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Biomedical subjects

M Kaliner

Publications and source records attributed to M Kaliner.

At least 55 records · Page 3Linked to original sources
PubMed1987

IgE-immunotoxins. II. IgE-ricin A-chain.

In order to develop a reagent capable of killing cells with high-affinity IgE Fc receptors, such as mast cells and basophils, ricin A-chain (the toxic portion of ricin) was conjugated to rat IgE myeloma protein, IR 162, via derivatization of the IgE by n-succinimidyl-3-(2-pyridyldithio)propionate (SPDP) thus creating an IgE-immunotoxin. Monensin (10(-7)-10(-8)M), a carboxylic ionophore, facilitated IgE-ricin A-chain (3 X 10(-7)M) toxicity in a dose-related fashion ith significant reductions in [3H]leucine incorporation compared to cells exposed only to monensin. This enhanced toxicity could be inhibited by the addition of both anti-ricin A-chain or anti-IgE, suggesting that different routes of intracellular processing may play a role in determining the toxicity of the IgE-ricin A-chain conjugate. Ricin B-chain (5 X 10(-7) and 5 X 10(-8)M) added to free ricin A-chain (10(-6)-10(-8)M) reproducibly facilitated toxicity, and this toxicity could be inhibited (30-90%) by lactose (50 mM). Ricin B-chain also facilitated IgE-ricin A-chain (2.75 X 10(-8)M) toxicity; however, this toxicity was not affected by lactose. The data suggest that ricin B-chain potentiates the cytosolic access of internalized IgE-immunotoxin and that the binding and internalization of the toxin was mediated via the IgE Fc receptor. A second type of IgE-ricin A-chain conjugate was synthesized whereby both IgE and ricin A-chain were derivatized with SPDP. RBL cells were killed in a dose-dependent manner by this IgE-ricin A-chain conjugate (2.5 X 10(-6)-2.5 X 10(-9)M) without requiring the addition of monensin or ricin B-chain. These data indicate that the intracellular route and processing of internalized immunotoxin is critical to eliciting toxicity.

Animals↗
PubMed1987

Immunohistochemical identification of lung cells responsive to beta-stimulation with a rise in cAMP.

To identify specific lung cells possessing functional beta-adrenergic receptors, we developed an immunoperoxidase-staining procedure capable of in situ localization of cells responding to beta-agonist stimulation with a rise in adenosine 3',5'-cyclic monophosphate (cAMP). Isoproterenol was instilled into the airways of excised intact guinea pig lungs for 5 min and resulted in a six to eightfold rise in cAMP. Immediately thereafter, the lungs were washed in and fixed with 10% buffered Formalin. Sections were then stained using immunoperoxidase techniques and monoclonal antibodies directed against cAMP. We found that isoproterenol-stimulated lungs had widespread increased staining for immunoreactive cAMP. The specific cells consistently demonstrating marked increases in staining were airway epithelial cells, airway smooth muscle cells, alveolar and parenchymal macrophages, and alveolar lining cells, including both type I and type II cells, and capillary endothelial cells. Of all tissues, the airway epithelium was the most intensely stained area for beta-agonist-induced immunoreactive cAMP. The techniques employed herein should make possible the in situ localization of cells responding to any stimuli capable of increasing cAMP, thereby allowing the specific identification of cells possessing functional adenylate cyclase-linked receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Mast cell mediators and asthma.

Mast cells are found beneath the basement membranes, near blood vessels in the submucosa, adjacent to submucous glands, scattered throughout the muscle bundles, in the interalveolar septa and in the bronchial lumen. The evidence that mast cells and mast cell-derived mediators play a role in allergic and non-allergic asthma is discussed. In allergic individuals, inhalation of specific allergens leads to mast cell degranulation and release of mediators. Many of the pathologic features of asthma may be attributed to the effects of mast cell-derived mediators. Their role is clear in allergic asthma and the presence of mast cell derived mediators in the plasma of individuals with exercise-induced and nocturnal asthma suggests involvement in other forms of asthma as well.

Animals↗
PubMed1987

Allergy and the pharyngeal lymphoid tissues.

Allergic reactions involving the pharyngeal lymphoid tissues are thought to play a role in several clinical disorders seen commonly in ear, nose, and throat surgical practices. The pathogenesis of the allergic reaction is discussed in relationship to disorders involving the tonsillar tissues, the upper airways and nasopharynx, and the ear.

