Inhibition of lytic programming by pharmacologic agents.
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Adenylyl Cyclases↗
Biomedical subjects
M Plaut
Publications and source records attributed to M Plaut.
Interleukin 1 production by human lung tissue. I. Identification and characterization.
Crucial to the development of inflammatory infiltrates is the localized production of mediators which promote adherence of leukocytes to the vascular endothelium. Previous in vitro studies, using monolayers of cultured human vascular endothelial cells (VEC), have identified various agents which promote the acquisition of adhesiveness in VEC for polymorphonuclear leukocytes. In the present studies, we report that human lung fragments cultured for 4 to 24 hr release a factor which acts on VEC to promote adherence of polymorphonuclear leukocytes. Adhesiveness in VEC stimulated by lung fragment culture supernatants was time- and dose-dependent. This adherence-promoting factor appears to be a mixture of the alpha and beta forms of interleukin 1 (IL-1) and has the following properties: 1) it is heat-labile; 2) it is not inactivated by polymyxin B; 3) it has mobility on Sephadex G-75 column chromatography corresponding to apparent m.w. of approximately 15,000, 30,000, and 70,000 (a pattern observed previously for IL-1); 4) it has activity in the thymocyte costimulation IL-1 assay, but no interleukin 2 activity, and 5) it is neutralized by anti-human IL-1 antisera but not by anti-human tumor necrosis factor antiserum. Production and release of IL-1 in vivo may play a role in the development of inflammatory infiltrates in human lung and other tissues by acting on endothelium to promote the localized adherence of leukocytes.
Cell Adhesion↗
Studies of IgE-dependent histamine releasing factors: heterogeneity of IgE.
Nasal lavage fluids from unstimulated individuals contain a histamine-releasing factor (HRF) similar to those which we have previously described from macrophages, platelets, and from blister fluids obtained during the late cutaneous reaction. The nasal HRF was partially purified by ion-exchange chromatography and gel filtration. Although some m.w. heterogeneity was observed, the majority of the HRF eluted at an apparent m.w. range of 15,000 to 30,000. This partially purified HRF induced histamine release from basophils of certain individuals. Histamine release occurred via a mechanism which is IgE-dependent in that: basophils desensitized by exposure to anti-IgE in the absence of calcium no longer respond to HRF, and desensitization with HRF reduces responsiveness to anti-IgE; and removal of IgE from the basophil surface by using lactic acid renders cells unresponsive to HRF. We have further defined this IgE dependence and have shown that the reason that only selected basophil donors respond to HRF is due to a previously unrecognized, functional heterogeneity of IgE. Thus, passive sensitization using sera from responders restored the responsiveness of acid-stripped basophils and conferred responsiveness to basophils of a nonresponder with naturally unoccupied IgE receptors. Sera from nonresponders failed to do this even though similar numbers of IgE molecules were put onto the basophil surface in each case. This property of responder sera was due to IgE because both heating sera at 56 degrees C for 2 hr and passage of sera over anti-IgE-Sepharose (which removes greater than 90% of the IgE) markedly reduced the ability of sera to induce responsiveness, and because an excess of either purified IgE myeloma or purified penicillin-specific IgE antibody from a nonresponder competitively inhibited the ability of IgE from responder sera to induce responsiveness to HRF. We conclude that nasal lavage fluids contain an HRF which induces basophil histamine release in a specific, IgE-dependent fashion but only from individuals with the appropriate type of IgE. Because we have shown that basophils are recruited into the nose during the late-phase reaction, we suggest that nasal HRF may induce these cells to release histamine and other mediators which could contribute to the symptomatology of the late-phase reaction.
Basophils↗
Lymphocyte hormone receptors.
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Antibody-Dependent Cell Cytotoxicity↗
Identification of histamine releasing factor(s) in the late phase of cutaneous IgE-mediated reactions.
We have shown that fluids collected from antigen-challenged skin blisters during the late phase reaction cause the release of substantial amounts of histamine (means = 42%, n = 14) from human basophils in vitro. Control fluids collected either during the immediate phase or from an unchallenged blister released less than or equal to 10% histamine from both basophils and lung mast cells. Late phase blister fluids induced low levels of histamine release from human lung cells (means = 11%, n = 4) that were slightly but not significantly greater than levels induced by control blister fluids. The characteristics of basophil release were similar to IgE-mediated stimuli in dose dependence, calcium and temperature requirements, and kinetics. The IgE dependence of the late phase blister fluid was demonstrated by desensitization of the basophils to anti-IgE, which obviated the response to anti-IgE and blister fluid but did not affect a non-IgE-mediated stimulus. Removal of the cell surface IgE with lactic acid also abolished the response to both anti-IgE and late phase blister fluid. Incubation of the "stripped" cells with serum containing IgE myeloma restored the response to anti-IgE but failed to affect response to late phase blister fluid. The characteristics of release obtained with this factor closely resemble those of an IgE-dependent histamine releasing factor from cultured macrophages previously described by our group.
