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Biomedical subjects

J Gauldie

Publications and source records attributed to J Gauldie.

At least 217 records · Page 12Linked to original sources
PubMed1985

Activation of alveolar macrophages following infection with the parasitic nematode Nippostrongylus brasiliensis.

Alveolar macrophages (AM) of rats infected with 3000 Nippostrongylus brasiliensis infective larvae for 2, 8 or 32 days (D2, D8 or D32 AM) quantitatively surpassed AM from uninfected rats in one or more of IgG- or C3-dependent phagocytosis indices, beta-D-glucuronidase release, or spontaneous release of thymocyte activating factor (interleukin-1, IL-1) and hepatocyte stimulation factor (HSF). These observations suggest that N. brasiliensis infection results in the activation of AM. We have reported previously that a greater proportion of AM from infected rats expressed C3 receptors and were helminthocidal in vitro in the presence of complement than normal AM which were not helminthocidal. The acquisition of the activated state by AM during infection may play a role in vivo lung resistance against migrating helminth parasites.

Animals↗
PubMed1984

The acute-phase response of cultured rat hepatocytes. System characterization and the effect of human cytokines.

Hepatocytes were isolated from adult livers and cultured for periods of up to 5 days as monolayers at an initial density of 10(6) cells/10cm2 in Williams E medium containing insulin, dexamethasone and 5% foetal-calf serum. The daily production of 11 plasma proteins was measured by electroimmunoassay and compared with the concentrations of the same proteins in the plasma of normal rats and of those with experimental inflammation. Hepatocytes from normal rats synthesized proteins in relative amounts which were similar to the relative proportions of the same proteins in the plasma of turpentine-injected animals. The pattern changed only slowly during 5 days in culture, but it did so profoundly either when the medium was devoid of dexamethasone or when human cytokines (from endotoxin-stimulated monocytes or unstimulated human squamous-carcinoma cell line COLO-16) were added. The cytokines consistently increased the synthesis of alpha 2-macroglobulin and fibrinogen and depressed that of albumin; variable increases in the synthesis of alpha 1-acute-phase globulin, alpha 1-acid glycoprotein, haptoglobin and alpha 1-proteinase inhibitor, and variable decreases in transferrin synthesis, were seen, whereas the synthesis of antithrombin III, alpha 1-macroglobulin and prothrombin remained virtually unaffected. The cytokine effects on protein synthesis required the presence of dexamethasone. The hepatocyte-stimulating activity derived from monocytes chromatographed on Sephadex G-100 corresponding to 30 000 Da, as opposed to the lymphocyte-activating factor, which was eluted as a molecule of approx. 15 000 Da. This suggests that both activities probably reside with distinct molecular species in the preparations of human cytokines.

Acute-Phase Proteins↗
PubMed1984

Sensitivity to suppression of cytotoxic T cell generation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on the Ah genotype of the murine host.

Susceptibility of mice to a variety of toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is genetically determined by the Ah locus. To determine if immunotoxicity following TCDD exposure was also regulated by the Ah locus, we tested the ability of low dose TCDD (4 ng/kg) to suppress the generation of allospecific cytotoxic T cells (CTL) by lymphocytes from "susceptible" C57B1/6, and "resistant" DBA/2, and from C57B1/6XDBA/2J F1 hybrid mice in vitro. To determine if TCDD acted directly on the "susceptible" lymphoid cells, the immune response of C57B1/6 leads to DBA/2 and DBA leads to C57B1/6 bone marrow chimeras was also measured. C57B1/6 and F1 mice proved susceptible to suppression consistent with the dominant effect of Ah. Susceptibility to suppression in chimeric mice, however, was determined by the Ah genotype of the host and not by the genotype of the grafted lymphomyeloid cells. Mixing experiments demonstrated that suppression of CTL generation by TCDD was due to suppressor T cells. The frequency of CTL precursors was not affected by TCDD. These results are consistent with the idea that TCDD acts by an Ah locus-dependent mechanism to indirectly promote development of suppressor T cells that block the generation of CTL from their precursors.

