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At least 19 recordsLinked to original sources
PubMed1953

Immunochemical studies of antitoxin produced in normal and allergic individuals hyperimmunized with diphtheria toxoid. III. Studies of the passive Arthus reaction in guinea pigs using human precipitating and nonprecipitating diphtheria antitoxin.

The Arthus reaction was studied in guinea pigs passively immunized with human diphtheria antitoxin. Diphtheria toxoid was given intradermally 24 hours following the intravenous administration of antitoxin and the subsequent reactions were graded and measured. The intensity of Arthus reactions was dependent upon the relative amounts of precipitating antitoxin and toxoid used. Severe lesions were caused by intravenous sensitization with 0.48 mg. precipitating antitoxin N and intradermal challenge with 0.05 or 0.17 toxoid N. Reactions of lesser intensity were caused by smaller amounts of antitoxin and toxoid. The nature of the antibody used for sensitization was of importance in the severity of Arthus reactions. In contrast to the behavior of precipitating antitoxin, amounts of non-precipitating antitoxin equivalent to 0.48 mg. N did not cause severe Arthus reactions when 0.05 or 0.17 mg. toxoid N was given intradermally. Precipitating antitoxic whole serum is altered by heating at 56 degrees C. for 5 hours so that its precipitability is lost without any appreciable loss of antitoxic strength. This modified antitoxin produced Arthus reactions of only intermediate severity in guinea pigs sensitized with 0.48 mg. antitoxin N. When fractions of precipitating antitoxic serum were obtained using a cold ethanol technique described by Deutsch (16), a mixture of the purified gamma(2)-globulin and the crude albumin fraction heated together at 56 degrees C. for 5 hours behaved similarly to whole serum. However, gamma(2)-globulin alone was not affected by the heating procedure, remained precipitable by toxoid, and was able to cause a severe Arthus reaction following sensitization with 0.48 mg. antitoxin N.

Administration, Intravenous↗
PubMed1952

Immunochemical studies of antitoxin produced in normal and allergic individuals hyperimmunized with diphtheria toxoid. II. A comparison between the immunological properties of precipitating and non-precipitating (skin-sensitizing) antitoxins.

1. The immunological properties of two contrasting types of human antisera, each containing a high titer of diphtheria antitoxin, have been investigated. 2. Sera which contain only non-precipitating antitoxin exhibit most of the properties of atopic reagin-containing sera. This type of antitoxin is capable of sensitizing normal human skin to toxin or toxoid and remains for many weeks in the injected area. It exhibits no Danysz effect, does not fix complement unless very large amounts of serum are used, and can be specifically coprecipitated by addition of precipitating antitoxin and toxin. On the other hand, it is capable of sensitizing guinea pigs to fatal anaphylactic shock. Heating at 56 degrees C. for 4 hours destroys the skin-sensitizing properties and results in almost quantitative conversion to a modified antitoxin which is capable of blocking the wheal and erythema reaction caused by injection of toxoid into sensitized skin. Heating at 56 degrees C. does not result in an appreciable loss of neutralizing power as judged by tests in rabbit and human skin. The anaphylactogenic property of nonprecipitating antibody is likewise unaffected by heat at 56 degrees C. 3. Precipitating antitoxin is incapable of sensitizing normal skin to toxin or toxoid and disappears rapidly from the injected sites. It fixes complement to high titer and sensitizes guinea pigs to fatal anaphylactic shock. It was possible to demonstrate inhibition of the wheal and erythema reaction in sensitized skin by injecting certain mixtures of precipitating antitoxin and toxoid. 4. The two antitoxic sera studied in greatest detail represented extreme cases. Many persons immunized with toxoid developed both precipitating and nonprecipitating antitoxin simultaneously.

Animals↗
PubMed1955

Immunochemical studies of antitoxin produced in normal and allergic individuals hyperimmunized with diphtheria toxoid. VI. Further investigations on the identity and specificity of non-precipitating skin-sensitizing antitoxin.

