IgE mimotopes of birch pollen allergen Bet v 1 induce blocking IgG in mice.

BACKGROUND: The induction of nonanaphylactogenic 'blocking' IgG antibodies capable of inhibiting the IgE/allergen interaction represents a favorable therapeutic concept for type I allergy. However, IgG antibodies to allergens may block or enhance specific IgE binding, depending on the recognized epitope. Taking the major birch pollen allergen Bet v 1 as a model, we developed a strategy for the precise induction of IgG antibodies of a desired epitope specificity. METHODS: Random phage display peptide libraries were applied to define peptide structures mimicking natural epitopes (mimotopes) of Bet v 1. Selections were performed with BIP 1, a murine monoclonal antibody known to enhance the IgE binding to Bet v 1, and with anti-Bet v 1 IgE purified from patients' sera. The characterized Bet v 1 mimotopes were used to localize the corresponding epitope at the surface of Bet v 1 by a computer-aided mathematical approach based on the three-dimensional structure and the chemical character of the amino acids. The Bet v 1 mimotopes were further used to immunize BALB/c mice. The specificity of the induced antibodies was tested by immunoblotting and inhibition assays. RESULTS: With the three-dimensional epitope search it became possible to localize a discontinuous IgE epitope on the surface of Bet v 1 in a substantial distance from the IgG epitope of the monoclonal antibody BIP 1. Moreover, we could demonstrate that phage displaying mimotopes are immunogenic vectors for the precise induction of epitope-specific IgG. Immunization with BIP 1 mimotopes induced IgG enhancing the IgE binding to Bet v 1, whereas immunization with IgE mimotopes resulted in IgG capable of blocking human IgE binding in vitro. CONCLUSION: Allergen mimotopes can be used for the induction of anti allergen IgG of desired specificity. We propose that mimotope immunotherapy based on IgE mimotopes generated by biopannings may represent a future concept for therapy of type I allergy.

Serum vasopressin (AVP) levels in polyuric brain-dead organ donors.

Hydromineral metabolism and serum arginine-vasopressin (AVP) levels were investigated in 11 patients who sustained brain death. They showed various degrees of polyuria with low osmolality and low fractional sodium excretion. Urine osmolality was always below that of serum, and AVP levels were between 1.3 and 50.0 pg/ml vs 0.7-8.0 pg/ml in ten normal subjects. Thus central diabetes insipidus was excluded. A renal mechanism inducing water diuresis has to be assumed. The type of renal lesion, however, remains unclear.

Nephrotoxicity of fumaric acid monoethylester (FA ME).

The nephrotoxic actions of high single oral doses of fumaric acid monoethylester (FA ME) have been investigated in the rat. Fifty mg of this substance produced morphologic lesions of the glomeruli without reducing GFR. Following 100 mg, the lesions were more pronounced and GFR was diminished by about 40%. Despite of hemorrhages in kidney cortex the urines did not contain erythrocytes. Urinary protein was augmented in single cases only. Fifty to 100 mg FA ME induced a marked concentration defect after water deprivation. In parallel FA ME reduced lactate production from glucose by kidney inner medulla in vitro. After in vivo application, however, no morphologic lesions were found in this zone of the kidney. FA ME had no effect on oxygen consumption of kidney slices despite of proximal tubular lesions observed histologically after 100 mg orally. Thus, 100 mg of FA ME have distinct nephrotoxic effects in the rat.

Effect of some uremic toxins on oxygen consumption of rats in vivo and in vitro.

In rats, oxygen consumption is reduced by about 40-50% 24 h after bilateral nephrectomy. This is also the case when the animals are pretreated with triiodothyronine, 3 x 0.75 mg/kg body weight orally, for 2-3 days. Indole, cresol, putrescine, methylguanidine or acetoine was given intraperitoneally to normal rats at doses of between 5 and 300 mg/kg body weight. Only low single doses of indole (5 mg/kg) reduced oxygen consumption significantly. Single doses of the other substances studied were ineffective even at tenfold higher doses. Some combinations of these substances, however, (10 mg/kg each), reduced the metabolic rate significantly. In contrast to the results in vivo, plasma of uremic rats, as well as the uremic toxins, dissolved in Krebs-phosphate buffer pH 7.4 at concentrations of 30 mg/dl each, had no influence on respiration of rat diaphragma or liver slices in vitro (single substances and different combinations).

Influence of some uremic toxins on oxygen consumption of rats in vivo and in vitro.

According to our present knowledge hypometabolism and hypothermia in uremia are most probably due to direct actions of toxic substances at the cellular level. A cardiovascular etiology seems less possible. A similar reduction of oxygen consumption as observed in uremia can be produced by 5 mg/kg body wt. indole i.p. Acetoine, m- and p-cresol, methylguanidine and putrescine do not reduce oxygen consumption even at tenfold higher doses. Some combinations of these substances, however, are effective when given only 10 mg/kg body wt. each. The effects in vivo cannot be reproduced by employing in vitro systems.

Metabolism of free fatty acids (FA) and triacylglycerol (TG) in acute and subacute fluoride intoxication of the rat.

In rats acute intoxication with 100 mg sodium fluoride/kg body wt. orally has the following metabolic consequences. Oxygen consumption is reduced by about 30-50%. Plasma free FA decrease in fed as well as in starved rats. Hepatic FA synthesis is enhanced, but TG secretion to the blood is not altered. Intravenously injected Intralipid 20% is removed at a normal rate. In subacute intoxication (30 mg sodium fluoride/kg body wt given orally per day over 1 week) oxygen consumption is not affected. TG secretion and removal of Intralipid remain in the normal range whereas hepatic FA synthesis is increased as in acute intoxication. TG concentration in the liver, however, increases by about 30% after 1 week.

Metabolic effects of water deprivation.

Under the conditions of pair feeding, water-deprived rats predominantly use fat as a metabolic fuel, whereas total energy turnover as measured by oxygen consumption is not altered. Plasma free fatty acids are elevated in dehydrated rats, indicating enhanced lipolysis. Reduced hepatic fatty acid synthesis and reduced triacylglycerol secretion into the blood seem to be the main factors for the decrease of plasma triacylglycerol, observed 48 hours after the onset of water deprivation. Enhanced plasma levels of corticosterone (about 100%) and glucagon (about 50%) may contribute to the metabolic situation observed in water deprivation.

Drug utilization study of antiepileptics in Hungary.

This paper describes drug utilization review activities on anticonvulsant drugs in Hungary. Data on the use of phenytoin, carbamazepine, primidone, and sulthiam in the 20 administrative regions of the country are presented. From 1971 to 1980, consumption of these anticonvulsants doubled, and most of them were used in combination therapy. Estimates of the numbers of epileptics in the country were calculated from data on the international incidence of epilepsy and from total drug consumption data in Hungary.