Animals↗
PubMed1984

Two populations of prelysosomal structures transporting asialoglycoproteins in rat liver.

Analyses by differential centrifugation of liver homogenates from rats that had received 131I-labeled asialoorosomucoid showed that, 1 min after injection, most of the intracellular ligand was associated with a particle that did not sediment at 2.5 X 10(5) g-min. However, by 10 min, undigested ligand became associated with a particle that did sediment at this speed. On analytical ultracentrifugation in sucrose gradients, both kinds of particles exhibited low densities (1.11-1.13 g X ml-1). In contrast to asialoorosomucoid, 125I-labeled asialotransferrin type 3, under noncatabolic conditions, remained largely confined to the nonsedimenting particle regardless of the duration of the study. Induction of catabolism of asialotransferrin was accompanied by the appearance of the ligand in the sedimentable particle. The nonsedimentable particle was separated by immunoadsorption from other subcellular particles contained in the low-density subcellular fraction. The adsorbant , prepared by immobilizing purified antibodies to the Gal/GalN-specific lectin from rat liver on coated polyacrylamide beads, removed 75-80% of the asialoorosomucoid and transferrin binding capacities present, together with a similar portion of the radioligands tested (asialoorosomucoid, asialotransferrin type 3, and human diferric transferrin). Significantly, the sialytransferase activity remained unadsorbed. From these findings, the nonsedimentable particle appears to be involved in the transport of ligands destined to such diverse fates as exocytosis or lysosomal degradation. The sedimentable particle, on the other hand, seems to represent a link between the first particle and the lysosome.

Animals↗
PubMed1984

Broncho-alveolar leucocyte responses during primary and secondary Nippostrongylus brasiliensis infection in the rat.

Using broncho-alveolar lavage, we have studied the cellular responses in the rat lung following primary and secondary infection with Nippostrongylus brasiliensis. During the primary infection, there was a biphasic increase in total broncho-alveolar leucocytes and in the absolute numbers of macrophages, neutrophils, eosinophils and lymphocytes. The first peak occurred on days 4-6, and the second peak occurred around day 16, after infection. During the secondary infection there was an anamnestic-like response by all cell types. These data suggest that the broncho-alveolar leucocyte responses to infection have an immunological basis and that in addition to the alveolar macrophage, neutrophils, eosinophils and lymphocytes may play a significant role in lung resistance against migrating helminth larvae.

Animals↗
PubMed1984

The acute phase response in parasite infection. Nippostrongylus brasiliensis in the mouse.

Systemic inflammatory reactions are a prominent feature of many parasitic infections and the cellular and humoral components of the acute phase reaction may have an impact on the host-parasite relationship. We examined serum changes of four acute phase reactants: alpha 1-proteinase inhibition (alpha 1Pi); complement C3; serum amyloid A protein (SAA); and serum amyloid P component (SAP), in mice undergoing a primary infection with Nippostrongylus brasiliensis. SAA and SAP showed changes within the first 2 days of infection indicating the presence of an acute phase response associated with inflammation in the lung. Alpha 1Pi and C3 serum levels were not altered. However, all four acute phase reactants were synthesized in greater amounts by primary cultures of hepatocytes taken from infected animals at this time. Subsequently, as parasite-mediated inflammatory changes occur in the gut, both serum and hepatocyte cultures demonstrate an acute inflammatory response in all four reactants. It is proposed that the early reaction between parasites and macrophage/monocyte lead to the release of a mediator of inflammation which initiates the hepatocyte response. In this infection, at least one of the APR is shown to localize to the site of inflammation influencing the host-parasite relationship.

Acute Disease↗
PubMed1984

Synthesis and turnover of prothrombin during experimental inflammation in rats.

