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Biomedical subjects

M Moser

Publications and source records attributed to M Moser.

At least 181 records · Page 10Linked to original sources
PubMed1995

B7.2 provides co-stimulatory functions in vivo in response to staphylococcal enterotoxin B.

Excessive T cell activation induced by bacterial superantigens plays an important role in the pathology associated with Gram-positive bacteremia. To gain insight into the early phases of T cell activation by bacterial enterotoxins in vivo, we investigated the ability of antibodies to well-defined co-stimulatory molecules to inhibit T cell activation and the subsequent toxic shock syndrome induced in BALB/c mice following the injection of staphylococcal enterotoxin B (SEB). We demonstrate here that a single dose of anti-B7.2 antibodies, but not anti-B7.1 antibodies, significantly inhibits T cell activation, as judged by lower systemic IL-2 release, blastogenesis and IL-2 receptor expression, and reduces the lethal effect of SEB in D-galactosamine-sensitized mice. These results demonstrate that co-stimulation through the B7.2 molecule plays an important role in the activation of T cells in response to SEB in vivo and suggest alternative therapies for septic shock caused by bacterial enterotoxins based on blocking antibodies to co-stimulatory molecules.

Animals↗
PubMed1995

Glucocorticoids down-regulate dendritic cell function in vitro and in vivo.

Exogenous glucocorticoid hormones are widely used as therapeutical agents, whereas endogenous glucocorticoids may act as physiological immunosuppressants involved in the control of immune and inflammatory responses. The optimal activation of T lymphocytes requires two distinct signals: the major histocompatibility complex-restricted presentation of the antigen and an additional co-stimulatory signal provided by the antigen-presenting cells. There is ample evidence that, among the cells able to present the antigen, the dendritic cells (DC) have the unique property to activate antigen-specific, naive T cells in vitro and in vivo, and are therefore required for the induction of primary immune responses. In this work, we tested whether glucocorticoids affected the capacity of DC to sensitize naive T cells. Our data show that, in vitro, the steroid hormone analog dexamethasone (Dex) affects the viability of DC, selectively down-regulates the expression of co-stimulatory molecules on viable DC, and strongly reduces their immunostimulatory properties. In vivo, a single injection of Dex results in impaired antigen presenting function, a finding which correlates with reduced numbers of splenic DC. These results show that glucocorticoids regulate DC maturation and immune function in vitro and in vivo and suggest that this mechanism may play a role in preventing overstimulation of the immune system.

Animals↗
PubMed1995

Activation of murine T cells by bacterial superantigens requires B7-mediated costimulation.

Staphylococcus enterotoxins bind class II MHC molecules on antigen-presenting cells (APC) and stimulate T cells expressing appropriate V beta gene products. Although the role of non-TcR-associated costimulatory receptors during antigen-specific T cell stimulation has been clearly established, the involvement of costimulatory activity in T cell activation by superantigens (SAgs) has been the matter of controversy. The aim of this study was to evaluate the role of the costimulatory-receptor ligand molecules CD28/B7 on bacterial SAg-mediated activation of naive murine T cells. We demonstrate in this report that a combination of monoclonal antibodies to murine B7.1 and B7.2 molecules inhibits the in vitro response of naive T cells to SAgs SEA, SEB, and TSST-1. The inhibition of T cell responses required simultaneous blocking of B7.1 and B7.2, suggesting that either B7.1 or B7.2 is sufficient to provide costimulatory signals to naive T cells in response to bacterial exotoxins. Inhibition of T cell activation by antibodies to B7-related molecules can be overcome by antibodies to CD28, a finding in agreement with the hypothesis that CD28-mediated signals participate in T cell activation by bacterial SAgs. These observations suggest that, as demonstrated for conventional antigen, T cell activation by SAgs requires the coordinated participation of TcR- and CD28-derived signals.

Animals↗
PubMed1995

Production and characterization of bispecific single-chain antibody fragments.

We report the construction, expression and purification of a bispecific single-chain Fv antibody fragment produced in Escherichia coli. The protein possesses a dual specificity: the single-chain FvB1 portion is directed to the Idiotype of BCL1 lymphoma cells, the single-chain Fv2C11 moiety binds to the CD3 marker on T cells. The two domains are joined by a flexible peptide linker. Using Immobilized Metal Affinity Chromatography, the recombinant protein was purified from bacterial insoluble membrane fractions. After refolding of the bispecific protein, it was affinity-purified. As demonstrated by flow cytometry, both binding sites are retained in the refolded protein. Retargeted cytotoxicity and T cell proliferation assays further prove the biological activity and specificity of the bispecific single-chain Fv. Thus, these bispecific molecules show a potential anti-tumor activity.

Animals↗
PubMed1995

Developmental expression of the prion protein gene in glial cells.

