Biomedical subjects

M Moser

Publications and source records attributed to M Moser.

At least 199 records · Page 11Linked to original sources

PubMed1994

Role of T-cell subsets in the bispecific antibody (anti-idiotype x anti-CD3) treatment of the BCL1 lymphoma.

We reported previously on the successful use of bispecific antibodies in two well characterized B-cell lymphoma models. These bispecific antibodies were hybrid-hybridoma antibodies with dual specificity for the TcR/CD3 complex and for the tumor-specific idiotype of the surface IgM expressed by the lymphoma cells. Class-matched control antibodies, either monovalent for CD3, monovalent for idiotype, or bivalent for these surface markers, were always used in parallel with the bispecific antibodies. We extended our studies to determine the relative contribution of antibody-dependent cellular cytotoxicity and a T-cell-mediated therapeutic effect in the BCL1 lymphoma model. In tumor-bearing mice depleted of CD4+, CD8+ or both T-cell subsets and treated with bispecific antibodies, we could show that both T-cell populations contribute to the therapeutic outcome and have an additive role. In vitro studies demonstrate that bridging BCL1 tumor cells to T-cells by bispecific antibodies induces T-cell activation and secretion of tumor growth inhibiting lymphokines by both CD4+ and CD8+ T-cell populations. Particularly gamma-interferon seems to be the major tumor-inhibiting substance for BCL1 tumor cells. However, in vivo experiments using anti-cytokine antibodies showed that both gamma-interferon and tumor necrosis factor alpha have an effect on the tumor growth. The former acts directly by inhibiting tumor growth, the latter via an indirect mechanism, possibly by activating macrophages. In conclusion, our results show that induction of targeted cytolytic activity by the direct CD3/TcR cross-linking and development of targeted cytotoxic activity, mediated by gamma-interferon, by both T-cell subsets, contribute to the therapeutic success of bispecific antibody therapy.

Animals↗

PubMed1994

The genomic structure of the human AP-2 transcription factor.

The transcription factor AP-2 is encoded by a gene located on chromosome 6 near the HLA locus. Here we describe the genomic organization of the AP-2 gene including an initial characterization of the promoter. We have mapped two mRNA initiation sites, the entire exon-intron structure and located two polyadenylation sites. The mature AP-2 mRNA is spliced from 7 exons distributed over a region of 18 kb genomic DNA. A recently cloned inhibitory AP-2 protein is generated by alternative usage of a C-terminal exon. The proline-rich transactivation motif is encoded by a single exon within the N-terminal region in contrast to the complex DNA binding and dimerization motif which involves amino acid residues located on four different exons. The sites of mRNA initiation are located 220 and 271 bases upstream from the ATG translation start site. Although the promoter contains no canonical sequence motifs for basal transcription factors, such as TATA-, CCAAT- or SP-1 boxes, it mediates cell-type-specific expression of a CAT reporter gene in PA-1 human teratocarcinoma cells and is inactive in murine F9 teratocarcinoma cells. We demonstrate that the promoter of the AP-2 gene is subject to positive autoregulation by its own gene product. A consensus AP-2 binding site is located at position -622 with respect to the ATG. This site binds specifically to bacterially expressed AP-2 as well as to multiple proteins, including AP-2, present in PA-1 and HeLa cell nuclear extracts. A partial AP-2 promoter fragment including the AP-2 consensus binding site is approximately 5-fold transactivated by cotransfection of an AP-2 expression plasmid.

Animals↗

PubMed1994

Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo.

The aim of this work is to induce tumor resistance to a B cell lymphoma in BALB/c mice using elements of the immune system. It has indeed been shown by us and by others that antigen-presenting cells (APC) like dendritic cells can induce efficient immune responses and can even substitute for Freund's adjuvant. Here we show that mice immunized with syngeneic dendritic cells pulsed in vitro with tumor antigen (BCL1 idiotype expressed by lymphoma cells) are protected against a subsequent tumor inoculation. The in vivo resistance can be correlated with the induction of a humoral response specific for the idiotype expressed by the tumor. No such protection can be achieved when B cells are used as APC. These data show that effector cells in tumor-bearing animals can be recruited and activated using dendritic cells, providing long-lasting immune surveillance.

Animals↗

PubMed1994

Immunoglobulin isotype regulation by antigen-presenting cells in vivo.