The response of prothrombin to inflammatory reactions was investigated in rats. Inflammation was induced by the administration of either subcutaneous turpentine or intraperitoneal endotoxin, and its effects were studied 24 h and 48 h later. Albumin and alpha 1-acute-phase globulin served as the controls. There were only insignificant changes in plasma prothrombin concentration during inflammation which contrasts sharply with a decrease in circulating albumin by approximately 25% and an increase in alpha 1-acute-phase globulin by 300-400%. These changes were paralleled by similar changes in the incorporation of [3H]lysine into these proteins during the incubation of liver slices from rats that had been pretreated with the phlogistic agents. Prothrombin catabolism, studied using 131I-prothrombin, was increased by approximately 20%; albumin turnover, studied simultaneously with 125I-albumin, was not significantly affected, though the capillary transfer rate of albumin was significantly elevated 48 h after the induction of inflammation. It is concluded that rat prothrombin is not an acute-phase protein.

Animals↗
PubMed1984

Complement-dependent killing of Nippostrongylus brasiliensis infective larvae by rat alveolar macrophages.

Histopathological studies have provided circumstantial evidence that helminth parasite destruction occurs in the lung; however controlled in vitro studies on the helminthocidal activity of lung cells have not been reported. This study presents evidence that Nippostrongylus brasiliensis infection in the rat induces alterations in broncho-alveolar lavage (BAL) cell numbers, differential counts, and in vitro helminthocidal activity. Normal, uninfected rats yielded 3.3 +/- 0.6 X 10(6) BAL cells/rat, consisting predominantly of alveolar macrophages (greater than 90%). However on days 2-8 post-infection there was a 1.5-2.4-fold increase in BAL cell numbers with a significant neutrophilia on day 2 and a significant increase in the absolute number of all cell types on day 8. On day 32 post-infection, BAL cell numbers had returned to control levels. Normal BAL cells neither adhered to nor killed N. brasiliensis infective larvae (L3) in the presence of rat complement. By contrast BAL cells recovered from infected rats on days, 2, 8 or 32 post-infection (D2, D8 and D32 BAL cells, respectively) adhered under similar conditions. However, only D8 and D32 BAL cells killed L3. This complement-dependent killing correlated with significantly increased numbers of C3 receptor bearing alveolar macrophages in D8 and D32 BAL cells. Complement-dependent alveolar macrophage helminthocidal activity may therefore play an important role in lung resistance against resident or migrating helminths.

Animals↗
PubMed1984

The relationship among platelet-associated IgG, platelet lifespan, and reticuloendothelial cell function.

Platelet-associated IgG (PAIgG) has been reported to be elevated in nonthrombocytopenic patients who have a normal platelet lifespan. This has been interpreted as indicating that PAIgG is a nonspecific finding in these patients and not a determinant of platelet survival. It is important to recognize that the reticuloendothelial (RE) system plays an important role in the clearance of antibody-sensitized cells. In this study, we related the level of PAIgG and the platelet lifespan to the RE function in patients with: (A) idiopathic thrombocytopenic purpura (ITP), and (B) five patients with elevated levels of PAIgG yet normal or near-normal platelet counts. RE function was assessed by measuring the clearance of autologous chromium-labeled red cells sensitized with a precise amount of alloantibody (2,000-3,600 molecules of IgG/cell). Eight patients with immune thrombocytopenia had significantly shortened platelet survivals (less than 2-113 hr). In contrast, the five patients with elevated PAIgG, yet normal or near-normal platelet counts, all had normal autologous platelet survivals (186-222 hr). These patients also had significantly impaired clearance of IgG-sensitized red cells, with an average of 85% of the infused red cells remaining in the circulation at 60 min (normal 42% +/- 14%, n = 10). In this study, every patient with elevated PAIgG and normal RE function had a shortened platelet lifespan. Those patients with elevated PAIgG and impaired RE function did not invariably have a shortened platelet lifespan. The observation that the PAIgG is elevated in some patients whose platelet survival is normal does not indicate that PAIgG is not biologically relevant. It indicates that these patients may have RE blockade and do not clear IgG-sensitized cells.

Blood Platelets↗
PubMed1983

Fc receptors for IgA and other immunoglobulins on resident and activated alveolar macrophages.