Studies were carried out on sera from eight subjects hyperimmunized with toxoid who developed marked immediate skin reactivity to toxoid associated with circulating non-precipitating antitoxin. With the use of the rabbit skin test, the agar diffusion technique, and three different methods for passive transfer of skin sensitivity, it was possible to obtain detailed qualitative and quantitative data relating to the antitoxin in these sera. It was found that specimens from six individuals contained only skin-sensitizing antitoxin. Two sera showed a lack of parallelism between antitoxin titers as obtained by rabbit skin test and titers as demonstrated by tests in human skin. It was presumed that these sera contained two different varieties of non-precipitating antitoxins, and that only one of them was skin-sensitizing antitoxin. A new technique is described for measurement of skin-sensitizing antitoxin. Its specificity is based upon the ability of this antitoxin to remain at skin sites and later neutralize the delayed specific toxic effects of intradermal Schick test reagent.

Animals↗
PubMed1954

Immunochemical studies of antitoxin produced in normal and allergic individuals hyperimmunized with diphtheria toxoid. IV. Differences between human precipitating and non-precipitating skin-sensitizing diphtheria antitoxin as shown by electrophoresis.

Electrophoresis on a starch-supporting medium was used to fractionate sera containing human diphtheria antitoxin of the following varieties (a) precipitating antitoxin, (b) non-precipitating skin-sensitizing antitoxin, and (c) mixtures containing precipitating and skin-sensitizing antitoxins. Aliquots of the protein fractions thus separated were tested for activity using the rabbit toxin neutralization test, precipitin techniques, and passive transfer tests in human skin. Non-precipitating, skin-sensitizing diphtheria antitoxin migrated largely as a fast moving gamma (gamma(1)) globulin. Passive transfer studies of isolated antitoxic fractions showed that they were as potent as whole serum in the ability to cause immediate wheal reactions. These fractions were not precipitable using appropriate quantities of purified toxoid. Precipitating diphtheria antitoxin migrated largely as a slow moving gamma (gamma(2)) globulin. Isolated antitoxic fractions of appropriate strength obtained from representative sera were precipitable by toxin and were unable to cause immediate wheal reactions upon toxoid challenge in human recipients. Mixtures of skin-sensitizing and precipitating antitoxins were separable by the technique of starch electrophoresis. The individual components removed from mixtures by this method retained the properties by which they could be characterized in whole serum.

Antibodies↗
PubMed1984

Antitoxin levels in botulism patients treated with trivalent equine botulism antitoxin to toxin types A, B, and E.

Serum levels of equine-botulism antitoxin to toxin types A, B, and E were measured in four type-A botulism patients who had received equine-botulism antitoxin. High circulating levels capable of neutralizing in excess of 1 X 10(8), 9 X 10(7), and 6 X 10(6) 50% mouse lethal doses of toxin of types A, B, and E, respectively, were detected. There was little depletion of type-A antitoxin even though two of the patients had circulating type-A toxin before treatment. The half-life for antitoxin persistence for one patient was calculated as being 6.5, 7.6, and 5.3 days for antitoxin types A, B, and E, respectively. Antitoxin levels were not proportionate to the amount (range, 2-4 vials) injected and did not appear to be affected by whether the route of administration was iv or im. Peak serum levels of antitoxin were 10-1,000 times higher than amounts needed to neutralize the toxin measured in the serum of these and other patients with botulism.

Botulinum Antitoxin↗
PubMed1978

Titration of tetanus antitoxin by passive hemagglutination. II. Serological characteristics of antitoxin production in rabbits and monkeys.

1) Production of tetanus antitoxin in rabbits and monkeys was followed by passive hemagglutination (HA) and toxin-neutralization (TN) tests. The HA activity was observed in both IgM and IgG in both animal species. 2) In rabbits, IgM antitoxin was detected as early as in 7 days, reached the maximum titer in 10--14 days, and disappeared in 3 weeks after the primary immunization. Antitoxin of IgG class was detected in 10 days, and increased gradually. The ratio of HA/TN titers ("serum ratio") was high at an early stage of primary immunization and approached the unity in 3--4 weeks. Unlike the case of guinea pigs, IgM was found to contribute greatly to this high level of ratio. Besides, most rabbits produced IgG antitoxin of high ratios at early stages of immunization. 3) The immune response of monkeys showed a pattern very similar to that of rabbits except a few days' delay in the time course of antitoxin titers. No IgG antitoxin with a high serum ratio was demonstrated. Therefore, the high serum ratio of early sera could be accounted for mainly by IgM. 4) In response to the secondary immunization, no IgM antitoxin was detected in either animal species. 5) No definite correlation between serum ratio and avidity in terms of "dilution ratio" was demonstrated. However, both the dilution ratio and serum ratio were high at an early stage of immunization and gradually decreased, though the magnitudes of the ratios were variable depending on individual animals.

