Time dependent factor IX inhibitor.
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Adult↗
Biomedical subjects
M Joseph
Publications and source records attributed to M Joseph.
A circulating suppressive factor of platelet cytotoxic functions after rush immunotherapy in Hymenoptera venom hypersensitivity.
A receptor for the Fc fragment of IgE has been described on human blood platelets. This receptor mediated the IgE-dependent stimulation of platelets by the specific allergen in Hymenoptera venom (HV) hypersensitivity. This platelet reactivity was abolished after rush desensitization. To understand the mechanism of such a down-regulation, we studied the effects of sera recovered from patients treated by HV rush desensitization on platelets of untreated HV sensitive patients. The present data describe the presence of a circulating factor able to suppress, in a dose-dependent manner, platelet stimulation by the specific allergen. This circulating factor was not allergen specific, not depleted by IgE or IgG antibody immunoadsorption, and was found at higher concentrations in the sera of patients receiving monthly high dosages of HV (200 micrograms maintenance dose). The physicochemical characterization showed that this circulating factor had a m.w. of 20,000 to 25,000, an isoelectric point of 4.2, was heat and acid stable, and sensitive to trypsin, but not to neuraminidase. These characteristics were similar to a newly described lymphokine, platelet activity suppressive lymphokine, suggesting the intervention of such a lymphokine in HV rush desensitization.
Bee Venoms↗
Covalent binding of [14C]-2,6-dimethylaniline to DNA of rat liver and ethmoid turbinate.
The xylidide 2,6-dimethylaniline (2,6-DMA) has produced carcinomas and papillary adenomas in the nasal cavity of rats at high dietary doses (3000 ppm) in a 2-yr bioassay. The objective of the present study was to measure the covalent binding of 2,6-DMA to DNA of rat ethmoid turbinate tissues and, for comparison, to DNA of rat liver. The potent hepatocarcinogen 2-acetylaminofluorene (AAF) was studied as a positive control for adduct formation and covalent binding index (CBI) calculation. Both 2,6-DMA and AAF were administered as 14C-(ring)-labeled agents to naive rats and to rats pretreated for 9 d with unlabeled 2,6-DMA or AAF. The CBI value for 2,6-DMA adduct formation with ethmoid turbinate DNA was below the assay's sensitivity limit in nonpretreated rats, but increased to 41.9 in rats pretreated with unlabeled 2,6-DMA. It also increased from 0.6 in nonpretreated to 7.9 in liver of pretreated rats. The opposite pattern, however, was observed for AAF. In nonpretreated rats considerable adduct formation was observed in liver (CBI = 271.5) and modest values (CBI = 39.3) were calculated for ethmoid turbinate tissues. Pretreatment with unlabeled AAF caused a significant decrease in CBI values, to 18.3 for liver and less than 0.5 for ethmoid turbinate. The results suggest that there may be value in conducting DNA covalent binding assays in both naive animals and animals pretreated with the test article.
Aniline Compounds↗
Inhibition of human eosinophil chemotaxis and of the IgE-dependent stimulation of human blood platelets by cetirizine.
Cetirizine is a new anti-allergic compound with a potent, long-acting, and specific antihistaminic property. Strongly active in the therapy of urticaria and seasonal or perennial rhinitis, it has been shown to inhibit the in vivo eosinophil attraction at skin sites challenged with allergen in atopic patients. In the present work, we confirmed that, at a therapeutical concentration, this molecule had a potent inhibitory action in vitro on eosinophil chemotaxis induced either by N-formyl-Met-Leu-Phe or platelet-activating factor and also on the IgE-dependent stimulation of platelets. These observations appear in favour of a possible role for cetirizine in the modulation of inflammatory cell interactions in allergic processes.
Blood Platelets↗
Local anaesthetic infiltration for caesarean section.
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Adolescent↗
Nedocromil sodium inhibition of IgE-mediated activation of human mononuclear phagocytes and platelets from asthmatics.
The demonstration of a specific receptor for IgE on non-mast cell or basophil leucocytes, such as mononuclear phagocytes, eosinophils and platelets, suggests that these cells may participate directly in immunological disorders of allergy. In this study, inhibition by nedocromil sodium of IgE-dependent activation of human alveolar macrophages, blood monocytes and platelets was investigated. Nedocromil sodium produced an inhibition of IgE-mediated generation of cytotoxic molecules from monocytes and platelets together with a concomitant inhibition of their oxidative metabolism, measured by chemiluminescence. In addition, nedocromil sodium reduced the ability of alveolar macrophages to synthesise and release mediators, estimated by beta-glucuronidase activity. Furthermore, nedocromil sodium inhibited the abnormal response to aspirin of platelets from aspirin-sensitive asthmatics at therapeutic concentrations. These studies confirm that nedocromil sodium acts on a cell compartment other than the classical mast cell population in IgE-dependent allergy and asthma.
Animals↗
Characterization of a suppressive factor of platelet cytotoxic functions in human and rat schistosomiasis mansoni.