Alveolar macrophage (AMO) were recovered by bronchoalveolar lavage from mice. We have examined the surface of these cells for receptors of immune effector molecules and compared the normal resident AMO to the 'activated' cell present during extensive lung inflammation caused by the parasite Nippostrongylus brasiliensis 2 days after subcutaneous inoculation. As has been shown previously, the resident alveolar macrophage expresses Fc receptors for IgG (90%) and IgE (17%). We now show that a significant proportion of resident AMO possess an Fc receptor for IgA (14%) and this proportion increases to nearly 30% upon activation of the cell, coincident with an increase in release of plasminogen activator and phagocytic activity. This newly described presence of IgA receptors on AMO represents an important demonstration of potential 'arming' of these cells by the predominant antibody in mucous secretions and direct involvement of the AMO in immune mediated reactions in the lung.

Animals↗
PubMed1983

Cellular and genetic basis for suppression of cytotoxic T cell generation by haloaromatic hydrocarbons.

Generation of allospecific cytotoxic T cells in C57Bl/6 mice is significantly impaired following exposure to TCDD at doses as low as 4 ng/kg. T helper activity, as assessed by the ability to produce Interleukin 2, and frequency of CTL precursors appear unaffected in treated animals and thus the TCDD-induced suppressor cells we have described are primarily responsible for the reduction in the CTL response. Suppression of CTL generation in DBA/2 mice requires a 10--100-fold greater dose than in C57Bl/6, consistent with the observation that the Ah locus gene(s) of DBA/2 mice code for TCDD receptors with low binding affinity for TCDD. Other haloaromatic hydrocarbons (3,3'4,4'-tetrachlorobiphenyl and Aroclor 1254), capable of binding to the TCDD receptor, also suppress CTL generation, whereas the 2,2',4,4',6,6'-hexachlorobiphenyl molecule that lacks affinity for the TCDD receptor does not suppress CTL. The immunotoxic effects of TCDD in C57B/6 and DBA/2 mice occur at dose levels below those required to induce mixed-function oxidase enzymes in the liver. Suppression of CTL by TCDD is associated with increased susceptibility to lethal herpes virus type II infection. These data suggest that low levels of TCDD may interact with cytoplasmic receptors for TCDD in the thymus and induce biologically significant immunosuppression through activation of suppressor cells.

Animals↗
PubMed1983

The measurement of platelet-associated IgG using an immunoradiometric assay.

The amount of IgG on the surface of washed platelets from healthy individuals varies according to the assay used. An immunoradiometric assay (IRMA) for IgG was developed, validated and used to measure platelet associated IgG. The platelet-associated IgG (PAIgG) on washed platelets was allowed to react with excess 125I-labelled anti-IgG. The unbound 125I-anti-IgG was then quantitated by the addition of sepharose beads to which IgG had been covalently bound. The 125I-anti-IgG/IgG-beads were separated from the platelet suspension by passage across a density gradient. The mean amount of IgG present on washed platelets from healthy individuals was 0.8 fg IgG/platelet, or approximately 4,000 molecules of IgG per cell. Inverse Scatchard analysis confirmed the validity of the assay calibration and identical results were obtained when five different anti-IgG antibodies were used. The specific binding of 125I-anti-IgG to platelet-bound IgG was complete by 30 min, but non-specific binding of radioactivity continued thereafter. This non-specific binding occurred not only with anti-IgG but with all antibodies tested and could give elevated estimates of PAIgG in direct binding assays.

Antibodies, Anti-Idiotypic↗
PubMed1983

Immune-mediated thrombocytopenia of malaria.