The isotype and magnitude of the B cell response clearly depends on the in vivo activation of T helper (Th) cells which secrete different lymphokines. Since Th are activated by the presentation of the antigen on specialized cells, we wished to test whether the nature of the antigen-presenting cells (APC) influences the isotypic profile of the humoral response. Data are presented showing that antigen-pulsed dendritic cells (DC) and peritoneal macrophages induce the synthesis of specific antibodies when injected in syngeneic animals. By contrast, a single injection of antigen-pulsed resting B cells does not prime the mice in vivo. Moreover, the injection of antigen-pulsed DC induces the synthesis of specific IgG2a and IgG1 antibodies, whereas peritoneal macrophages favor the production of IgG1 and IgE antibodies specific for the antigen. These data show that the isotype and the amplitude of the B cell response can be regulated by the nature of the APC, and indirectly suggest that Th cell differentiation is controlled at the level of antigen presentation.

Animals↗

PubMed1994

In vivo immunosuppression induced by a weakly mitogenic antibody to mouse CD3: evidence that induction of long-lasting in vivo unresponsiveness requires TcR signaling.

The use of anti-CD3 monoclonal antibodies (mAb) to treat allograft rejection has been complicated by the morbidity observed during the first days of treatment, secondary to T cell activation and cytokine release. Available evidence in a mouse model indicates that F(ab')2 fragments of an anti-CD3 mAb are not mitogenic in vitro and can be injected in vivo without apparent toxicity. However, their immunosuppressive capacity is dramatically reduced, suggesting that long-term immunosuppression mediated by anti-CD3 antibodies in vivo may be associated to their mitogenic capacity. This paper demonstrates that a poorly mitogenic anti-CD3 mAb is able to induce potent immunosuppression in vivo with reduced morbidity. This finding suggests that immunosuppression in vivo by anti-CD3 mAbs is not directly related to their activation properties but nevertheless requires signaling capacities. Therefore, immunosuppression in vivo may be best achieved by using antibodies able to deliver an incomplete activation signal to T cells (thus avoiding systemic cytokine release), possibly leading to anergy. The implications of this study for the development of immunosuppressive antibodies are discussed.

Animals↗

PubMed1994

Diagnostic value of recombinant Aspergillus fumigatus allergen I/a for skin testing and serology.

BACKGROUND: We report a clinical study comparing the recombinant Aspergillus fumigatus allergen I/a (rAsp f I/a) to two commercial A. fumigatus extracts in skin prick tests, intradermal tests, and serologic assays. METHODS: Patients with allergic bronchopulmonary aspergillosis and A. fumigatus-allergic patients with asthma, and control subjects, including allergic patients with asthma without allergy to A. fumigatus and healthy subjects, were investigated. RESULTS: All patients with allergic bronchopulmonary aspergillosis (n = 15) reacted to skin prick tests with the commercial extracts, and eight were sensitized to rAsp f I/a. Of 10 patients with well-characterized A. fumigatus-allergic asthma nine showed positive skin prick test results to at least one of the commercial extracts, and five reacted to rAsp f I/a. There was a strong correlation between skin test reactivity to rAsp f I/a and rAsp f I/a-specific serum IgE as determined by an antigen-specific ELISA. The healthy control subjects (n = 7) and allergic patients with asthma without A. fumigatus allergy (n = 6) did not react in skin prick and intradermal tests to rAsp f I/a, nor did they have detectable amounts of rAsp f I/a-specific IgE. In addition, patients with allergic bronchopulmonary aspergillosis showed significant elevated levels of rAsp f I/a-specific IgG4 and IgG1 but no significant differences in rAsp f I/a-specific serum IgA levels when compared with the healthy control subjects. CONCLUSIONS: The data show that rAsp f I/a is a major allergen with biologic relevance in some A. fumigatus-allergic individuals as evaluated by skin prick tests, intradermal tests, or serologic methods. Furthermore, no discrepancies were observed between skin test results and rAsp f I/a-specific IgE. Hence the correlation between rAsp f I/a skin test results and serologic data indicates the potential of recombinant allergens for clinical applications and diagnosis of allergies.

Adult↗

PubMed1994

Iron status, erythropoiesis, meat colour, health status and growth performance of veal calves held on and fed straw.

Two experiments were designed to study the iron (Fe) status in veal calves (62 intact males) fed and held on straw. In experiment 1, two groups were fed 20 mg Fe/kg milk replacer (MR) and held unattached on rye or barley straw litter. In experiment 2, groups were fed 20 mg Fe/kg MR and held unattached on rye straw litter or on sawdust or attached on wooden slatted floors without straw litter or were fed 50 mg Fe/kg MR and held unattached on sawdust. Fe concentrations in tested straw sorts (rye, barley, wheat, triticale) were similar and ranged from 15 to 85 mg Fe/kg dry matter. Growth performance and health status were not significantly influenced by Fe intake through MR or straw. Straw intake in the group fed straw was greater (P < 0.01) at the end than at the start of the growth period, but intake of different straw sorts was similar. Calves fed 20, but not those fed 50 mg Fe/kg MR, developed marked hypoferraemia, but only moderate anaemia. Total iron binding capacity (TIBC) was significantly (P < 0.05) and transferrin (Tf) concentration was numerically higher in calves fed 20 than in those fed 50 mg Fe/kg MR on slaughter day. TIBC and Tf were positively correlated (r = 0.63). Haemin concentration and lightness of m. rectus abdominis were significantly (P < 0.01), whereas myoglobin concentration was numerically greater in calves fed 50 than in those fed 20 mg Fe/kg MR. In conclusion, haematological and blood chemical parameters and meat colour were influenced only by high Fe intake through MR, but not if calves were held on straw litter or were fed straw.