Replication of prions is dependent on the presence of the host protein PrPc. During the course of disease, PrPc is converted into an abnormal isoform, PrPSc, which accumulates in the brain. Attempts to identify the cell type(s) in which prion replication and PrP conversion occur have reached conflicting results. Although PrP mRNA is present in high amounts in neurons throughout the life of the animal, PrPSc initially accumulates in astrocytes and possibly other glial cells and, later in the course of the disease, spreads diffusely in the tissue, often in white matter. We report here that PrP mRNA is expressed not only in neurons but also in astrocytes and oligodendrocytes throughout the brain of postnatal hamsters and rats. The level of glial Prp mRNA expression in neonatal animals was comparable to that of neurons and increased two-fold during postnatal development. A substantial portion of brain PrP mRNA is therefore contributed by glial cells. Our results provide an explanation for the accumulation of PrPSc in white matter tissue and in the cytoplasm of glial cells and argue for a direct involvement of glia in prion propagation.

Aging↗
PubMed1995

Co-stimulation lowers the threshold for activation of naive T cells by bacterial superantigens.

Staphylococcus enterotoxins bind class II MHC molecules on antigen presenting cells (APC) and stimulate T cells expressing appropriate V beta gene products. Although the role of non-TCR associated co-stimulatory receptors during antigen-specific T cell stimulation has been clearly established, the involvement of co-stimulatory activity in T cell activation by superantigens has been the matter of controversy. In this report, we examine the role of co-stimulation provided by selected APC populations in the response to bacterial exotoxins (staphylococcal enterotoxin A, staphylococcal enterotoxin B and toxic shock syndrome type 1). We demonstrate that the APC population able to activate naive T cells to IL-2 production is heterogeneous, comprising both adherent (presumably dendritic) and non-adherent (mostly B lymphocytes) cells. By stimulating naive T cells in the presence of graded doses of superantigens, we have observed that half-maximal IL-2 production was achieved at lower doses of superantigens in the presence of dendritic cells. Similarly, addition of antibodies to CD28 or B7.1-transfected cell lines increased the sensitivity of naive T cells to lower doses of superantigens. These observations indicate therefore that superantigens can be presented to naive T cells by APC displaying distinct levels of co-stimulatory activity, although with different efficacy. Thus, naive T cells are sensitive to CD28-mediated co-stimulation during superantigen-mediated responses but IL-2 production can be induced by high doses of superantigens in the presence of APC expressing weak co-stimulatory activity. These observations are compatible with the hypothesis that CD28-mediated signals participate in T cell activation by lowering T cell sensitivity to TCR ligands.

Animals↗
PubMed1995

The national dose registry for radiation workers in Switzerland.

The national dose registry began operation in Switzerland in 1990. It is a database maintained by the Federal Office of Public Health. It contains personal, employment, and dosimetric data for all the radiation workers in the country. The data for about 60,000 currently employed radiation workers are transferred from ten external dosimetry services to the registry every month or every three months. The registry was initiated to assist national authorities in controlling and safekeeping of the occupational doses and to allow statistical evaluations. In autumn 1994 the new Radiation Protection Regulations came into effect. Based on the ICRP recommendations, the Regulations introduced lower limits for the annual dose, for the average dose over five years, and for pregnant women and defined the internal dose as an additive component to the total dose. All these items require a high quality registration of occupational doses. This can hardly be achieved without a central registry. This paper describes the design of the Swiss national dose registry in the frame of the particular organization of the personal dosimetry in this country. The database structure and the information content are presented. Special solutions for the data transfer have been found, as the registry is running completely decoupled from the dosimetry services. Applications of the registry for regulatory control, particularly in connection with the new Regulations are described. Some results of statistical analyses are presented. The possibilities and the limitations of using the registry for radioepidemiological studies are discussed.

Databases, Factual↗
PubMed1995

Iodine distribution in a porcine eye model following iontophoresis.

Iodine distribution was studied in isolated porcine eyes after iontophoresis using 131I-labelled solutions and chemical methods. After a 15-min treatment with a therapeutically used iodine brine, the iodine content in the ocular tissues showed the following rank order: cornea > retina > vitreous body > anterior chamber fluid > lens. Replacement of the brine by 0.15 M NaI increased the uptake values in a different way, but the same rank order was maintained. The increase was highest in the cornea (5.6-fold) and only about 2-fold in the lens, nevertheless approaching now the level of 10(-4) M, a concentration which was regarded as being optimal for the antioxidant effect of I-. Among the other eye components, the relatively high iodine enrichment of the retina was remarkable. The data are discussed with respect to a possible protective, antioxidative and OH-scavenging efficacy of I- and to previous results in the literature concerning iodine uptake in ocular tissues.

Animals↗
PubMed1995

Identification of allergic bronchopulmonary aspergillosis in cystic fibrosis patients by recombinant Aspergillus fumigatus I/a-specific serology.