Adenoids↗
PubMed1987

Recurrent anaphylaxis in menstruating women: treatment with a luteinizing hormone-releasing hormone agonist--a preliminary report.

Recurrent idiopathic anaphylaxis is an illness consisting of recurring anaphylactic or anaphylactoid attacks of unknown cause. A patient has been described whose attacks appeared to be associated with endogenous progesterone secretion and who was treated successfully with an analog of luteinizing hormone-releasing hormone (LHRH). This report summarizes the treatment of four additional women with recurrent anaphylaxis in a randomized, double-blind trial of an LHRH agonist and placebo. Two out of the four women experienced remission of their symptoms with the LHRH analog. The patients who responded to therapy had experienced systemic anaphylactoid reactions after provocation with an LHRH infusion and the intradermal injection of medroxyprogesterone; the nonresponders had no adverse reactions to either challenge. Ovarian suppression with LHRH agonist may benefit a subset of women with recurrent idiopathic anaphylaxis.

Adult↗
PubMed1986

Exercise-induced anaphylactic syndromes. Insights into diagnostic and pathophysiologic features.

To differentiate the diagnoses of exercise-induced anaphylaxis and cholinergic urticaria/anaphylaxis, we developed reproducible diagnostic provocative challenges. The data derived from the study of two representative patients, one with cholinergic urticaria and the other with exercise-induced anaphylaxis, suggest approaches to distinguishing these diagnoses. After specific exercise challenges, both patients developed symptoms consistent with anaphylaxis and had associated increases in plasma histamine levels. After passive heat challenges inducing increases in core body temperature more than 0.7 degrees C, only the patient with cholinergic urticaria developed anaphylactic symptoms and had a rise in the plasma histamine level. Neither patient developed symptoms of anaphylaxis when core body temperatures were increased after administration of intravenous endotoxin. Thus, passive heat challenges are extremely valuable in differentiating these two exercise-related syndromes. Although not important in exercise-induced anaphylaxis, specific thermoregulatory mechanisms appear to play an intricate part in the pathophysiology of cholinergic urticaria/anaphylaxis.

Adult↗
PubMed1986

Human respiratory mucus.

Respiratory mucous glycoproteins may serve a number of protective functions for the airways; however, excessive secretions contribute to the morbidity of a variety of diseases including asthma, chronic bronchitis, and cystic fibrosis. Respiratory secretions are a mixture of cells, fluid, transudated and locally produced proteins, and mucous glycoproteins. The mucous glycoproteins give these secretions their characteristic viscosity and elasticity. While the physiologic control of mucous glycoprotein secretion is not completely understood, cholinergic, alpha-adrenergic, and beta-adrenergic stimuli may all contribute. Respiratory mucus hypersecretion seen in immediate hypersensitivity or inflammatory states may be due to reflex hypersecretion, to a variety of mediators (including histamine and cyclooxygenase or lipoxygenase pathway metabolites of arachidonic acid), or to substances released from phagocytic cells (such as macrophages, monocytes, or neutrophils). The limited number of specific approaches currently available for treating respiratory mucus hypersecretion include therapy of any underlying or intercurrent disease, improving clearance of secretions, and reducing mucus secretion with the use of glucocorticosteroids or anticholinergic drugs.

Animals↗
PubMed1986

Prevention of mast-cell degranulation by ketotifen in patients with physical urticarias.

The capacity for ketotifen to prevent mast-cell degranulation in vivo was studied in patients with physical urticarias. Patients were exposed to the appropriate stimulus to elicit their physical urticaria before and during ketotifen therapy. Histamine concentrations in plasma samples, obtained before and serially after the physical provocation, were determined by radioenzymatic thin-layer chromatography. Ketotifen therapy was associated with marked reductions in plasma histamine levels after stimulation and in clinical evidence of urticaria in each patient. A direct correlation of ketotifen therapy and a reduction in histamine release was confirmed in a patient with a cold-induced urticaria who was studied again after discontinuation and again after reinstitution of therapy. Although the mechanism of action is unknown, this report shows that ketotifen is capable of inhibiting cutaneous mast-cell degranulation and its accompanying symptoms. These findings suggest important therapeutic alternatives for patients with mast-cell-mediated diseases.

Adult↗
PubMed1985

Characterization of histamine H-1 receptors on human peripheral lung.