Animals↗
PubMed1956

The alpha antitoxin content of the international reference preparations of Clostridium welchii types B and D antitoxins.

The alpha antitoxin contents of the International Reference Preparations of Clostridium welchii Types B and D Antitoxins were assayed against two type A test toxins-Cl. welchii (perfringens) test toxin P2, issued by the Statens Seruminstitut, Copenhagen, and Cl. welchii test toxin AGX 1373, issued by the Wellcome Research Laboratories, England-the alpha toxin contents of which were first determined against the International Standard Alpha Antitoxin. Three methods of assay were used: mouse killing (the L+ test); haemolysis of red blood cells (the Lh test); and production of turbidity in egg-yolk solution (the lecithinase or Lv test).Taking the mean of all tests, it was found that the International Reference Preparation of Cl. welchii Type B Antitoxin contained 282 units of alpha antitoxin per ml, while the International Reference Preparation of Cl. welchii Type D Antitoxin contained 93 units of alpha antitoxin per ml.

Animals↗
PubMed2005

The YoeB toxin is a folded protein that forms a physical complex with the unfolded YefM antitoxin. Implications for a structural-based differential stability of toxin-antitoxin systems.

The chromosomal YoeB-YefM toxin-antitoxin module common to numerous strains of bacteria is presumed to have a significant role in survival under stringent conditions. Recently we showed that the purified YefM antitoxin is a natively unfolded protein, as we previously reported for the Phd antitoxin in the P1 phage Doc-Phd toxin-antitoxin system. Here we report the purification and structural properties of the YoeB toxin and present physical evidence for the existence of a tight YoeB. YefM polypeptide complex in solution. YoeB and YefM proteins co-eluted as single peaks in sequential Ni-affinity FPLC and Q-Sepharose ion-exchange chromatography implying the formation of a YoeB. YefM complex. The unstable antitoxin was removed from the mixture by natural proteolysis, and the residual YoeB protein was purified using ion exchange chromatography. Fluorescence anisotropy studies of the purified YoeB and YefM proteins showed a 2:1 stoichiometry of the complex, providing direct evidence for a physical complex between the proteins. Near- and far-UV circular dichroism spectroscopy of the purified toxin revealed that, similar to the Doc toxin, YoeB is a well-folded protein. Thermal denaturation experiments confirmed the conformational stability of the YoeB toxin, which underwent reversible thermal unfolding at temperatures up to 56 degrees C. The thermodynamic features of the toxin-antitoxin complex were similar. Taken together, our results support the notion of a correlation between differential physiological and structural stability in toxin-antitoxin modules.

Anisotropy↗
PubMed1998

Antitoxin-in-membrane and antitoxin-in-well assays for detection of toxigenic Corynebacterium diphtheriae.

The Elek culture plate precipitin test is routinely used for the detection of exotoxin from toxigenic strains of Corynebacterium diphtheriae. Recently, the World Health Organization standardized this test to ensure accuracy, reliability, and reproducibility. In this study, we further modified the standard Elek test by using the antitoxin-in-membrane (AIM) and antitoxin-in-well (AIW) approaches. In the AIM tests, each strain was stabbed and streaked backwards and away from a point approximately 7 mm from the edge of a sterile cellulose acetate-cellulose nitrate filter membrane disk (pore size, 0.45 microm; diameter, 25 mm) containing 25 IU of diphtheria antitoxin. For AIW tests, a central well (diameter, 5 mm) containing 9 microl of antitoxin (4.5 IU) was surrounded by eight equidistant stab-streaks of each strain placed 10 mm from the well. In both methods, precipitin bands of identity typically were noted after 24- and 48-h incubations at 37 degrees C. Both toxigenic and weak toxigenic strains gave clear and reproducible results. Compared with the standard Elek test, the AIM and AIW tests each use 50% less medium and 75 and 87% less antitoxin, respectively. AIM has the potential to test up to 14 isolates and AIW has the potential to test up to 24 isolates on the same plate. Furthermore, clearer positives were noted with weak toxigenic strains. In a blinded test of 209 verified C. diphtheriae isolates, a 99.5% agreement with the standard Elek test was obtained overall. Both modifications conserve reagents and medium, permit the simultaneous testing of a larger number of strains, and may be particularly suitable for reference laboratories or hospitals involved in diphtheria epidemic settings.