Anemia, Iron-Deficiency↗

PubMed1994

Blood serum transferrin concentration in cattle in various physiological states, in veal calves fed different amounts of iron, and in cattle affected by infectious and non-infectious diseases.

Transferrin (Tf) concentrations were determined in cattle in various physiological states, in energy-deficient (ketotic) cows, in situations of several acute and chronic infections, after endotoxin administration and in animals with bovine leucocyte adhesion deficiency (BLAD). Tf concentrations varied between 1.5 and 8.5 g/l and in healthy animals were in the range of 2.0 and 6.6 g/l. Tf concentrations in adult animals were smaller than in young animals and increased in veal calves with iron deficiency above 8 g/l, resulting in a negative correlation between Hb and Tf. In veal calves total iron binding capacity (TIBC) and Tf concentration were rather closely correlated (r = 0.63). Chronic infectious diseases (such as paratuberculosis) were characterized by relatively low Tf levels (below 2 g/l), while during acute infections, after endotoxin-administration and during ketosis Tf concentrations were not changed.

Animals↗

PubMed1994

Recombinant expression and antigenic properties of a 32-kilodalton extracellular alkaline protease, representing a possible virulence factor from Aspergillus fumigatus.

A 32-kDa nonglycosylated alkaline protease (EC 3.4.1.14) with elastolytic activity, secreted by the opportunistic pathogen Aspergillus fumigatus ATCC 42202, is suggested to be a virulence factor of this fungus. The enzyme is a serine protease of the subtilisin family, and its cDNA nucleotide sequence has recently been reported. We have cloned the cDNA encoding the mature protease into a high-level Escherichia coli expression plasmid and produced the recombinant protease as a fusion protein with a six-adjacent-histidine affinity tag at the carboxy terminus. Subsequently, the recombinant protease was purified to homogeneity, with affinity chromatography yielding 30 to 40 mg of recombinant protease per liter of E. coli culture. Refolded recombinant protease, in comparison with native protease, demonstrated weak enzymatic activity but similar immunochemical characteristics as analyzed by antigen-specific enzyme-linked immunosorbent assay (ELISA), competition ELISA, and immunoblotting assays. To assess the allergenic potential of the protease, sera from patients with allergic bronchopulmonary aspergillosis and sera from healthy control individuals were analyzed by ELISA and immunoblotting techniques. Sera from patients with allergic bronchopulmonary aspergillosis did not have protease-specific immunoglobulin E (IgE) antibodies and, remarkably, did not show significantly elevated protease-specific IgG antibody levels compared with those in sera from healthy control individuals. This suggests that the alkaline protease from A. fumigatus does not elicit IgE antibodies and has weak immunogenicity, a property which may explain fungus persistence in allergic individuals.

Amino Acid Sequence↗

PubMed1994

Effect of diuretics on morbidity and mortality in the treatment of hypertension.

Diuretic-based hypertension treatment trials have universally demonstrated a reduction in cardiovascular morbidity and mortality in treated compared with placebo or control subjects. Progression to more severe hypertension has been reduced together with reversal of left ventricular hypertrophy if present and prevention of congestive heart failure. The incidence of fatal and non-fatal strokes as well as coronary heart disease events have both been significantly reduced by diuretic-based treatment. Speculation that diuretic-induced adverse effects on lipid and glucose metabolism have negated the beneficial effects of blood pressure lowering has not been substantiated. Diuretics remain one of the preferred initial therapies in the management of hypertension.

Cerebrovascular Disorders↗

PubMed1994

Heart rate variability as a prognostic tool in cardiology. A contribution to the problem from a theoretical point of view.