Allergens↗
Human lung macrophage-derived histamine-releasing activity is due to IgE-dependent factors.
Human lung macrophages obtained from surgical specimens spontaneously secreted a factor(s) (which we term macrophage factor) during 24-hr culture that induced calcium-dependent histamine release from human basophils and lung mast cells. Macrophage factor induced noncytotoxic histamine release from purified (85%) basophils. The kinetics of release were relatively slow and similar to that of anti-IgE. We performed a series of experiments to test the IgE dependence of macrophage factor-induced release. Preincubation of basophils with anti-IgE in calcium-free medium resulted in complete desensitization to macrophage factor-induced histamine release (i.e., when calcium and macrophage factor were added to the basophils, no histamine release occurred), and preincubation with macrophage factor in calcium-free medium resulted in partial desensitization to anti-IgE-induced histamine release. Pretreatment of basophils with pH 3.9 lactic acid buffer, which dissociates basophil IgE from its receptors, markedly reduced the capacity of basophils to release histamine in response to macrophage factor. Basophils that were incubated with IgE myeloma (but not with IgG) after lactic acid treatment partially or completely regained their capacity to release histamine in response to macrophage factor. Fluid-phase IgE myeloma (15 micrograms/ml) (but not IgG) inhibited basophil histamine release induced by two macrophage-derived supernatants, whereas IgE myeloma (200 micrograms/ml) did not inhibit release due to other supernatants. IgE-affinity columns removed the histamine-releasing activity of five macrophage-derived supernatants, and IgG-affinity columns had similar effects. However, neither affinity column removed the histamine-releasing activity of three other macrophage-derived supernatants. On Sephadex G-75 chromatography, nearly all of the histamine-releasing activity migrated as single peak with an apparent m.w. of 18,000. These results suggest that, although macrophage factor are heterogeneous, they are related, as they are a IgE-dependent factors that induce histamine release by interacting with cell surface IgE. These macrophage factors may be responsible for stimulation of basophil/mast cell mediator release in chronic allergic reactions.
Basophils↗
Abnormalities of basophil "releasability" in atopic and asthmatic individuals.
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Asthma↗
Inflammatory mediators in late antigen-induced rhinitis.
To investigate the mechanisms responsible for the late-phase response in patients with allergies, we measured four biochemical mediators (histamine, tosyl-L-arginine methyl ester [TAME]-esterase, kinin, and prostaglandin D2) in nasal secretions after nasal challenge with pollen antigen in 12 patients with allergy. Nine patients had an immediate response and a recurrence of symptoms 3 to 11 hours after challenge. The clinical symptoms during recurrence were accompanied by a second increase in levels of histamine, TAME--esterase, and kinin over base-line values, although kinin levels were lower than during the immediate response. In contrast, although the levels of prostaglandin D2 were significantly increased during the immediate response, they did not increase above base line during the late response. Rechallenge with allergen 11 hours after the initial provocation, however, was associated with reappearance of all four biochemical mediators, including prostaglandin D2. We conclude that the late response to nasal challenge with allergen is accompanied by a second increase in the concentrations of histamine and TAME--esterase but differs from the immediate response in the lack of prostaglandin D2 production and in the amount of kinin generated. Since histamine is released only by mast cells and basophils and prostaglandin D2 is not produced by basophils, we suggest that these cells are partly responsible for the late-phase response.
Adult↗
Role of human basophils and mast cells in the pathogenesis of allergic diseases.
The role of human basophils and mast cells in the pathogenesis of allergic diseases has been analyzed. Purified human basophils and mast cells release several known mediators of allergic reactions, including histamine, sulfidopeptide leukotrienes, kinin-forming enzymes, and, in the case of the mast cell, PGD2. These same mediators are released in vivo after experimental challenge in the upper airways with either allergen or cold, dry air, a stimulus used to simulate exercise-induced bronchospasm. The appearance of mast cell mediators in vivo after such challenges further implicates mast cells in the pathogenesis of allergic diseases of the airways that occur as a result of exposure to allergen or physical stimuli. During the LPR after experimental challenge of the upper airways, the pattern of mediators released (i.e., histamine, leukotrienes, and others, but no PGD2) suggests that basophils may contribute to the LPR. Antiallergic drugs that prevent mediator release in vitro, such as antihistamines, also prevent the appearance of mediators in vivo, strengthening both the validity of the in vitro test as a model of the disease and the hypothesis that mediator release is an essential element of the disease process. A model discussing the pathogenetic mechanism is presented.