Thrombocytopenia frequently complicates malarial infections but the mechanism has not been elucidated. We studied 28 patients with malarial infections and noted that 16 of 17 thrombocytopenic patients had elevated levels of platelet-associated IgG (PAIgG). In all thrombocytopenic patients studied, the level of PAIgG returned to normal as the platelet count rose to normal levels. To study the mechanism of the elevated platelet-bound IgG, IgG and F(ab')2 from patients with recurrent Plasmodium falciparum infections was purified and radiolabeled. Labeled and unlabeled P. falciparum antigen was also prepared. IgG did not nonspecifically bind to malaria-damaged platelets. Binding studies with 3H-malarial antigen demonstrated platelets have saturable binding sites for malarial antigen. Increasing concentrations of malarial antigen displaced the 125I-IgG antimalarial antibody from the platelets. The binding of 125I-IgG and 125I-F(ab')2 was similar and this excluded significant immune complex binding. The thrombocytopenia that complicates at least some malarial infections is caused by immune mechanisms; specific IgG binds to platelet-bound malaria antigen through the Fab portion of the immunoglobulin molecule.

Binding Sites, Antibody↗
PubMed1983

Detection of human fetal fibrinogen in umbilical cord plasma by parallel assays of immunoreactive and thrombin-clottable protein.

Putative fetal fibrinogen was detected in normal human umbilical cord plasma by parallel assays of immunoreactive and thrombin-clottable protein. The 'excess' of immunoassayable fibrinogen was not due to products of proteolysis and the apparent 'insensitivity' to thrombin was reflected in delayed fibrin polymerization. Fetal fibrinogen was partially separable from the adult protein by two-dimensional immunoelectrophoresis.

Adult↗
PubMed1982

Mucosal mast cells. I. Isolation and functional characteristics of rat intestinal mast cells.

We have developed a procedure for the dispersion of mast cells from the intestinal lamina propria (LP) and epithelium of rats infected with the intestinal nematode, Nippostrongylus brasiliensis. The dispersed cells are morphologically and histochemically similar to intestinal mucosal mast cells (MMC) in situ and are distinguishable from peritoneal mast cells (PMC). MMC derived from the LP or epithelium of parasitized animals secrete histamine in response to the specific parasite antigens as well as anti-IgE. Unlike PMC, these cells are unresponsive to the basic secretagogues 48/80 and bee venom peptide 401. Similarly, bee venom peptide 401 conjugated with dansyl chloride binds to PMC and mast cells in the thymus and intestinal serosa, but not to mast cells in or derived from the intestinal LP and epithelium. Studies on PMC treated by the intestinal cell isolation procedure show that the functional characteristics of the MMC cannot be solely attributed to the isolation procedure. Thus, MMC have been isolated and shown to be morphologically, histochemically, and functionally different from PMC, as suggested by previous in vivo studies of the normal intestine.

Animals↗
PubMed1982

Mucosal mast cells. II. Effects of anti-allergic compounds on histamine secretion by isolated intestinal mast cells.

Functional mast cells have been isolated from the lamina propria of the small intestine of rats infected with the nematode Nippostrongylus brasiliensis. The cells released histamine on challenge with specific antigen, anti-rat IgE, concanavalin A, and calcium ionophores but were less responsive than peritoneal mast cells (MMC) from the same animals. Intestinal mucosa mast cells (PMC) were refractory to the action of the basic secretagogues peptide 401 from bee venom and compound 48/80. The anti-allergic compounds disodium cromoglycate (less than or equal to 10(-3) M), AH 9679 (less than or equal to 10(-4) M), and theophylline (less than or equal to 10(-2)) did not inhibit antigen-induced histamine secretion by MMC, although these compounds were effective against PMC. In contrast, doxantrazole (10(-5) to 10(-3) M) inhibited the secretion of histamine from both MMC and PMC in a comparable dose-dependent fashion. Thus, we have established that mast cells from different sites are functionally heterogeneous not only in their response to various stimuli for histamine secretion, but also in their responses to different pharmacologic modulators of secretion. It cannot be assumed that anti-allergic compounds effective against mast cells in one tissue site or organ will be equally efficacious against mast cells in other sites. The extent of this functional heterogeneity must be established, and its investigation may provide new insights into the biochemical events involved in mast cell secretion.

Animals↗