In a previous study we demonstrated that mitogen-stimulated CD8+ CD4-T cells from normal donors produce a suppressive lymphokine (PASL) of IgE-dependent platelet cytotoxicity. Here we demonstrate the production, after antigenic-stimulation, of this suppressive factor during ongoing infections by Schistosoma mansoni in man and in the rat. The T lymphocyte subpopulation producing this factor was also identified as expressing the marker of the suppressive subset. Because of the absence of species restriction, the relevance in vivo of PASL was determined in the rat model. In these conditions we observed a complete abolition of the protection normally conferred against a challenge infection by the passive transfer of platelets from immune to normal rats after treatment of transferred platelets with T lymphocyte supernatants.
Animals↗
Interaction of a hydrophobic model peptide and its fatty acid derivative with lipid vesicles.
The interaction of a peptide [Lys-Phe-Phe-Phe-Ile-Ile-Trp-OCH3] and its fatty acid derivatives [Lys-(epsilon-palmitoyl)-Phe-Phe-Phe-Ile-Ile-Trp-OCH3 and Lys-(epsilon-12-(9-anthroyloxy)stearic acid)-Phe-Phe-Phe-Ile-Ile-OCH3] with model membranes was investigated by fluorescence spectroscopy. The emission characteristics of the Trp fluorophore indicated that only the peptide with the fatty acid chain is associated with lipid vesicles. Quenching experiments with spin probes suggest an orientation for the fatty acylated peptide wherein the fatty acid chain is perpendicular to the bilayer surface and the peptide chain parallel to the bilayer surface.
Acylation↗
Onchocerca volvulus. Monoclonal anti-idiotype antibody as antigen signal for the microfilaricidal cytotoxicity of diethylcarbamazine-treated platelets.
Over the past 35 yr, diethylcarbamazine (DEC) has been the most widely used agent for the treatment of filarial diseases, particularly in onchocerciasis. The microfilaricidal action of DEC has been recently shown to be mediated by blood platelets with the additional triggering of a filarial excretory Ag (FEA). This FEA could be detected by using mAb in the serum of infected patients. By using one mAb (IA2(23] directed against Onchocerca volvulus and recognizing circulating Ag (Ab1), we purified by affinity chromatography the target molecule of IA2(23) (an O. volvulus glycoprotein recognized by IA2(23) mAb). This compound had a dose-dependent effect on the cytotoxic action of DEC-treated platelets. We subsequently produced an anti-idiotype mAb to Ab1 (Ab2), and considered the possibility of replacing the O. volvulus glycoprotein recognized by IA2(23) mAb by Ab2. Ab2 was selected according to its ability to inhibit the binding of radioiodinated Ab1 to the filarial target Ag. It induced the production of anti-O. volvulus antibodies (Ab3) in rats. At a constant concentration of DEC platelets, the addition of increasing amounts of Ab2 led to a dose-dependent cytotoxic effect against parasite larvae. Experiments performed with Ab2 on detergent solubilized surface proteins of platelets identified four bands of Mr 18, 26, 43.5, and 100 kDa, supporting the idea of the presence of binding sites on the platelets for a FEA required for the microfilaricidal cytotoxicity of DEC-treated platelets.
Animals↗
Recombinant tumor necrosis factors mediate platelet cytotoxicity to Schistosoma mansoni larvae.
The involvement of platelets in the immunity directed toward the parasite Schistosoma mansoni has been demonstrated in vitro and in vivo. The killing properties of platelets were shown previously to involve specific IgE after their binding to a membrane receptor. More recently, we have demonstrated that lymphokines released by S. mansoni Ag- or lectin-stimulated CD4+/CD8-T cells were able to induce the platelet cytotoxicity. The isoelectric focusing of the T lymphocyte supernatants showed that two factors were able to stimulate the platelet killing functions. One of them was clearly identified as being IFN-gamma. The present work demonstrates that the second lymphokine was TNF. Indeed the rTNF-beta and, to a lesser extent, rTNF-alpha, induce normal platelets into killer cells for the young larvae of schistosome. Moreover, an additive effect of the TNF-alpha and IFN-gamma has been observed.
Adult↗
Recombinant human interferon-gamma induces increased IgE receptor expression on human platelets.
Human recombinant interferon-gamma (IFN-gamma) significantly increased the expression of receptors for IgE (Fc epsilon RII) on blood platelets. Fc epsilon RII was measured by specific binding of 125I-labeled IgE or flow cytometry experiments. Scatchard analysis of 125I-labeled IgE binding curves revealed that treatment with IFN-gamma increased the number of Fc epsilon RII but did not change the value of the association constant of Fc epsilon RII for 125I-labeled IgE. IFN-alpha had no effect on the expression or affinity of Fc epsilon RII. In addition to Fc epsilon RII, IFN-gamma also modified the expression of the glycoprotein IIb-IIIa complex on the platelet membrane.
Blood Platelets↗
Platelets in allergy. Assays and interpretation.
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Antibody-Dependent Cell Cytotoxicity↗
In vitro and in vivo immunomodulation by LF 1695 of human and rat macrophages and platelets in schistosomiasis.