Antitoxins↗
PubMed1975

Titration of tetanus antitoxin by passive hemagglutination. I. Titration of guinea-pig antitoxins at various periods of immunization.

An improved technique for passive hemagglutination (HA) for titration of tetanus antitoxin was described. The use of highly purified tetanus toxoid and of improved diluent increased the specificity and reproducibility of the test. Several hundreds of specimens of guinea-pig serum taken at various stages of immunization were titrated by HA and toxin neutralization (NT) in mice. The ratio of HA to NT titers varied significantly depending on the immunization stage; higher at early stages and lower at later stages. The high HA/NT ratio was not due to the IgM antitoxin, which is very rare in guinea pigs. The variation in discrepancy between HA and NT titers decreased considerably by grouping the serum specimens with respect to the stage of immunization. Thus, it is possible to predict the in vivo titer of a tetanus antitoxin accurately enough for clinical study. The HA test may be useful as an alternative method for titrating tetanus antitoxin in the field trials. Moreover, it can be used for the study of characteristics of antitoxins.

Animals↗
PubMed2006

The chromosomal relBE2 toxin-antitoxin locus of Streptococcus pneumoniae: characterization and use of a bioluminescence resonance energy transfer assay to detect toxin-antitoxin interaction.

Proteic toxin-antitoxin (TA) loci were first identified in bacterial plasmids, and they were regarded as involved in stable plasmid maintenance by a so-called 'addiction' mechanism. Later, chromosomally encoded TA loci were identified and their function ascribed to survival mechanisms when bacteria were subjected to stress. In the search for chromosomally encoded TA loci in Gram-positive bacteria, we identified various in the pathogen Streptococcus pneumoniae. Two of these cassettes, sharing homology with the Escherichia coli relBE locus were cloned and tested for their activity. The relBE2Spn locus resulted to be a bona fide TA locus. The toxin exhibited high toxicity towards E. coli and S. pneumoniae, although in the latter, the chromosomal copy of the antitoxin relB2Spn gene had to be inactivated to detect full toxicity. Cell growth arrest caused by expression of the relE2Spn toxin gene could be reverted by expression of the cognate antitoxin, relB2Spn, although prolonged exposition to the toxin led to cell death. The pneumococcal relBE2Spn locus is the first instance of a chromosomally encoded TA system from Gram-positive bacteria characterized in its own host. We have developed a bioluminescence resonance energy transfer (BRET) assay to detect the interactions between the RelB2Spn antitoxin and the RelE2Spn toxin in vivo. This technique has shown to be amenable to a high-throughput screening (HTS), opening new avenues in the search of molecules with potential antibacterial activity able to inhibit TA interactions.

Antitoxins↗
PubMed1963

FIFTH INTERNATIONAL STANDARD FOR GAS-GANGRENE ANTITOXIN (PERFRINGENS) (CLOSTRIDIUM WELCHII TYPE A ANTITOXIN).

The Fifth International Standard Gas-Gangrene Antitoxin (Perfringens) (Clostridium welchii Type A Antitoxin) was prepared from serum from immunized horses. It was freeze-dried in ampoules each containing 1 ml.Seven laboratories collaborated in assaying its potency in terms of the Fourth International Standard by the intravenous inoculation of mice. The geometric mean value, taking the results of all the laboratories, was 270 International Units per ampoule and the maximum variation between laboratories was 15%.In vitro (lecithinase) tests were also done by three laboratories, giving an average of 261 International Units per ampoule.The dry weight contents of ampoules, determined in three laboratories, varied by less than 3%, with an average of 90.35 mg per ampoule.The standard was stable for 120 hours at 56 degrees C.Each ampoule of the Fifth International Standard for Gas-Gangrene Antitoxin (Perfringens) contains 270 International Units, and one International Unit is contained in 0.3346 mg of the International Standard.

