Arthus Reaction In Guinea Pigs Research Articles

Immunostimulatory activity of Picrorhiza kurroa leaf extract

A 50% ethanolic extract of Picrorhiza kurroa Royle ex Benth. (Scrophulariaceae) leaves (PKLE) was found to stimulate the cell-mediated and humoral components of the immune system as well as phagocytosis in experimental animals. PKLE elicited a dose-related increase in SRBC, induced 4 h (early) and 24 h (delayed) hypersensitivity reactions in mice and rats, and horse serum induced Arthus reaction in guinea pigs. It also enhanced the humoral immune responses in mice and rats and phagocytic function of the cells of the reticuloendothelial system in mice. PKLE exhibited no mitogenic activity but augmented the responsiveness of murine splenocytes to T cell mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A) and B cell mitogen lipopolysaccharide (LPS E. colt).

Human recombinant soluble decay accelerating factor inhibits complement activation in vitro and in vivo.

Complement plays a role in activating the inflammatory response and has been implicated in the pathogenesis of some inflammatory diseases. With a view toward controlling unwanted C activation, we evaluated the C regulator, human decay accelerating factor (DAF). Three forms of recombinant DAF were purified from transfected Chinese hamster ovary cells: glycophosphatidylinositol (GPI)-linked membrane DAF (mDAF) extracted from cell membranes; spontaneously shed soluble DAF (sDAF) derived from mDAF; and a novel secreted protein (seDAF), generated by deletion of the signal for GPI attachment. We show that all three molecules inhibit both the classical and alternative pathways of C activation. The following observations indicate that mDAF extracted from Chinese hamster ovary cells reincorporates into RBC membranes via its GPI anchor: 1) cells that are preincubated with mDAF and then washed remain fully protected from C-mediated hemolysis; 2) incubation with phosphatidylinositol-specific phospholipase C abolishes this protection; and 3) sDAF and seDAF, which lack a GPI anchor, do not associate with cell membranes. mDAF is a more potent inhibitor of C-mediated hemolysis than either sDAF or seDAF, suggesting that incorporation into cell membranes greatly enhances the efficiency with which DAF inhibits C activation on the cell surface. In contrast, C activation in the fluid phase is inhibited by sDAF and seDAF, but not by mDAF, possibly due to interference by serum lipoproteins. A reversed passive Arthus reaction in guinea pigs was used to evaluate the ability of recombinant seDAF to inhibit C activation in vivo. When administered at dermal sites, seDAF reduced the severity of immune complex-mediated inflammatory reactions induced by a reversed passive Arthus reaction, as judged by both gross and histologic examination. These data indicate that seDAF may be useful as an anti-inflammatory therapeutic.

ＹＭ‐１３６５０のＩ〜ＩＶ型アレルギー反応および抗体産生に対する作用

The effects of YM-13650 on experimental animal models of cell-mediated immune responses (type IV), antibody formation and type I to type III allergic reactions were investigated. YM-13650 in the dose range of 6.3 to 100 mg/kg, p.o., inhibited the picrylchloride-induced delayed type hypersensitivity (Pc-DTH) in mice when administered during the induction and the effector phases. The compound also inhibited the Pc-DTH enhanced by the pretreatment with cyclophosphamide, and even bilateral adrenalectomy failed to reduce the inhibitory effect of the compound on Pc-DTH in mice. YM-13650 in doses of 25 and 50 mg/kg, p.o., prolonged the survival time of allogenic skin grafts in mice. However, no significant effect was observed on hapten-specific IgE and HA antibody production and PFC formation in mice in doses up to 300 mg/kg, p.o. YM-13650 inhibited the passive Arthus reaction in guinea pigs and the reversed passive Arthus reaction in rats (type III). On the other hand, YM-13650 did not show any inhibitory effect on passive cutaneous anaphylaxis in rats (type I), Forssman shock in guinea pigs (type II) and carrageenin-induced paw edema in rats. These results indicate that YM-13650 suppresses not only cell-mediated immune responses but also type III allergic reactions without any influence on type I and type II allergic reactions as well as an acute inflammatory reaction.

Pharmacological Properties of YM-11124, a Selective Immunosuppressive Agent for Cell-Mediated Immunity

Effect of YM-11124 on cell-mediated immune responses, type I to type III allergic reactions and inflammatory reaction was determined in mice, rats and guinea pigs. YM-11124 inhibited picryl chloride- and methylated bovine serum albumin-induced delayed-type hypersensitivity reactions by the treatment during both the sensitization and the elicitation phases in mice. Bilateral adrenalectomy did not prevent the suppression of DTH response by YM-11124. YM-11124 significantly prolonged the survival time of allogenic skin grafts in mice. Furthermore, YM-11124 inhibited the passive Arthus reaction in guinea pigs and the reversed passive Arthus reaction in rats. However, YM-11124 did not affect the passive cutaneous anaphylaxis reaction in rats, Forssman shock in guinea pigs and paw edema in rats. These results indicate that YM-11124 suppresses not only cell-mediated immune responses (type IV allergic reactions) but also type III allergic reactions without influence on types I and II allergic reactions as well as acute inflammation.

