F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins.

High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)2-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)2-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)2. This binding could interfere with the role of C3a and C5a in inflammation.

Enfermedad de Kawasaki. Revisión / Kawasaki disease. A review

La enfermedad de Kawasaki es una arteritis sistémica que afecta predominantemente a los niños < 5 años de edad y cuya etiopatogenia permanece desconocida. En los países desarrollados, ha sustituido a la fiebre reumática como principal causa de cardiopatía adquirida en la infancia. El diagnóstico se basa fundamentalmente en los hallazgos clínicos. El tratamiento específico con dosis altas de gammaglobulina IV y aspirina en los primeros diez días de la enfermedad o mientras persista la fiebre reduce el riesgo de complicaciones cardiovasculares de un 20-25 por ciento a un 3-4 por ciento. En este artículo se revisa la epidemiología, etiologías posibles, manifestaciones clínicas y tratamiento de la enfermedad de Kawasaki (AU)

Impaired endothelial function in the brachial artery after Kawasaki disease and the effects of intravenous administration of vitamin C.

BACKGROUND: Previous studies in patients with a history of Kawasaki disease have focused on vascular endothelial function in coronary arteries, and the endothelial function of systemic arteries is not fully understood. Furthermore the effect of vitamin C on systemic endothelial function after Kawasaki disease has not been elucidated. OBJECTIVES: We attempted to analyze endothelium-dependent vasodilatation in the brachial artery after Kawasaki disease by using high resolution ultrasonography and to investigate whether the acute administration of vitamin C could restore such systemic endothelial dysfunction. METHODS: We compared 39 patients (7.1 +/- 2.7 years) 1.0 to 9.6 years after acute Kawasaki disease with 17 matched healthy subjects (7.0 +/- 3.1 years) as controls. Using high resolution vascular ultrasound, we measured brachial artery responses to reactive hyperemia (with increased flow causing endothelium-dependent dilatation) and sublingual nitroglycerin (causing endothelium-independent dilatation). RESULTS: The percent change in diameter of the brachial artery induced by reactive hyperemia in the patients with a history of Kawasaki disease (6.2 +/- 3.9%) was significantly lower than that in the control group (14.1 +/- 6.8%; P < 0.0001). No significant difference could be found in percent change in diameter induced by sublingual administration of nitroglycerin between the control (33.2 +/- 13.7%) and the patients with a history of Kawasaki disease (30.6 +/- 9.2%; P = 0.49). There was no significant difference in percent change in diameter of the brachial artery induced by reactive hyperemia between the patients who received gamma-globulin (6.0 +/- 4.0%) and those who did not receive gamma-globulin (7.9 +/- 3.3%; P = 0.33). Intravenous infusion of vitamin C significantly increased the percent change in diameter of brachial artery induced by reactive hyperemia in 19 patients with history of Kawasaki disease (6.6 +/- 3.5 to 13.0 +/- 5.5%; P < 0.0001), whereas no significant increase was seen in the percent change in diameter of brachial artery induced by reactive hyperemia in 20 patients with history of Kawasaki disease after placebo administration (6.5 +/- 4.5 to 7.3 +/- 4.9%; P = 0.20). CONCLUSIONS: Our study showed decreased percent change in diameter of the brachial artery induced by reactive hyperemia in patients with history of Kawasaki disease compared with the healthy children, indicating that systemic endothelial dysfunction exits after Kawasaki disease. Although such systemic endothelial dysfunction after Kawasaki disease is not influenced by early treatment with high dose gamma-globulin in the acute stage of Kawasaki disease, it can be restored by the acute intravenous administration of vitamin C.

Endotoxin inactivation by enterally applied colostrum of different composition.

BACKGROUND AND PURPOSE: Enteral applied bovine colostrum can significantly reduce endotoxin concentration in plasma. Since colostrum is a mixture of biological active ingredients 3 possible substances which are able to influence the endotoxin elimination were concentrated in 3 different colostrum products. Immunoglobulin-, lactoferrin- and casein-enriched colostra and lactoferrin alone were orally administered to endotoxinaemic rats. METHODS: Endotoxinaemia was induced to rats by enteral application of 10(10) E. coli together with 40 mg Nebacetin. Control animals received albumin. From all rats plasma samples were taken over the time of 5 h and endotoxin concentration determined with limulus lysate and chromogenic substrate. RESULTS: Whereas in control animals as well as in animals treated with casein-enriched colostrum a marked increase of endotoxin values to over 130 EU/dl could be observed after 5 h, the oral application of gammaglobulin-enriched and especially lactoferrin-enriched colostrum decreased endotoxin values by more than 50%. The most effective endotoxin elimination was seen with lactoferrin alone. CONCLUSIONS: From this results it can be concluded that not only gammaglobulin but especially lactoferrin seems to be responsible for the elimination of endotoxin with regard to enterally applied colostrum preparations.

