 on Th2 cells, although expressed at similar levels as on Th1 cells, did not support binding to P-selectin. Thus, the P-selectin-binding form of PSGL-1 distinguishes Th1 cells from Th2 cells. Furthermore, PSGL-1 is relevant for the entry of Th1 cells into inflamed areas of the skin. This is the first demonstration for the importance of PSGL-1 for mouse leukocyte recruitment in vivo.

Animals↗
PubMed1997

Depth separation in ten observers with a new stereoscopic X-ray acquisition system.

The aim of this work was to assess the depth separation of a new X-ray digital stereo angiographic system through visualization on a stereoscopic monitor. Before starting the clinical trial of this new stereo-digital angiographic system, it seemed to us mandatory to assess the inherent performance of the system to depict depth information, as well as the ability of the users to work with it. With this idea we designed a global test based on the observation of a physical test object by the potential users of the system, during a session long enough to simulate an angiographic study. The acquisition system consisted of a twin focal-spot X-ray tube and a standard DSA DG 300 (General Electric/CGR). The stereo display was controlled by a liquid crystal modulator placed in front of a black-and-white monitor. Special polarized glasses worn by the observers allowed right- and left-image separation. Depth separation was measured in ten observers by means of a stereoscopic test object. Six of the ten observers were able to locate accurately three-dimensional patterns separated by a 12- to 1.5-mm gap. No learning effect was noticed. This result suggested that stereo display through wireless polarized glasses coupled to up-to-date digital subtraction angiography technology may provide an accurate and ergonomic way to a dimensional enhancement of X-ray angiography.

Angiography, Digital Subtraction↗
PubMed1997

[Analysis of the diagnostic value of endovascular ultrasound with roc curves. Practical implications].

Intravascular ultrasound enables detection of the components of atherosclerotic plaques. The diagnostic value was assessed by ROC (receiver operating characteristic) curves on images acquired in vitro and correlated with the histological findings in 61 arteries. Five questions were asked of each operator; the reply was represented by a continuous variable in order to express all nuances of judgement. The area under the ROC curve, Az, was the criterion of performance (0.5 : chance response : 1.0 : all replies were accurate). Detection of plaque was satisfactory (Az = 0.89). The three layer appearance of muscular arteries was well recognised (Az = 0.94). The fibrous composition of a plaque was only just satisfactory (Az = 0.88) with 38.7% interindividual variability. The lipid composition of the plaque was poorly recognised (Az = 0.76) with large interindividual variability (52.8%) : hypoechogenicity was too ambiguous a sign from the acoustic point of view. A hypoechogenic zone must not be synonymous with a lipid plaque but a cellular zone. Calcium can almost always be detected (Az = 0.98) with a very low interindividual variability (10.7%), fibrohyaline progression of some plaques can be confusing. The authors present a more objective description of endovascular ultrasonographic images. They conclude that the diagnostic performance of 30 MHz intravascular ultrasound is satisfactory but several limitations are apparent in the interpretation of images, especially hypoechogenic zone and hyper-reflective zones with high attenuation.

Arteries↗
PubMed1997

[An experimental study of the treatment of aneurysms using an intravascular prosthesis].

Intracranial aneurysms occur frequently with the risk of major damage. Neurosurgery or endovascular techniques can be used for treatment. Current techniques are not well adapted for aneurysms with a wide implantation (or neck). The aim of this experimental work was to study a technique for treating aneurysms which can be used for wide neck aneurysms. A metal stent is implanted facing the neck of the aneurysm to allow occlusion. In the first part of the study, the stent was inserted alone. Ten aneurysms were created surgically in five dogs. The stents were positioned facing seven of the ten aneurysms. The stent led to immediate occlusion of the aneurysm in six of the cases. One aneurysm remained patent despite the correct position of the stent. One dog developed secondary thrombosis of the carotid. Three dogs have been followed for sixty days after insertion of the stent. Two aneurysms thrombosed and one was patent. Since these results were less than satisfactory, a second part of the study was undertaken to cover the stent with a fragment of the autologous vein. Results in five aneurysms, evaluated three and eight weeks after treatment, showed partial or total repermeabilization of the aneurysms. In the third part of the study, we associated stents and detachable coils. Twelve aneurysms of the carotid artery in pigs were thrombosed and two aneurysms were completely occluded after stent implantation. In the nine other cases, the aneurysms were completely occluded after stent implantation. In the nine other cases, the aneurysms remained patent despite the stent and treatment was then completed with a coil. Six of the animals have been followed for thirteen weeks. One carotid artery thrombosed. In the five other cases, the carotid arteries were patent and the aneurysms were occluded at the control angiogram. Histology results showed the presence of a fibromuscular endothelialized neointima at the neck of the aneurysm in four of the five cases. The technique described here could be proposed for the treatment of wide-neck aneurysms implanted low on the carotid artery in man. Improvements should render the system more flexible.