BACKGROUND: Recent clinical studies have proposed standard deviation of heart rate as a diagnostic tool for the outcome of cardiac infarction. Mathematical analysis of heart rate variability shows that heart rate is influenced by different frequency components derived from different parts of the autonomous nervous system. In the experimental part of this study, we investigated the possibility of calculating a variable describing the parasympathetic branch of the autonomous nervous system exclusively. METHODS AND RESULTS: In 60 healthy volunteers, heart rate was measured to 1 millisecond during two different conditions: 5 minutes of rest, and 5 minutes of intermittent handgrip dynamometry; the latter is known to increase sympathetic arousal selectively. Heart rate was found to be lower at rest (65.9 +/- 9.7 beats per minute) than during dynamometry (72.8 +/- 10.4 beats per minute, P < .001). Respiratory sinus arrhythmia (RSA) calculated from the mean absolute differences between successive heart beats showed no significant change (3.01 +/- 1.62 beats per minute at rest versus 2.97 +/- 1.30 beats per minute during dynamometry). In contrast, standard deviation increased from 5.19 +/- 1.98 to 9.22 +/- 3.56 beats per minute (P < .001). CONCLUSIONS: It can be concluded from these data as well as from other plots presented in this article that RSA is a measure of the parasympathetic vagal tone, whereas standard deviation is increased by both sympathetic and parasympathetic arousal. Clinical evidence and data from physiological experiments are presented to show that a selective measure of vagal tone like RSA may offer advantages over standard deviation as a prognostic tool in cardiology.

Autonomic Nervous System↗

PubMed1994

[Molecular cloning of a new AP-2 transcription factor, AP-2beta, and its function in cell differentiation].

Transcription factor AP-2 has been previously shown to play an important function in embryonal development and cell differentiation. We have investigated the possibility that AP-2 function in embryonic development is exerted by a multigene family of AP-2 related transcription factors. Here we describe the molecular cloning of such an AP-2 related gene, AP-2 beta, and prove that it encodes for a functional transcription factor. In situ hybridizations of murine embryo sections revealed a temporally restricted and tissue-specific expression pattern that indicates a function of AP-2 beta in the development of the midbrain in the differentiation of sensory neurons for taste, olfaction and palpation.

Animals↗

PubMed1994

[Diabetes prevalence in a school population of Avellaneda, Argentina].

An interview system was used to survey 56,199 students in Avellaneda between the ages of 3 and 20 years, representing 60.6% of the population of that age group in the census. The study covered 178 of the 201 pre-schools, grade schools, high schools and special schools in the area. Thirty three diabetic children were identified (18 girls, 15 boys), with a mean of 12.5 years of age. This represents a prevalence of diabetes in the school age population of 0.45/1000 in the 3-12 year old group, 1.25/1000 in the 13-20 year old group, with 0.59/1000 for the total of children surveyed. (93.82 of ascertainement, 95% CI 0.34 to 0.42/1000). Similar figures have resulted from studies in developed countries. The most frequent initial symptoms were the typical ones, with only 15% showing acidosis or diabetic coma as the initiation of the illness. Viral infections and stress appeared to be related to the onset of the disease. Diabetes was in the family history of 48.5% of the diabetic children, and 24.5% of the non-diabetics. The most common diabetic relative was the paternal grandfather. The maternal side showed a higher number of diabetic relatives with preponderance of males. No socio-economic differences were found between diabetics and non-diabetics.

Adolescent↗

PubMed1994

[Changes in selenium status, antioxidant enzyme activity and lipid peroxide level after drinking cures in Bad Hall health resort].

61 spa patients, predominantly with heart and vascular diseases, were divided into 2 therapeutic groups. In addition to the usual balneotherapeutic program, one group (J) received a course of "iodine brine concentrate" for drinking (2 x 100 ml, daily iodine uptake approximately 9 mg), and the control group (CI) received isotonic NaCl in the same way. The patients were mostly on a reduced-fat and -calorie diet. The following parameters were determined at the beginning and at the end of the 26-day treatment period: total cholesterol, HDL-cholesterol, triglycerides, lipoprotein (a) (in serum); selenium (Se), malondialdehyde (MDA), and activities of Se-dependent, Se-independent, and total glutathione peroxidase (GSH-PX) (in plasma). In the J group, a significant increase was found in Se-independent (+17%) and total GSH-PX (+5%) and a significant decrease in total cholesterol (-6.9%) and MDA (-13.2%). At the end of the cure, Se levels were higher in the J group than in the C1 group. The only significant change in the C1 group was a decrease in HDL-cholesterol. Positive correlations were found between selenium and Se-dependent GSH-PX (r = 0.253) and between total GSH-PX and Se-dependent GSH-PX (r = 0.665). A negative correlation was obtained between Se-dependent and Se-independent GSH-PX (r = -0.331). The results are discussed with regard to the importance of antioxidant defense mechanisms in several degenerative diseases (atherosclerosis, diabetes, cataract etc.), and also respecting interactions between iodine and selenium metabolism, as well as normalization effects conditioned by the balneotherapy itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993