１‐（２‐Ｅｔｈｏｘｙｅｔｈｙｌ）‐２‐（４‐ｍｅｔｈｙｌ‐１‐ｈｏｍｏｐｉｐｅｒａｚｉｎｙｌ）ｂｅｎｚｉｍｉｄａｚｏｌｅ ｄｉｆｕｍａｒａｔｅ（ＫＢ‐２４１３）の抗アレルギー作用

The effects of KB-2413 on four types of allergic reactions classified by Coombs and Gell were investigated. KB-2413 inhibited homologous passive cutaneous anaphylaxis and passive anaphylactic bronchoconstriction in guinea pigs mediated by IgE-like antibody, and ED50 values were 0.0017 mg/kg, p.o., and 0.022 mg/kg, p.o., respectively. KB-2413 also inhibited IgG-mediated anaphylactic bronchoconstriction in guinea pigs actively sensitized with egg albumin. Both complement-dependent immune hemolysis and complement-independent hypotonic hemolysis were inhibited by KB-2413 in a concentration-dependent manner. KB-2413 had no effect on the Forssman systemic reaction. The passive Arthus reaction in guinea pigs sensitized with anti-egg albumin rabbit serum was unaffected by KB-2413. However, the early stage of the active Arthus reaction in rabbits sensitized with egg albumin was inhibited. KB-2413 had an inhibitory effect on the efferent phase of delayed-type hypersensitivity induced by picryl chloride (PC-DTH) in mice. On the other hand, the afferent phase of PC-DTH in mice was unaffected. These results suggest that KB-2413 strongly suppresses type I allergic reactions, and it slightly suppresses type II, III and IV allergic reactions.

Differential effects of pharmacologic agents on the reverse passive Arthus reaction in guinea pigs.

Five different pharmacologic agents were examined for their effects upon edema, hemorrhage, and vascular infiltration by neutrophils in the reverse passive Arthus reaction (RPAR) in guinea pigs. Two agents, colchicine (3.0 mg/kg p.o.) and ibuprofen (100 mg/kg p.o.) significantly inhibited all three parameters of RPAR. Cobra venom factor (100 units/kg i.p.) inhibited edema and hemorrhage but it did not inhibit neutrophil infiltration. Aminophylline and sulfinpyrazone (100 mg/kg p.o.) inhibited only hemorrhage; they did not inhibit edema or neutrophil infiltration. The results from these studies with five chemically or biologically unrelated pharmacologic agents suggest that the RPAR in guinea pigs can be separated into its basic components (edema, hemorrhage, and neutrophilic infiltration) by selective inhibitors. Inhibition of edema and hemorrhage, or hemorrhage alone of the two-hour RPAR in guinea pigs is not dependent upon inhibition of neutrophilic infiltration.

Effect of (±)-2-[p-(2-Thenoyl) Phenyl] Propionic Acid (Suprofen) on Experimental Allergic Reactions

The effects of (±)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen), a new anti-inflammatory agent, on experimental allergic reaction and antibody formation were examined. The action was compared with those of ketoprofen, ibuprofen, indomethacin, tranilast, chlorpheniramine, prednisolone and/or cyclophosphamide. Suprofen inhibited homologous PCA in rats, immunological histamine release from rat peritoneal mast cells and guinea pig lung tissues, Forssman cutaneous vasculitis (FCV) and the Arthus reaction in guinea pigs. The potency for inhibition of the PCA reaction was similar to that of ketoprofen and more potent than ibuprofen and trailast. As for the release of anaphylactic mediators, suprofen was less potent than tranilast in terms of histamine release, but not the release of the slow reacting substance of anaphylaxis (SRS-A). Suprofen inhibited FCA more potently than other nonsteroidal anti-inflammatory drugs (NSAID). The inhibition of the Arthus reaction by suprofen was similar to those of other NSAID and prednisolone. Suprofen hardly affected delayed hypersensitivity in guinea pigs and antibody (IgM or IgE) formation in mice or rats.

Effect of (+/-)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen) on experimental allergic reactions.