Enfermedad de Kawasaki / Kawasaki disease

La enfermedad de Kawasaki es un cuadro de descripción reciente con una etiopatogenia confusa y con un diagnóstico fundamentalmente clínico. Existen formas muy típicas de la enfermedad que son fáciles de diagnosticar, pero cada vez se presentan más casos atípicos o incompletos que pueden pasar inadvertidos o que se diagnostican tardíamente. Es un síndrome que puede tener graves alteraciones cardiovasculares, por lo que es imprescindible realizar un diagnóstico y un tratamiento precoces para intentar evitar su morbimortalidad (AU)

Enfermedad de Kawasaki de presentación incompleta / Kawasaki disease of atypical presentation

Presentamos el caso de una niña de 7 años con un cuadro de fiebre elevada de larga evolución, sin respuesta a distintos trata-mientos antibióticos, acompañada de exantema generalizado. Durante su evolución padeció una hepatosplenomegalia de aparición y resolución recortadas en el tiempo y una trombocitosis progresiva, junto con descamación laminar de los dedos de manos y pies, por lo que se instauró tratamiento con gammaglobulina intravenosa, con la consiguiente remisión de la fiebre y el exantema. A pesar de que los sucesivos controles ecocardiográficos practicados fueron normales, pensamos que se trata de una forma incompleta de enfermedad de Kawasaki. Queremos incidir en la importancia de sospechar este cuadro clínico ante todo niño con fiebre de origen desconocido, aunque no se cumplan todos los criterios diagnósticos, por la existencia de numerosas referencias en la literatura acerca de casos de presentación incompleta que desarrollan aneurismas coronarios (AU)

A complex of histamine/mouse gamma-globulin preferentially inhibits allergen-induced peritoneal accumulation of eosinophils, but not neutrophils, in mice.

A complex of histamine/human gamma-globulin (HhG) has been widely used in Japan for more than 25 years as a nonspecific hyposensitization drug in the treatment of allergic diseases. It has been reported that HhG decreases the number of eosinophils in the nasal secretions and peripheral blood of patients with allergy. In this study we used a mouse system to explore the possibility that HhG may actively inhibit the accumulation of eosinophils at inflammation sites. A complex of 0.15 microg of histamine dihydrochloride/12 mg of mouse gamma-globulin (HmG) was incubated for 2 hours in saline solution in the normal fashion for HhG. HmG at 50 to 150 mg/kg/day inhibited the peritoneal accumulation of eosinophils induced by ragweed pollen in BALB/c mice in a dose-dependent fashion when the HmG was administered subcutaneously six times during a 20-day sensitization period. The inhibitory effect of HmG on this eosinophil accumulation was significant at 24 and 48 hours after challenge, but HmG had no effect on neutrophil accumulation. Complexes of serotonin/mouse gamma-globulin (mgammaG), glutamine/mgammaG, and histamine dihydrochloride (His)/mouse albumin had no inhibitory effect when administered in the same way. The optimum combination ratio was between 0.15 microg of His/12 mg of mgammaG and 0.015 microg of His/12 mg of mgammaG for this eosinophil inhibition. Moreover, a 1- to 2-hour incubation period of His and mgammaG was needed to induce a plateau inhibition of the eosinophil accumulation. These results in mice suggest that HhG may actively inhibit allergen-induced eosinophil accumulation, which may be therapeutically useful in the treatment of allergic disease.

Prophylactic use of human endotoxin-core hyperimmune gammaglobulin to prevent endotoxaemia in colostrum-deprived, gnotobiotic lambs challenged orally with Escherichia coli.

The efficacy of human IgG polyclonal antibody to endotoxin-core in preventing endotoxaemia and subsequent disease was studied in colostrum-deprived gnotobiotic lambs challenged orally at about 5 h old with 10(9) cfu Escherichia coli. Human endotoxin-core hyperimmune gammaglobulin was given intravenously to 5 lambs at 1.9 g IgG/kg bodyweight prior to challenge. Human albumin was given intravenously to 3 control lambs. Bacteraemia was observed in all lambs, but the incidence was lower (P < 0.01) and the onset later (P < 0.05) in gammaglobulin pre-treated lambs. These lambs showed no signs of disease, whereas clinical endotoxaemia, manifesting as watery mouth disease, was diagnosed in 2 of the 3 control lambs which were killed between 18 and 22 h after challenge. Thus, prophylactic treatment of colostrum-deprived lambs with human IgG enriched in endotoxin-core antibodies was effective in reducing the degree of bacteraemia and preventing endotoxaemia, leukopenia and clinical disease following oral challenge with E. coli.