Histamine H-1 receptors in human peripheral lung were characterized by radioligand and biochemical assays employing binding of the H-1 receptor antagonist [3H]pyrilamine to plasma membrane preparations. Simultaneous computerized analyses of the data from fourteen separate equilibrium-binding assays indicated the presence of three distinct classes of binding sites with Kd values of 81 +/- 35 pM, 7 +/- 3 microM, and 320 +/- 167 microM and binding capacities of 23 +/- 3 pmoles, 10 +/- 5 nmoles, and 297 +/- 119 nmoles/mg protein respectively. Dissociation kinetics of [3H]pyrilamine binding also supported the presence of three binding sites or states. Further, competition binding curves for histamine receptor agonists and antagonists also indicated the presence of multiple binding sites for the H-1 receptor. The effect of exogenous stimulation of histamine H-1 receptors on human cyclic nucleotides was also examined. Both histamine and the H-1 agonist 2-methyl histamine caused dose-related increases in the cyclic guanosine monophosphate (GMP) content of human lung. The effects of 2-methyl histamine were selective for cyclic GMP. The histamine-induced increase in cyclic GMP peaked within 1.0 min and was effectively prevented by the H-1 antagonist pyrilamine. Thus, human lung possesses a large number of H-1 receptors which exhibit three binding states and produce cyclic GMP, but not cyclic adenosine monophosphate (AMP), when stimulated.

Binding, Competitive↗
PubMed1985

Anaphylatoxin C3a enhances mucous glycoprotein release from human airways in vitro.

Because C3a may be generated during the course of pulmonary inflammatory reactions, we investigated the ability of C3a to affect mucous glycoprotein (MGP) secretion from cultured human airways. C3a, but not C3a des Arg, caused a dose-related increase in MGP release (maximal after 4-6 h), with as little as 15 micrograms of C3a per milliliter stimulating a 40% increase. The experimental evidence suggested that immunologically specific C3a was required for the secretagogue actions, as monospecific anti-C3a inhibited the reaction, as well as specifically absorbing the secretagogue from solution. Moreover, it appeared that C3a does not require mast cell activation, eicosanoid generation, or macrophage-derived mucus secretagogue synthesis for its effect, since (a) no evidence of histamine release accompanied C3a-induced MGP release, and dibutyryl cAMP failed to affect C3a-induced MGP release, while reducing the actions of reversed anaphylaxis; (b) MGP release caused by C3a was not influenced by eicosatetraynoic acid or specific cyclooxygenase inhibitors, and no leukotrienes were detectable on the supernatants of C3a-stimulated airways; and (c) cycloheximide failed to affect C3a secretion-stimulating actions. Thus, C3a is a potent mucus secretagogue, and, possibly, acts directly as a glandular stimulant. It seems likely that C3a generated in the course of pulmonary inflammation might contribute to the mucus secretion associated with pulmonary infections.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1985

Mechanisms of glucocorticosteroid action in bronchial asthma.

Although their precise mechanisms of action are undefined, the usefulness of CCS in the treatment of asthma is unquestioned. It is clear that they act at multiple sites. Among the general actions of CCS felt to be applicable to asthma are their ability to facilitate beta-adrenergic responsiveness and to suppress inflammation. More specific actions relevant to asthma are their inhibition of eicosanoid formation (e.g., reduction in leukotriene formation), prevention and reversal of LPR (probably through CCS anti-inflammatory effects), and reduction in mucus secretion. Actions that have not yet been clarified but that may be useful include possible reductions in airway hyperreactivity (or at least the prevention of increases in reactivity superimposed upon overreactive airways) and suppression of basophil (but not mast cell) mediator release.

Adenylyl Cyclases↗
PubMed1985

Mediator release in local heat urticaria: protection with combined H1 and H2 antagonists.

Two patients with local heat urticaria were examined for evidence of histamine release and for changes in mast cell morphology after local heat challenge. Both patients demonstrated significant release of histamine into the draining venous blood in the challenged arm. Biopsy specimens revealed mucosal edema after 30 min, followed by a mononuclear, perivascular infiltrate by 6 hr, and increasing in intensity by 24 hr. Degranulated mast cells were observed by electron microscopy. Heat challenge was repeated after treatment with hydroxyzine, cimetidine, or a combination of both drugs. Neither hydroxyzine nor cimetidine alone affected the clinical response to challenge, but both drugs together completely abolished the clinical response. In addition, the combination of both drugs taken regularly completely prevented symptoms. This observation suggests that histamine is one of the major mediators of this disorder and that both H1 and H2 receptors are operative.