The effects of (+/-)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen), a new anti-inflammatory agent, on experimental allergic reaction and antibody formation were examined. The action was compared with those of ketoprofen, ibuprofen, indomethacin, tranilast, chlorpheniramine, prednisolone and/or cyclophosphamide. Suprofen inhibited homologous PCA in rats, immunological histamine release from rat peritoneal mast cells and guinea pig lung tissues, Forssman cutaneous vasculitis (FCV) and the Arthus reaction in guinea pigs. The potency for inhibition of the PCA reaction was similar to that of ketoprofen and more potent than ibuprofen and trailast. As for the release of anaphylactic mediators, suprofen was less potent than tranilast in terms of histamine release, but not the release of the slow reacting substance of anaphylaxis (SRS-A). Suprofen inhibited FCA more potently than other nonsteroidal anti-inflammatory drugs (NSAID). The inhibition of the Arthus reaction by suprofen was similar to those of other NSAID and prednisolone. Suprofen hardly affected delayed hypersensitivity in guinea pigs and antibody (IgM or IgE) formation in mice or rats.

The effect of sulphinpyrazone and other drugs on the platelet response during the acute phase of the active Arthus reaction in guinea pigs

It has been shown that a systemic platelet response follows the induction of the active Arthus reaction in guinea-pigs. This response was quantified by measurement of the transiet fall in circulating platelet count and by measurement of the sequestration of platelets, partially as aggregates, in the vascular beds of the lungs and liver. Administration of inhibitors of the platelet secretion reaction, sulphinpyrazone, phenylbutazone, aspirin and indomethacin resulted in partial inhibition of the thrombocytopenia. Two metabolites of sulphinpyrazone, the sulphoxide (G 31442) and the p-hydroxy derivative (G 32642) were tested and of the two the sulphoxide was slightly more potent than the parent compound.

Effect of 6-Ethyl-3-(1H-Tetrazol-5-YL)Chromone (AA-344) on the Immediate and Delayed Hypersensitivity Reactions

Effects of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) on the experimental models of the type I-IV allergic reactions were studied in comparison with those of disodium cromoglycate (DSCG), dexamethasone and other agents. AA-344 showed inhibitory effects on the homologous passive cutaneous anaphylaxis and the passive systemic anaphylaxis in guinea pigs. However, it had only a slight or little effect on the Forssman shock in guinea pigs, the complement-dependent cytolysis of mast cells in rats, the Arthus reaction in guinea pigs and the tuberculin reaction and the contact sensitivity in mice. DSCG was less effective, using these experimental models. Dexamethasone showed a suppressive effect on the type III and IV allergic reactions. The results indicate that AA-344 selectively suppresses the type I allergic reaction.

Effect of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) on the immediate and delayed hypersensitivity reactions.

Effects of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) on the experimental models of the type I-IV allergic reactions were studied in comparison with those of disodium cromoglycate (DSCG), dexamethasone and other agents. AA-344 showed inhibitory effects on the homologous passive cutaneous anaphylaxis and the passive systemic anaphylaxis in guinea pigs. However, it had only a slight or little effect on the Forssman shock in guinea pigs, the complete-dependent cytolysis of mast cells in rats, the Arthus reaction in guinea pigs and the tuberculin reaction and the contact sensitivity in mice. DSCG was less effective, using these experimental models. Dexamethasone showed a suppressive effect on the type III and IV allergic reactions. The results indicate that AA-344 selectively suppresses the type I allergic reaction.

In Vivo and in Vitro Inhibition of Complement by Chlorazol Fast Pink

Abstract Chlorazol Fast Pink (CFP) is a sulfonic acid azo dye, first described as an in vitro complement inhibitor in 1952 (Lambert & Richley, B. J. Exp. Path. 33, 327, 1952). We have examined CFP in vivo and in vitro and found that it inhibits complement dependent lesions in laboratory rodents, and that these effects are correlated with depression of serum complement. In some cases, CFP has been compared with pentosan polysulfate (PPS), another anionic complement inhibitor. CFP and PPS, injected intraperitoneally, block Forssman shock and Forssman cutaneous vasculitis in guinea pigs and the reverse passive Arthus reaction in guinea pigs and rats. Inhibition of these reactions is accompanied by an inhibition of serum complement, demonstrable by an assay of “undiluted” serum. In this assay, serum is laid over EA embedded in an agarose matrix in a capillary tube, and the zone of lysis measured with an optical micrometer.

Anti-complement activities of 2,4-bis(2-hydroxybenzamido)benzoic acid and its diacetylated derivatives.

