Molecular characterization of an interleukin-4-inducing factor from Schistosoma mansoni eggs.

The eggs of the parasitic trematode Schistosoma mansoni are powerful inducers of a T helper type 2 (Th2) immune response and immunoglobulin E (IgE) production. S. mansoni egg extract (SmEA) stimulates human basophils to rapidly release large amounts of interleukin (IL)-4, the key promoter of a Th2 response.

A glycoprotein from Schistosoma mansoni eggs binds non-antigen-specific immunoglobulin E and releases interleukin-4 from human basophils.

We have recently shown that soluble extracts from Schistosoma mansoni eggs (SmEA) triggered basophils from nonsensitized donors to rapidly release interleukin (IL)-4. Assuming that this mechanism might play a role in vivo in biasing the immune response towards a Th2 phenotype, we determined basic properties of the IL-4-inducing activity contained in SmEA. Sensitivity to pepsin digestion indicated protein nature.

Purification of morphologically and functionally intact human basophils to near homogeneity.

Certain studies on basophils require highly purified functionally intact cell preparations. Here, a three-step procedure is described that meets these requirements. The procedure consists of a Ficoll density gradient step, counterflow elutriation and negative selection by magnetic cell sorting (MACS).

Early interleukin-4: its role in the switch towards a Th2 response and IgE-mediated allergy.

The etiology of IgE-mediated allergies is complex and, thus far, not completely understood. A common feature, however, is the overproduction of IgE-inducing cytokines, e.g.

Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils.

Dietary lectins, present in beans and other edible plant products, pose a potential threat to consumers due to their capacity to induce histamine release from basophils. In this study, we analyzed the capacity of 16 common, in particular dietary, lectins to induce human basophils to secrete IL-4 and IL-13, the key promoters of Th2 responses and IgE synthesis. Several of the lectins, especially concanavalin A, lentil lectin, phytohemagglutinin, Pisum sativum agglutinin and Sambucus nigra agglutinin, triggered basophils to release IL-4 at concentrations of up to 1 ng/10(6) basophils.

Leukotriene receptor antagonists. III. Pharmacological and chemical studies with LY137617, a leukotriene D4 and leukotriene E4 receptor antagonist.

A series of chlorophenoxyalkyl acids were prepared and evaluated as pharmacological antagonists of leukotriene D4. Structure-activity relationship studies pointed to LY137617 as a compound with possible therapeutic value. In experiments on isolated smooth muscles from the guinea-pig, this agent was a selective and moderately potent antagonist of leukotriene D4 and also leukotriene E4.

Leukotriene receptor antagonists. 2. The [[(tetrazol-5-ylaryl)oxy]methyl]acetophenone derivatives.

A series of [[(tetrazol-5-ylaryl)oxy]methyl]acetophenones was synthesized and evaluated as antagonists of leukotriene D4 induced contractions of guinea pig ileum. Substitutions at the 3-position of the acetophenone with ethyl (66), propyl (68), butyl (83), and isobutyl (84) gave -log IC50 values of 7.9, 8.

Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives.

A series of derivatives of 2,4-dihydroxy-3-propylacetophenone(1) were prepared and examined for their ability to block leukotriene D4 (LTD4) induced contraction of guinea pig ileum. Straight-chain carboxylic acids where the carboxyl group was separated from the acetophenone moiety by varying numbers of methylenes were evaluated, and maximum activity was obtained with the pentamethylene acid (6). Examination of ring substitution showed that the 2-propyl-3-hydroxy-4-acetyl substitution pattern was required for maximum LTD4 antagonist activity.

Pharmacologic analysis of LY188695 (KB-2413), 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate, a potent histamine1 receptor antagonist.

LY188695 was evaluated both in vitro and in vivo in the guinea pig to determine its pharmacologic profile. The compound antagonized histamine-induced contractions of ileum, aorta, and trachea with pKB values of 9.9, 9.

Evaluation of LY163443, 1-[2-hydroxy-3-propyl-4-([4- (1H-tetrazol-5-ylmethyl)phenoxy]methyl) phenyl]ethanone, as a pharmacologic antagonist of leukotrienes D4 and E4.

LY163443,1-[2-hydroxy-3-propyl-4-([4- (1H-tetrazol-5-ylmethyl)phenoxy]- phenoxy]methyl)phenyl]ethanone, antagonized LTD4-induced contractions of guinea pig ileum, trachea, and lung parenchyma. Tracheal contractions to LTE4 were also inhibited by LY163443. The compound had minimal effect against ileal responses to LTC4 and parenchymal contractions to LTB4.

LY171883, 1-less than 2-hydroxy-3-propyl-4-less than 4-(1H-tetrazol-5-yl) butoxy greater than phenyl greater than ethanone, an orally active leukotriene D4 antagonist.

LY171883, 1-less than2-hydroxy-3-propyl-4-less than 4-(h-tetrazol-5-yl)butoxy greater than phenyl greater than ethanone, proved to be a potent antagonist of leukotriene (LT) D4 in guinea-pig ileum, trachea and lung parenchyma. The compound had little or no effect on contractions of isolated tissues to LTB4, prostaglandin F2 alpha, serotonin, histamine, bradykinin or carbamycholine. Responses of trachea to U46619, a thromboxane A2 mimetic, were antagonized by LY171883, but the doses required were approximately 10-fold higher than those necessary to produce the same degree of antagonism against LTD4.

Pharmacologic analysis of two novel inhibitors of leukotriene (slow reacting substance) release.

LY83583 , a quinolinedione , and LY151364 , a quinoxalinedione , were developed as inhibitors of leukotriene (slow reacting substance of anaphylaxis) release. They preferentially inhibited the release of leukotrienes over histamine from fragmented guinea-pig lung and rat peritoneal cells in vitro, regardless of whether the mediators were released immunologically by antigen or chemically by the divalent cationic ionophore, A23187. Similar results were obtained with rat peritoneal cells in vivo.

Slow reacting substance of anaphylaxis (SRS-A) release from guinea-pig lung parenchyma during antigen- or ionophore-induced contraction.

A dual isolated organ technique comprised of a guinea-pig lung parenchymal strip and a guinea-pig ileum was used to determine if slow reacting substance of anaphylaxis (SRS-A) is released from parenchyma during contractions evoked by antigen (ovalbumin) or by ionophore (A23187). An immunologically sensitized parenchyma served as the primary target organ for ovalbumin and either a sensitized or unsensitized parenchyma was the target tissue for A23187; an unsensitized ileum functioned as the assay organ. In the presence of pyrilamine and indomethacin, ovalbumin or A23187 produced contractions of the parenchyma and concomitantly caused release of SRS-A from the lung strip which was indicated by a contraction of the ileum.

Schultz-Dale reaction in mouse trachea.

A method was developed to induce contraction of immunologically sensitized mouse trachea by antigen (Schultz-Dale reaction). The response was mediated by immunoglobulin (Ig) E antibody directed against either the hapten DNP, the hapten carrier conjugate DNP-keyhole limpet hemocyanin (KLH), or the unmodified carrier KLH. Tracheal contractions were elicited by DNP-KLH, KLH, or DNP-bovine serum albumin (BSA) but not by DNP or BSA alone.