Adrenal Cortex Hormones↗
Effect of seasonal ragweed exposure on immunoglobulin E antiragweed antibodies in cultures of peripheral mononuclear cells, plasma and nasal secretions.
To determine the effects of seasonal ragweed exposure on in vitro IgE antibody production, the antiragweed IgE antibody content of 7-day cultures of peripheral blood mononuclear cells was assessed in samples obtained before, during and after the ragweed season, in 4 ragweed-allergic and 11 nonallergic individuals. The levels of ragweed-specific IgE and total IgE in unstimulated culture supernatants were measured by solid phase radioimmunoassays. Antiragweed IgE antibody was apparently detectable in the 7-day culture supernatants of both allergic and nonallergic individuals, and the antibody concentrations increased after natural ragweed exposure. However, the bindable counts of IgE antibody in supernatants from allergic patients were inhibited by soluble ragweed antigen, while those from nonallergics were not inhibitable, suggesting that supernatants from nonallergics did not contain true ragweed-specific IgE antibody. Because, for most subjects, the quantity of IgE in culture supernatants from 7-day cultures of living cells was the same as that derived from cells which were either frozen and thawed prior to culture, or briefly exposed to pH 3.7 buffer, the majority of IgE antibody in supernatants from allergic subjects, and of total IgE in supernatants from all subjects, was apparently not newly synthesized, but was preformed, and appeared to be largely derived from the cell surface. IgE antiragweed antibody was detected in the nasal secretions and plasma of allergic, but not nonallergic individuals, and the levels of antibody in allergic subjects increased after seasonal exposure. The fraction of total IgE protein accounted for by IgE antiragweed antibody in nasal secretions collected postseasonally was higher than that in both culture supernatants and plasma, suggesting that ragweed-specific IgE antibody is synthesized locally in the nose.
Antibody Affinity↗
Human lung macrophages induce histamine release from basophils and mast cells.
Human lung macrophages isolated from surgical specimens, when cultured for 24 h, acquired the capacity to induce histamine release from human basophils. This releasing activity was entirely accounted for by soluble, nondialyzable factor(s) (molecular weight, more than 2,000 daltons) released from cultured macrophages. The basophil release reaction was dose-dependent, and also Ca++ (optimal concentration = 5 mM) and temperature (optimal = 37 degrees C) dependent. Supernatants derived from the equivalent of 3 X 10(6) macrophages/ml released 50% histamine from basophils of sensitive donors. The supernatants also induced histamine release from lung mast cells. These results are the first report of a human macrophage-derived product that activates basophils and mast cells to release histamine.
Basophils↗
Histamine release from human basophils is induced by IgE-dependent factor(s) derived from human lung macrophages and an Fc epsilon receptor-positive human B cell line.
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B-Lymphocytes↗
Dyspnea and cough in keeper of pet pigeon.
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Adult↗
Deuterium-oxide-induced histamine release from basophils of allergic subjects. I. Responsiveness to deuterium oxide requires an activation step.
Basophils from many atopic persons, and especially asthmatic patients, have been shown to release histamine in response to 44% deuterium oxide (D2O), whereas basophils from nonatopic persons do not release histamine. The present experiments analyzed the mechanisms by which D2O mediated release. It was found that although D2O induced release from washed leukocytes, it failed to induce release from whole blood or from leukocytes that had sedimented but had not been washed. The kinetics of release after washing were rapid and were equivalent regardless of the temperature at which cells were sedimented (O degrees or 37 degrees C). Washed cells became desensitized to the action of D2O within 30 to 60 min at 37 degrees C, whereas unwashed leukocytes did not become desensitized. Serum or plasma inhibited D2O-induced release, although high concentrations (1/5) were less inhibitory than lower ones (1/10 to 1/100). Basophils from D2O responders also released histamine in response to a "platelet enhancing factor" (PEF), whereas those from D2O nonresponders did not. As with D2O-mediated release, PEF-mediated release occurred only with washed leukocytes, desensitized within 30 to 60 min at 37 degrees C, and was inhibited by serum. These results suggest that D2O induces histamine release by augmenting the effects of an endogenous activation mechanism, and that PEF acts on the same (D2O-responsive) donors to augment this activation mechanism. Cell activation, as well as desensitization of this activation mechanism, occurs rapidly when basophils are washed free of plasma inhibitors and placed at 37 degrees C.
Asthma↗
Inhibition of T cell-mediated cytotoxicity by anti-inflammatory steroids.