Before specific therapy, such as oral corticosteroids, can be commenced it is essential to distinguish full-blown allergic bronchopulmonary aspergillosis (ABPA) from allergy to A. fumigatus in patients with cystic fibrosis (CF). For this purpose we have evaluated the diagnostic value of recombinant A. fumigatus allergen I/a (rAsp f I/a)-specific serology in 55 patients with CF. Based on clinical presentation and laboratory data, 10 CF patients had ABPA, 27 had Aspergillus allergy, and 18 were not allergic to A. fumigatus (CF control group). The serologic assays revealed a 10-fold increase in rAsp fI/a-specific IgE, a 5-fold increase in rAsp fI/a-specific IgG1, and a 4-fold increase in rAsp fI/a-specific IgG4 antibodies in ABPA patients compared with the Aspergillus allergy and CF control groups. Sera from 11 CF patients were analyzed without knowledge of their clinical state or diagnosis of ABPA. All ABPA patients (4 of 11) were accurately identified. We conclude that rAsp fI/a-specific serology is a highly sensitive and specific test that can be used to identify ABPA reliably in CF patients.

Adolescent↗
PubMed1995

Cloning and characterization of a second AP-2 transcription factor: AP-2 beta.

AP-2 has been characterized previously as a unique 52 x 10(3) M(r) transcription activator encoded by a single gene that is expressed in a restricted pattern during embryonic morphogenesis of the peripheral nervous system, face, skin and nephric tissues. Here we report the isolation of genomic and cDNA clones encoding for a second AP-2 related transcription factor, designated AP-2 beta. AP-2 beta binds specifically to a series of well-characterized AP-2 binding sites, consensus to the sequence G/CCCN3GGC, and transactivates transcription from a reporter plasmid under the control of an AP-2-dependent promoter. A C-terminal domain known to mediate homodimerization of the previously cloned AP-2 alpha transcription activator is highly conserved and sufficient to mediate interaction between the two proteins. Northern blot and in situ hybridizations revealed that the two genes are expressed in murine embryos between days 9.5 and 19.5 p.c. Coexpression of both mRNAs was detected in many tissues at day 13.5 and 15.5 of embryogenesis but some regions of the developing brain and face including the primordium of midbrain and the facial mesenchyme differed in their expression pattern of AP-2 genes. AP-2 alpha and AP-2 beta signals in the central and peripheral nervous system overlapped with regions of developing sensory neurons. In adult tissues AP-2 alpha expression was found mainly in the skin, eye and prostate and AP-2 beta expression in the kidney. In summary, our analyses of embryonic and adult mice demonstrate that two different AP-2 transcription factors are specifically expressed during differentiation of many neural, epidermal and urogenital tissues.

Amino Acid Sequence↗
PubMed1995

Black-white differences in response to antihypertensive medication.

There appear to be differences in degree and rate of response of black and white subjects to various antihypertensive medications. Diuretics and calcium channel blockers are more effective on average in older black patients than beta blockers or ACE inhibitors. White patients, especially younger individuals, appear to respond somewhat better to beta blockers and ACE inhibitors than to diuretics or calcium channel blockers. When any medications, such as beta blockers, ACE inhibitors, or calcium channel blockers, are combined with small doses of diuretics, the black-white difference in response disappears; black and white patients appear to respond equally well to combination therapy.

Antihypertensive Agents↗
PubMed1994

Crystal structures of Escherichia coli aspartate aminotransferase in two conformations. Comparison of an unliganded open and two liganded closed forms.

Three crystal structures of wild type E. coli aspartate aminotransferase (E.C.2.6.1.1) in space group P2(1) have been determined at resolution limits between 2.6 and 2.35 A. The unliganded enzyme and its complexes with the substrate analogues maleate and 2-methylaspartate resulted in different conformations. The unit cell parameters of the unliganded and the inhibited enzyme are a = 87.2, b = 79.9, c = 89.8 A and beta = 119.1 degrees, and a = 85.4, b = 79.8, c = 89.5 A and beta = 118.6 degrees, respectively. The crystallographic symmetry is pseudo-C222(1). The liganded enzyme structures were solved by difference Fourier techniques from that of a Val39-->Leu mutant partially refined to an R-factor of 0.22 at 2.85 A. They have a "closed" conformation like the chicken mAATase:maleate complex. The models were refined to R-factors of 0.19 (maleate complex) and 0.18 (2-methylaspartate complex) by molecular dynamics and restrained least squares methods. The unliganded crystal form was solved by molecular replacement and refined to an R-factor of 0.19 at 2.5 A resolution. The structure is in a "half-open" conformation, with the small domain rotated about 6 degrees from the closed conformation. The cofactor pyridoxal phosphate has a more relaxed conformation than in mAATase. Both maleate and 2-methylaspartate are hydrogen-bonded to the active site as in mAATase. The C alpha-CH3 bond of 2-methylaspartate is oriented at right angles to the cofactor pyridine ring, the most productive orientation for alpha-deprotonation of the substrate L-aspartate. Comparisons with earlier determined eAATase structures in space group C222(1) revealed differences that can probably be attributed to the somewhat lower resolution of the orthorhombic structures and/or mutations in the eAATases used in those studies. The present P2(1) structures confirm the justification of extrapolating properties of active site point mutants to the vertebrate isozymes. They will serve as reference in the interpretation of the properties of further site-directed mutants in continued studies of structure-function relationships of this enzyme.

Amino Acid Sequence↗