Adult↗
PubMed1985

In situ degranulation of human nasal mucosal mast cells: ultrastructural features and cell-cell associations.

Mucosal mast cells in human nasal turbinates obtained at surgery were studied by electron microscopy before and after exposure en bloc to a degranulating stimulus. Mast cells occurred as solitary cells and in islets typically containing one mast cell and one to three mononuclear cells. All islets and most solitary mast cells were associated with thin cytoplasmic processes of distinctive, branched stromal cells that also phagocytosed debris from pyknotic mast cells. Mast cells were grouped into three categories based largely on published ultrastructural criteria. Resting (nondegranulating) mast cells possessed secretory granules that typically packed the cytoplasm and contained a densely stained amorphous material and scroll-like crystalline profiles. Granules in some resting cells were larger, more polymorphic, and appeared nearly homogeneous. Secretory granules of degranulating mast cells possessed crystalline, scroll-like, or reticular constituents predominantly with interspersed amorphous material. Granules were fewer in number and were often concentrated in the peripheral cytoplasm. Few degranulating mast cells exhibited labyrinth formation or exocytosis of granule contents. Largely degranulated mast cells had few if any typical granules but possessed small vacuoles containing recognizable granule remnants. Resting and degranulating mast cells possessed very long cell surface projections that, in places, interdigitated to form stacks of parallel folds above the plasmalemma, resulting in a threefold increase in cell-surface area. The surface membrane of the folds appeared to be continuous with that lining intracytoplasmic channels extending from the cell surface to the Golgi zone.

Cell Membrane↗
PubMed1985

Characterization of histamine H-1 receptors on human mononuclear cells.

Histamine H-1 receptors on peripheral human mononuclear cells were characterized by radioligand binding of the H-1 receptor antagonist [3H]pyrilamine to lymphocyte-rich preparations. Simultaneous computerized analyses of sixteen separate equilibrium-binding assays indicated the presence of two distinct classes of binding sites with dissociation constants (Kds) of 4 +/- 1 nM and 55 +/- 9 microM and binding capacities of 21 +/- 7 fmol and 117 +/- 15 pmol/million cells, respectively. Competition binding curves for displacement of [3H]pyrilamine binding by histamine receptor agonists and antagonists also indicated the presence of multiple binding sites for the H-1 receptor. Further, the ED50 values determined for histamine receptor agonists and antagonists were entirely consistent with the expected rank order of potency for interactions with H-1 receptors. Thus, human mononuclear cells have a large number of H-1 receptors that exhibit two distinct binding sites, and the Kds for these sites are within the range of histamine concentrations achieved either in physiologic states or after mast cell (or basophil) degranulation.

Humans↗
PubMed1985

Human monocyte-derived mucus secretagogue.

Human peripheral monocytes were stimulated with opsonized zymosan or protein A-containing Staphylococcus aureus to examine whether factors might be released that were capable of stimulating mucous glycoprotein release from cultured human airways, as has recently been described with human pulmonary macrophages. While the supernatant from monocytes exposed to opsonized zymosan or protein A-containing S. aureus caused an impressive activity was found in the control samples that were cultured in parallel and exposed to nonactivated zymosan or S. aureus that was deficient in protein A. The responsible factor was termed monocyte-derived mucus secretagogue (MMS). The maximum MMS release was reached 4-8 h after stimulation, and the amount of MMS released was dependent on the dose of opsonized zymosan added. Chromatographic analyses of MMS indicate that its molecular weight was approximately 2,000 and that the isoelectric point (pI) was 5.2, with a smaller second peak of 7.4 on isoelectric focusing. MMS itself was not detected in monocyte lysates, nor was it formed by monocytes treated with the protein synthesis inhibitor, cycloheximide, before exposure to activating particles. MMS was not a prostaglandin, could not be extracted into organic solvents, and is probably not an eicosanoid. Based on these observations, we conclude that stimulated human peripheral monocytes synthesize a small, acidic molecule, termed MMS, that is capable of stimulating human airways to secrete mucus and in nearly every respect is identical to pulmonary macrophage-derived MMS.

Chromatography↗