We have tested the capacity of glucocorticoids to modulate the effector function of splenic cytotoxic T lymphocytes (CTL) obtained after i.p. immunization with allogeneic cells. Although acute exposure to glucocorticoids did not inhibit the activity of freshly obtained splenic CTL, preincubation of these CTL for several hours with subnanomolar concentrations of several different glucocorticoids caused marked inhibition. The relative inhibitory potency of the steroids tested correlated with their reported activity both in glucocorticoid receptor binding assays and in assays of anti-inflammatory potency in man. The inhibitory effects of low concentrations (10(-10) M to 10(-9) M) of dexamethasone were reversed by human or mouse interleukin 2 (IL 2)-containing supernatants, but were not reversed by IL 1-containing supernatants. The inhibitory effects of higher concentrations (10(-8) M to 10(-7) M) of dexamethasone could not be reversed even by very high doses of mouse IL 2. In contrast to previous reports of minimal direct glucocorticoid effects on CTL activity, the present results suggest that after preincubation, splenic CTL from in vivo-immune mice are sensitive to inhibition by glucocorticoids, and that the glucocorticoids may act both indirectly (on IL 2 production) and directly on the CTL.
Administration, Topical↗
Human lung macrophages enhance and inhibit lymphocyte proliferation.
To evaluate the effector functions of human lung macrophages, cell preparations containing 70 to 95% macrophages were obtained from surgically resected lungs of cancer patients and were co-cultured with allogeneic or autologous peripheral blood mononuclear cells (PBMC) and Con A. In contrast to previous reports of either marked stimulatory or inhibitory effects of human lung macrophages on lymphocyte function, the present results demonstrate that the proliferative response was a complex function of both the numbers of PBMC and macrophages. In the presence of low numbers of PBMC, small numbers of macrophages enhanced proliferation, whereas larger numbers inhibited proliferation; in the presence of larger numbers of PBMC, macrophages only inhibited. Inhibition was not mediated by cyclo-oxygenase products of arachidonic acid metabolism, because indomethacin did not reverse it. The enhancing effect of macrophages was greater when tested with PBMC depleted of monocytes. Lung macrophages were 10-fold more potent in mediating enhancement than corresponding numbers of peripheral blood monocytes. Both the enhancing and the inhibitory activities could be reproduced by lung macrophage lysates or supernatants derived from macrophages cultured in serum-free medium. Macrophages cultured at high density yielded inhibitory supernatants, which on dilution resulted in enhancing activity. The enhancing activity appeared in supernatants maximally after 24 hr, and its appearance was not inhibited by culturing macrophages in the presence by culturing macrophages in the presence of cycloheximide. Sephacryl S-200 chromatography of such supernatants yielded two peaks of enhancing activity, with apparent m.w. of 160,000 and 40,000, which we call lung macrophage-derived lymphocyte-activating factors (LM-LAF). Fractions with LM-LAF activity contained no IL 1 activity (assessed by augmentation of mitogen-induced proliferation of mouse thymocytes), but IL 1 activity was present in a peak of m.w. of 15,000. The 15,000 m.w. fraction did not enhance the proliferation of human PBMC. These results demonstrate that human lung macrophages are potent modulators of lectin-mediated proliferation of human PBMC. The effects are mediated in part by the release of soluble, pre-formed factors that appear to be distinct from previously described monokines.
Cells, Cultured↗
The role of cyclic AMP in modulating cytotoxic T lymphocytes. II. Sequential changes during culture in responsiveness of cytotoxic lymphocytes to cyclic AMP-active agents.
Agents that increase cyclic AMP (cAMP) levels inhibited the activity of cytotoxic T lymphocytes (CTL) obtained from spleens of mice immunized with allogeneic cells. Cultured CTL, however, were desensitized to cAMP-active agents, in that the capacity of these agents to inhibit the activity of cultured CTL was markedly reduced. The capacity to inhibit CTL activity was reduced more rapidly for some agents than for others; the percent inhibition by histamine and PGE2 was reduced after 4 hr and was reduced more than 20% after 24 hr, whereas the percent inhibition by dibutyryl cAMP, theophylline, and cholera enterotoxin was reduced less than 6% after 24 hr, and was reduced significantly only after 48 hr. Culture in the presence of antigen accelerated desensitization to the latter three agents. CTL populations were also tested for their capacity to increase cAMP levels in response to agonists. The capacity of histamine to increase cAMP levels of the CTL was lost within 4 hr (i.e., as rapidly as its capacity to inhibit CTL activity) and was never restored, whereas the capacity of PGE2 to increase cAMP levels persisted throughout culture. These results suggest that culture induces multiple alterations in cAMP metabolism of CTL. These alterations, which result in dissociation of CTL activity from cAMP-mediated regulatory steps, may include loss of histamine receptors and/or histamine receptor-adenylate cyclase coupling, and also loss of one or more biochemical reactions that link elevated cAMP levels to inhibition of lysis.
Animals↗