Effects of dopamine on immunoreactive growth hormone-releasing factor and somatostatin secretion from rat hypothalamic slices perifused in vitro.

The effects of dopamine (DA) on the release of GRF and somatostatin (SRIF) from the hypothalami of adult male rats were examined in an in vitro perifusion system using horizontal hypothalamic slices, 400 micron thick, including the median eminence and arcuate nuclei. When hypothalamic slices from five animals were perfused in a chamber with artificial cerebrospinal fluid (ACSF) at a flow rate of 100 microliters/min under a gaseous phase of 95% O2 and 5% CO2 at 37 C, rat (r) GRF- and SRIF-like immunoreactivities (-LI) were constantly detected in 30-min perifusates at least until 240 min of perifusion, and during the perifusion with 60 mM K+, the concentrations of rGRF-LI and SRIF-LI were increased 2.1 and 3.2 times, respectively, over basal values. Under the perifusion with ACSF containing normal goat gamma-globulin, the addition of 10(-8) M DA resulted in a significant increase in SRIF-LI from 8.2 +/- 0.3 to 14.3 +/- 1.5 pg/hypothalamus.30 min, but conversely, it caused a slight but significant decrease in rGRF-LI from 4.5 +/- 0.9 to 2.0 +/- 0.3 pg/hypothalamus.30 min. On the other hand, 10(-8) and 10(-6) M DA significantly stimulated rGRF-LI release from hypothalamic slices perifused with ACSF containing anti-SRIF goat gamma-globulin. These findings suggest that DA is a secretagogue for both SRIF and rGRF in the hypothalamus, but the rGRF-stimulating effect of DA is masked unless the action of endogenous SRIF is attenuated.

Effects of adrenocorticotropin and dietary ascorbic acid on delayed type hypersensitivity to human gamma globulin in chickens.

Three trials were conducted to assess the effects of adrenocorticotropin (ACTH) and dietary ascorbic acid (AA) on delayed type hypersensitivity (DTH) to human gamma globulin (HGG) in chickens. Broiler chicks received AA at 0, 150, or 300 mg/Kg of feed (ppm) continuously from hatching, were sensitized at 5 wk of age to HGG emulsified in complete Freund's adjuvant, and 2 wk postsensitization, were challenged with an intradermal injection of HGG into a wattle. Birds from each AA group received ACTH at either HGG sensitization, challenge, or both. There were uninjected controls and a vehicle control group, which received gelatin at both sensitization and challenge. The ACTH and gelatin injections were given at 12-h intervals beginning 12 h prior to HGG. Responses to DTH were determined as wattle indices. In all three trials, birds that received ACTH at challenge exhibited a DTH response at 18 and 24 h postchallenge that suppressed, compared with that of controls. Birds that received ACTH at sensitization had a greater wattle response than that of birds that received ACTH at challenge, and this effect was enhanced by dieting AA. In Trial 2, birds that received ACTH at sensitization had a greater wattle response at 18 h post HGG challenge than that of controls. Total leucocyte numbers were unaffected; however, heterophil:lymphocyte ratios were lower in birds that received ACTH at sensitization than in birds that received ACTH at challenge and birds that received ACTH at challenge had fewer lymphocytes. Whether given at challenge or at sensitization, ACTH decreased plasma AA when measured at those times. The 300 ppm level of AA increased plasma AA concentration. Adrenal gland and wattle AA levels were unaffected; however, spleen AA concentration was lower in birds given ACTH at challenge.

Stress-induced secretion of alpha-melanocyte-stimulating hormone and its physiological role in modulating the secretion of prolactin and luteinizing hormone in the female rat.