Animals↗
PubMed2005

Crystal structure of archaeal toxin-antitoxin RelE-RelB complex with implications for toxin activity and antitoxin effects.

The Escherichia coli chromosome encodes toxin-antitoxin pairs. The toxin RelE cleaves mRNA positioned at the A-site in ribosomes, whereas the antitoxin RelB relieves the effect of RelE. The hyperthermophilic archaeon Pyrococcus horikoshii OT3 has the archaeal homologs aRelE and aRelB. Here we report the crystal structure of aRelE in complex with aRelB determined at a resolution of 2.3 A. aRelE folds into an alpha/beta structure, whereas aRelB lacks a distinct hydrophobic core and extensively wraps around the molecular surface of aRelE. Neither component shows structural homology to known ribonucleases or their inhibitors. Site-directed mutagenesis suggests that Arg85, in the C-terminal region, is strongly involved in the functional activity of aRelE, whereas Arg40, Leu48, Arg58 and Arg65 play a modest role in the toxin's activity.

Antitoxins↗
PubMed2005

Energetics of structural transitions of the addiction antitoxin MazE: is a programmed bacterial cell death dependent on the intrinsically flexible nature of the antitoxins?

The Escherichia coli mazEF addiction module plays a crucial role in the cell death program that is triggered under various stress conditions. It codes for the toxin MazF and the antitoxin MazE, which interferes with the lethal action of the toxin. To better understand the role of various conformations of MazE in bacterial life, its order-disorder transitions were monitored by differential scanning calorimetry, spectropolarimetry, and fluorimetry. The changes in spectral and thermodynamic properties accompanying MazE dimer denaturation can be described in terms of a compensating reversible process of the partial folding of the unstructured C-terminal half (high mean net charge, low mean hydrophobicity) and monomerization coupled with the partial unfolding of the structured N-terminal half (low mean net charge, high mean hydrophobicity). At pH<or=4.5 and T<50 degrees C, the unstructured polypeptide chains of the MazE dimer fold into (pre)molten globule-like conformations that thermally stabilize the dimeric form of the protein. The simulation based on the thermodynamic and structural information on various addiction modules suggests that both the conformational adaptability of the dimeric antitoxin form (binding to the toxins and DNA) and the reversible transformation to the more flexible monomeric form are essential for the regulation of bacterial cell life and death.

Antitoxins↗
PubMed1952

Immunochemical studies of antitoxin produced in normal and allergic individuals hyperimmunized with diphtheria toxoid. I. Relationship of skin sensitivity to purified diphtheria toxoid to the presence of circulating, non-precipitating antitoxin.

Among a group of 131 young adults tested, there was a high degree of correlation between the occurrence of immediate skin reactions of the wheal and erythema type produced by purified diphtheria toxoid and personal or familial history of allergy of the hay-fever type. Of 39 Schick-negative subjects who received a "booster" dose of purified diphtheria toxoid, 19 showed no immediate skin reactions before immunization. The development of skin sensitivity in these subjects was associated with the production of non-precipitating circulating antitoxin. Three subjects produced 20 units or more antitoxin per cc. serum following immunization, without demonstrable precipitins. Despite the fact that none showed immediate skin reactions to Schick toxoid prior to immunization, all 3 possessed a high degree of skin sensitivity to toxoid following immunization.

Adult↗
PubMed1977

Escherichia coli heat-labile enterotoxin: comparison of antitoxin assays and serum antitoxin levels.

The mouse adrenal tumor cells (Y-1 strain) and the Chinese hamster ovary cells, two routinely used tissue culture assays for Escherichia coli heat-labile enterotoxin (LT), were used to detect serum antitoxin responses in culture-positive patients from several well-defined sources. There was no correlation between a significant antitoxin response and isolation of LT-producing E. coli in two "domestic" diarrheal outbreaks. Serum samples from a third group of individuals in a rural cholera-endemic area consistently demonstrated significant rises in neutralizing antibody to LT.

Antibodies, Bacterial↗