Based on the report that 2, 4-bis (2-hydroxybenzamido) benzoic acid (AB-23) inhibits immune hemolysis in vitro, the site of the action of this compound was studied. AB-23 had no effect on the binding of hemolysin to sheep erythrocytes (E). A high concentration of AB-23 was required for inhibition of higher dose C-induced hemolysis. E which escaped hemolysis in the presence of AB-23, were normally hemolyzed by readdition of fresh C after removal of the drug. Inhibition by AB-23 of C fixation to sensitized E was suggested from these results and confirmed by the finding that AB-23 interferes with immune adherence hemagglutination. The effect of AB-23 was apparently not due to chelation of Mg2+ or Ca2+. AB-23, but neither ethylene diamine tetraacetic acid nor ethylene glycol tetraacetic acid showed inhibitory activity even when added 8 or 15 min after C addition. This suggests that AB-23 inhibits the sequence of later components of C from C3 to C9. This possibility was strongly supported by the following finding that AB-23 prevents the consumption of C activity by zymosan via an alternative pathway. Additionally, 2, 4-bis (2-acetoxybenzamido) benzoic acid, which is easily changed to AB-23 in the body, inhibited the passive Arthus reaction in guinea-pigs and also prevented urinary protein excretion in rats after nephrotoxic serum injection in which complement is known to play an important role. These results suggest the anti-complement effect of AB-23 in vivo.

A specific inactivator of mammalian C'4 isolated from nurse shark (Ginglymostoma cirratum) serum.

A material which specifically inactivates mammalian C'4 was isolated from low ionic strength precipitates of nurse shark serum. The C'4 inactivator was not detected in whole serum. The conditions of its generation and its immunoelectrophoretic behavior seem to indicate that it is an enzymatically formed cleavage product of a precursor contained in whole shark serum. The inactivator was partially purified and characterized. It had an S-value of 3.3 (sucrose gradient) which was in agreement with its retardation on gel filtration, was stable between pH 5.0 and 10.0, had a half-life of 5 min at 56 degrees C, pH 7.5, was inactivated by trypsin and was nontoxic. Its powerful anticomplementary activity in vitro and in vivo was solely due to the rapid inactivation of C'4; no other complement components were affected. No cofactor requirement was observed for the equally rapid inactivation of highly purified human and guinea pig C'4. The kinetics of C'4 inactivation and TAME hydrolysis, the greater anodic mobility of inactivated human C'4, and the influence of temperature on the rate of inactivation suggest that the inactivator is an enzyme and C'4 its substrate. This conclusion was supported by the more recent detection of a split product of C'4. Intravenous administration of the C'4 inactivator could prevent lethal Forssman shock and suppress the Arthus reaction in guinea pigs; it prolonged significantly the rejection time of renal xenografts but had no detectable effect on passive cutaneous anaphylaxis. Anaphylatoxin could be generated in C'4 depleted guinea pig serum with the cobra venom factor, but not with immune precipitates. The possible relationship between C'1 esterase and the C'4 inactivator is discussed on the basis of similarities and dissimilarities.

The chemosuppression of chemotaxis.

The effects of various drugs on chemotaxis of polymorphonuclear leukocytes (PMN's) in vitro and in vivo have been studied. Response of rabbit PMN's in vitro to the chemotactic factor of rabbit serum, consisting of an activated protein-protein complex of the fifth and sixth (and probably seventh) components of complement (C'), is suppressed by hydrocortisone, methyl prednisolone, and chloroquine. Drug concentrations causing 50% inhibition of chemotaxis in vitro were found to be: hydrocortisone, 2.9 x 10(-4)M; methly prednisolone, 1.2 x 10(-4)M; and chloroquine 8.5 x 10(-6)M. The hydrocortisone effect on PMN's appeared to be irreversible, since washing of the cells did not restore their chemotactic response. 2, 4-Dinitrophenol (DNP), vitamin A, and endotoxin did not inhibit chemotaxis. Hydrocortisone and chloroquine did block serum C' activity in vitro, but only at substantially higher concentrations. Using the reversed passive Arthus reaction in guinea pigs as a model for chemotaxis in vivo, systemic treatment of animals with hydrocortisone or chloroquine inhibited development of the vasculitis. Circulating antigen and C' were fixed in vascular structures, and serum C' was not perceptibly altered. Nevertheless, PMN infiltrates failed to occur. Local administration of hydrocortisone also prevented influx of PMN's in the Arthus reaction, in spite of the fact that immune reactants were found fixed in the vascular walls. Systemic treatment of guinea pigs with DNP did not diminish the intensity of the Arthus reactions. Phagocytosis of zymosan particles by rabbit PMN's was inhibited by hydrocortisone, methyl prednisolone, and chloroquine, but not by DNP or endotoxin. The concentrations of drugs inhibitory in phagocytosis were substantially higher than those required for inhibition of chemotaxis in vitro. These findings suggest that hydrocortisone and chloroquine inhibit the inflammatory process by preventing the response of leukocytes to chemotactic stimuli.