The pattern of alpha MSH release during immobilization stress in ovariectomized rats was determined and correlated with that of plasma PRL and LH. Stress induced a marked elevation in plasma immunoreactive alpha MSH, with a time course identical to that of plasma PRL. The increment in plasma PRL was greater than that in plasma alpha MSH. Plasma LH was markedly lowered by stress. Analysis of pituitary and hypothalamic alpha MSH indicated a significant (P less than 0.05) increase in the neurointermediate lobe and anterior lobe content of alpha MSH. The alpha MSH content in the hypothalamus was lowered by stress when expressed as tissue content (P less than 0.025), although no significant differences in content in this area were detected when the results were expressed in terms of tissue protein. Stress induced a marked increase (P less than 0.01) in the median eminence levels of alpha MSH. Intraventricular (third ventricle) injection of the gamma-globulin fraction of a specific antiserum raised against alpha MSH increased basal PRL levels (P less than 0.025) and prevented the decline in plasma PRL that occurred 60 min after the onset of stress in the normal rabbit serum-injected rats. The stress-induced suppression of plasma LH was attenuated and delayed by the administration of alpha MSH antibodies. In conclusion, alpha MSH of brain origin is released during stress and is involved in lowering plasma PRL to basal levels and producing a partial suppression of plasma LH.

[Pharmacological and clinico-pharmacological studies of a combination preparation for calves having antianemia and general tonic action]. / Kombiniran preparat za teleta s protivoanemichno i obshtoukrepvashto deistvie--farmakologichni i kliniko-farmakologichni izsledvaniia.

A combined preparation, biofer, was studied, defining its clinical and pharmacological capacity. Featuring in its composition are: normal bovine gammaglobulin, 8.0 g; ferridextran (dextrofer-100), 32 cm2 (= 3.2 g Fe); cuprum sulfuricum, 0.32 g (= 0.08 Cu); Co chloride, 0.18 g (= 0.08 Co); cyancobalamin, 0.0032 g; and protein hydrolysate up to 100 cm3, at pH = 7.0-7.2. The local and total tolerance of animals for biofer was studied along with the acute toxicity, absorption, and retention in the body of test animals and calves as well as the antianemic action in albino mice and calves. It was found that at 4 degrees C to 8 degrees C the shelf life of biofer was 2 years. Its LD50 at subcutaneous injection to albino rats was 11.7 cm3/kg body mass. At the rate of 0.6 cm3/kg (i/m) rabbits did not manifest local and total intolerance; at 1.8 cm3/kg there was no local inflammation, however, a transient drop of appetite was seen; at 3 cm3/kg rabbits manifested intoxication with exitus. At i/m introduction to rabbits and calves biofer was more slowly absorbed than dextrofer-100. The liver and spleen of animals injected with biofer showed higher values for copper. In i/m application to anemic albino rats biofer showed a better antianemic effect than dextrofer-100. In calves it activated to a better extent both erythropoiesis and leukopoiesis.

[Morphofunctional changes in the glands of the tracheobronchial system following gamma globulin administration]. / Morfofunktsional'nye izmeneniia zhelez trakheobronkhial'noi sistemy posle vvedeniia gamma-globuliny.

Morpho-functional changes and synthesis of carbohydrate compounds in the mucous membrane of the rat and cat trachea and bronchi have been studied 2, 4, 7, 14 and 24 days after a single and twice administration of gamma-globulin into the respiratory tract and after repeated intrapleural and intramuscular administration following sensibilization with a complete Freund's adjuvant. Dynamic of the changes observed depends, to a great extent, on the mode and multiplicity of administration of the adjuvant. When gamma-globulin is administered into the respiratory tract or intrapleurally, a more active incorporation of 3H-glucose and 35S-sodium sulfate into chondroitinsulphate A, C, sialic acids and glycogen, which are synthesized by cells of the tracheobronchial system glands, occurs. In 14-24 days after gamma-globulin has been administered by any mode, sulfated glycosamineoglycans (of chondroitinsulfate B and heparin type), as well as proteoglycans and sialic acids resistive to treatment with sialidase are accumulating in discharge from the glands. The accumulation of the sulfated glycosamin sulfates is accompanied with an increased level of serum antibodies specific for the administered antigen.

Induction of immunologic tolerance in nursing neonates by absorption of tolerogen from colostrum.

Deaggregatedhuman gamma-globulin (DHGG) injected into female mice within 24 hr after delivery of a litter enters the colostrum and is absorbed intact through the intestine by nursing neonates. This absorbed HGG was present in the neonatal circulation at concentrations of 0.3 to 0.6 mg/ml of serum under the experimental conditions used. This absorption of HGG by the nursing neonate resulted in a complete, specific, tolerant state to HGG. This tolerant state was stable upon adoptive cell transfer and could not be abrogated by transfer of normal syngeneic spleen cells.

The influence of particulate carriers and of mineral oil in adjuvants on the antibody response in rabbits to human gamma globulin.

A single inoculation of rabbits with human gamma globulin, administered with polystyrene latex particles and mineral oil as adjuvant, gave rise to at least the same level and duration of antibody formation as could be achieved with classical Freund's adjuvant made "complete" with killed mycobacteria.