The activity of the synthetic immunomodulator LF 1695 on the efficiency of two effector cell populations--macrophages and blood platelets--involved in IgE-dependent cytotoxic processes against parasites, was evaluated. Oxygen metabolite production and anti-parasite cytotoxic properties of both macrophages and platelets were increased following LF 1695 treatment in vivo (in rat) or in vitro (in rat and in man). The phagocytic properties of rat peritoneal macrophages were also potentiated by their in vitro incubation with the drug. In addition to these effector functions, the lysosomal enzyme content and the migration ability of rat peritoneal macrophages were stimulated after incubation with LF 1695. In the presence of the drug, rat macrophages were also shown to produce increased level of IL-1--measured by the mitogen-induced proliferation of murine thymocytes--when compared to unstimulated phagocytes. Finally, the oral treatment of rats with LF 1695, in the course of an experimental infection with schistosome parasites, induced a higher degree of immune protection (80%) against a challenge infection than untreated, infected control rats (40%). These results bring evidence of a stimulatory role for LF 1695 on immune effector functions of cells participating to defense mechanisms against multicellular pathogens.
Adjuvants, Immunologic↗
Effect of disodium cromoglycate on inflammatory cells bearing the Fc epsilon receptor type II (Fc epsilon RII).
Disodium cromoglycate (DSCG) has well-established stabilizing properties on mast cells and basophils. However, the potential inhibitory effect of DSCG has been little demonstrated on the IgE stimulation of cell populations expressing epsilon receptors type II, (Fc epsilon RII), such as mononuclear phagocytes, eosinophils or platelets. Therefore, using various parameters of IgE-mediated triggering, we demonstrated the inhibitory role of DSCG on: (i) the release of neutrophil chemotactic factor by human alveolar macrophages, (ii) the oxygen metabolite-dependent chemiluminescence of human alveolar macrophages, rat peritonal macrophages, human eosinophils, human and rat platelets, and (iii) the beta-glucuronidase release and synthesis by human alveolar macrophages. The inhibition of IgE-dependent stimulation ranged from 60% to 80%, according to the cells and to the measured parameter. It could therefore be considered that the action of DSCG was not restricted to its effects on mast cells and basophils, but also on other cells expressing Fc epsilon R leading to a potential reduction of the physiopathological consequences of allergic asthma and, possibly, of the late phase reaction sometimes associated with the disease, insofar as these cells are involved.
Animals↗
Variation in the expression of macrophage Fc epsilon receptors in relation to experimental rat schistosome infection.
The relationship between IgE and rat peritoneal macrophages during the course of Schistosoma mansoni infection was examined. Immune macrophages exhibited an IgE-dependent schistosomulicidal activity mainly between the 5th and the 7th weeks. At this period the percentages of anti-IgE rosettes whose variations appeared consecutive to the variations in the serum IgE level were higher. Following incubation in a serum-free medium immune macrophages could release membrane-associated IgE, to a certain extent, and consequently formed rosettes with IgE-coated erythrocytes, indicating the existence of Fc epsilon receptors. Thus, in terms of rosettes, their number varied in the course of the disease. In fact IgE-rich serum (i.e. at day 42) as IgE molecules could induce this macrophage Fc epsilon receptor. Moreover when transferred to syngeneic rats in association with parasite-specific IgE Fc epsilon R2+ macrophages led to some protection against challenge infection. All the data reported here emphasize the determining role of macrophages and IgE in immunity to schistosomiasis.
Animals↗
Regulation of IgE-dependent antiparasite functions of rat macrophages and platelets by nedocromil sodium.
The IgE-dependent stimulation of mononuclear phagocytes and blood platelets can be measured by antiparasite cytotoxicity, oxygen-mediated chemiluminescence and, in macrophages, lysosomal enzyme activity. Using these parameters, the present study demonstrated an inhibition by nedocromil sodium of the IgE-mediated triggering of the nonmast cell inflammatory populations in the rat. These observations suggest that nedocromil sodium may be of value in the modulation of IgE-dependent cell activation inducing the release of inflammatory mediators.
Animals↗
Inhibition by nedocromil sodium of IgE-mediated activation of human mononuclear phagocytes and platelets in allergy.
The demonstration of a specific receptor for IgE on nonmast cell or basophil leukocytes, such as mononuclear phagocytes, eosinophils, and platelets, suggests that these cells may participate directly in immunological disorders of allergy. Thus, a full understanding of the mode of action of antiallergic or antiasthma drugs must take into account their activity on these nonmast cell leukocytes. Consequently, inhibition by nedocromil sodium of IgE-dependent activation of human alveolar macrophages, blood monocytes and platelets, was investigated. This compound induced an inhibition of the IgE-mediated generation of cytotoxic molecules from monocytes and platelets, together with a concomitant inhibition of their oxidative metabolism, measured by chemiluminescence, and a reduction of the potential ability of alveolar macrophages to synthesize and release mediators, estimated by lysosomal beta-glucuronidase activity. These observations confirm the hypothesis that nedocromil sodium acts on a cell compartment other than the classical mast cell population, in IgE-dependent allergy and, more particularly, in asthma.
Airway Obstruction↗