Aneurysm↗
PubMed1996

Inhibition of endothelial cell activation by adenovirus-mediated expression of I kappa B alpha, an inhibitor of the transcription factor NF-kappa B.

During the inflammatory response, endothelial cells (EC) transiently upregulate a set of genes encoding, among others, cell adhesion molecules and chemotactic cytokines that together mediate the interaction of the endothelium with cells of the immune system. Gene upregulation is mediated predominantly at the transcriptional level and in many cases involves the transcription factor nuclear factor (NF) kappa B. We have tested the concept of inhibiting the inflammatory response by overexpression of a specific inhibitor of NF-kappaB, I kappa B alpha. A recombinant adenovirus expressing I kappa B alpha was constructed (rAd.I kappa B alpha) and used to infect EC of human and porcine origin. Ectopic expression of IkappaBalpha resulted in marked, and in some cases complete, reduction of the expression of several markers of EC activation, including vascular cell adhesion molecule 1, interleukins 1, 6, 8, and tissue factor. Overexpressed I kappa B alpha inhibited NF-kappa B specifically since (a) in electrophoretic mobility shift assay, NF-kappa B but not AP-1 binding activity was inhibited, and (b) von Willebrand factor and prostacyclin secretion that occur independently of NF-kappa B, remained unaffected. Functional studies of leukocyte adhesion demonstrated strong inhibition of HL-60 adhesion to I kappa B alpha-expressing EC. These findings suggest that NF-kappa B could be an attractive target for therapeutic intervention in a variety of inflammatory diseases, including xenograft rejection.

Adenoviridae↗
PubMed1996

ROC assessment of compressed wrist radiographs.

The aim of this paper is to validate a compression scheme applied on a medical image database of digitized wrist radiographs. The compression scheme adapts itself to local statistical properties of the images. The diagnostic quality of the reconstructed images is evaluated using a ROC protocol involving five medical experts. The results of this evaluation enable us to validate the compression scheme on this database with a compression ratio of 40 (0.2 bits per pixel).

Humans↗
PubMed1995

Cyclin-dependent kinase site-regulated signal-dependent nuclear localization of the SW15 yeast transcription factor in mammalian cells.

Control over the nuclear transport of transcription factors (TFs) represents a level of gene regulation integral to cellular processes such as differentiation, transformation and signal transduction. The Saccharomyces cerevisiae TF SWI5 is excluded from the nucleus in a cell cycle-dependent fashion, mediated by phosphorylation by the cyclin-dependent kinase (cdk) CDC28. Nuclear entry occurs in G1. beta-galactosidase fusion proteins carrying SWI5 amino acids 633-682, including the nuclear localization sequence (NLS: Lys-Lys-Tyr-Glu-Asn-Val-Val-Ile-Lys-Arg-Ser-Pro-Arg-Lys-Arg-Gly-Arg-Pro- Arg-Lys655) were analyzed for subcellular localization in appropriate temperature-sensitive yeast strains blocked in G1 or G2/M using indirect immunofluorescence, and for nuclear import kinetics in living rat hepatoma or Vero African green monkey kidney cells microinjected with fluorescently labeled bacterially expressed protein and quantitative confocal laser microscopy. Cell cycle-dependent nuclear localization in yeast was both NLS and cdk site-dependent, whereby mutation of the cdk site serines (Ser646 and Ser664) to alanine resulted in constitutive nuclear localization. In mammalian cells, the SWI5 fusion proteins were similarly transported to the nucleus in an NLS-dependent fashion, while the mutation to Ala of the cdk site serines increased the maximal level of nuclear accumulation from about 1- to over 8-fold. We suggest that phosphorylation at the cdk sites inhibits nuclear transport of SWI5, consistent with our previous observations for the inhibition of SV40 large tumor antigen nuclear transport by phosphorylation by the cdk cdc2. The results indicate for the first time that a yeast NLS and, fascinatingly, its regulatory mechanisms are functional in higher eukaryotes, implying the universal nature of regulatory signals for protein transport to the nucleus.

Amino Acid Sequence↗