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PubMed2006

A review of WHO International Standards for botulinum antitoxins.

Clostridium botulinum produces the most potent known toxins, with seven distinct serotypes currently defined (A-G). These toxins can cause a life threatening systemic toxicity whether through natural causes such as food poisoning, infant botulism, wound botulism, or through use as bio-terror agents (e.g. inhalational botulism). It was realised early on that standard reference botulinum antitoxins were required to reduce the variation between assays and ensure a consistent potency of therapeutic antitoxins and vaccines, and to define the serotype. This led to the International Unit being defined by the World Health Organisation (WHO) in the 1960s with the establishment of the first International Standards (IS) for serotypes A-F. Since then botulinum antitoxin ISs have been used world wide as the 'yard stick' to measure the neutralising potency of antitoxins. These primary WHO ISs are used to calibrate in house working reagents that are more extensively utilised. A definition of the International Unit for serotype G antitoxin has yet to be defined or accepted by the WHO and urgently needs addressing. However, before September 11th 2001 there was very little interest in botulinum antitoxin IS and as a result stocks of most of the original preparations are now completely exhausted or depleted and replacements long overdue. We have reviewed the extensive history and availability of the primary WHO ISs and interim materials. All type A and B antitoxin materials were recently assayed and their relative activities confirmed against the original IS preparations. The recent increase in demand for these materials has further exacerbated the shortage. We describe here the production and characterization of stable freeze dried potential candidate replacements along with a new prospective first IS for type G antitoxin. Available toxin A reference preparations are also briefly reviewed.

Animals↗
PubMed1983

A comparison of enzyme-linked immunosorbent assay (ELISA) with the toxin neutralization test in mice as a method for the estimation of tetanus antitoxin in human sera.

An enzyme-linked immunosorbent assay (ELISA) has been developed for the measurement of tetanus antitoxin in human sera as an alternative to the toxin neutralization test in mice, the currently accepted method of assay. The ELISA was found to be simple and quick to perform and required only small amounts of materials. In addition, the assay was found to give reproducible estimates of antitoxin levels and to measure antitoxin at levels as low as 0.01 IU per ml, a sensitivity similar to that of the neutralization test. Furthermore, a comparison of the results of the ELISA and the neutralization test involving 80 human sera, including sera with both high and low antitoxin levels, showed close agreement in antitoxin levels obtained by the two methods. It was concluded that ELISA was an acceptable alternative to the toxin neutralization test in mice for the measurement of tetanus antitoxin levels in human sera.

Animals↗
PubMed1964

BOTULISM.

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Animals↗
PubMed1992

Determination of neutralizing antibodies and specific immunoglobulin isotype levels in infants after vaccination against diphtheria.

Serum samples were obtained from 44 infants vaccinated against diphtheria at the ages of 3, 5 and 12 months with an aluminium-adsorbed diphtheria-tetanus toxoid vaccine containing 15 Lf units of diphtheria toxoid. Toxin-neutralizing antibodies (antitoxin) were measured by the Vero cell assay and IgG, IgM and IgA antibodies against diphtheria toxoid by enzyme-linked immunosorbent assay. A neutralizing antibody titer of 10 corresponded to 0.01 IU/ml, the level considered necessary for short-term protection. Geometric mean neutralizing antibody titers at 3, 5, 6, 12, 13 and 30 months were 28, 21, 173, 61, 1076 and 61. All children had titers of greater than or equal to 10 (greater than or equal to 0.01 IU/ml) between 6 and 30 months of age. At 30 months only 48% had titers of greater than or equal to 100 (greater than or equal to 0.01 IU/ml), the level considered necessary for long-term protection. Geometric mean IgG antibody levels were 13, 36, 216, 64, 649 and 57. IgG antibodies significantly correlated with neutralizing titers and predicted neutralizing antibodies above or below 10 and 100 with an accuracy of 96 and 82%, respectively. IgG antibodies could not, however, be used to predict individual neutralizing antibody titers with great accuracy. IgM antibodies were only detected after the third vaccination. IgA antibodies were not detected in any serum sample from ten infants tested. In conclusion, the Swedish vaccination schedule results in protective antibody levels in infants until at least 30 months of age. The decline of the antibody titers indicates a need for further studies to establish the duration of protection.

Animals↗
PubMed1997

Effects of the intravenous administration of Clostridium perfringens type D epsilon toxin on young goats and lambs.

Young goats (n = 18) and lambs (n = 10) were compared in respect of the effects of Clostridium perfringens type D epsilon toxin. Toxin produced neurological signs within 0.5-3 h of intravenous injection in (1) all of six kids given doses of 250, 185 or 120 mouse lethal doses 50% (MLD50)/kg body weight, (2) two of the three kids given 60 MLD50/kg, and (3) all of five lambs given 250 or 120 MLD50/kg. Six kids and three lambs given 45, 30 or 15 MLD50/kg, one lamb given 60 MLD50/kg, and three kids and one lamb given saline (controls) all remained clinically normal. Gross post-mortem changes were observed only in the kids and lambs that showed clinical signs. In the kids these changes consisted of severe acute interstitial and alveolar oedema of the lungs. However, only two out of five lambs that presented clinical signs showed pulmonary oedema. No histological changes were observed in the brain of any of the kids inoculated with epsilon toxin. In the brain of four out of the five lambs given doses of 120 or 250 MLD50/kg, there were histological lesions consisting of perivascular proteinaceous oedema and haemorrhages. These results show that kids and lambs are equally susceptible to the intravenous injection of epsilon toxin, but that they differ in the histological response of the central nervous system to the toxin.

Animals↗
PubMed1989

Rationale for immunotoxin therapy of metastatic prostate carcinoma formatted as a multi-stage delivery system.

A family of triple hybridomas secreting hybrid monoclonal antibodies has been developed in our laboratory. The hybrid monoclonal antibodies exhibit bimolecular specificity towards both antigenic determinants on the prostate carcinoma cell surface as well as toxin or toxic moieties (ricin A chain and pokeweed antiviral protein). These hybrid antibodies, when bound univalently to their cognate toxin, constitute the primary reagents responsible for selective in vitro prostate carcinoma cell kill; oncolytic impact is achieved by binding of the hybrid antibody-toxin complex (primary hybrid immunotoxin) to a prostate carcinoma cell surface-expressed antigen by the remaining univalent binding site of the hybrid antibody, allowing access of the toxin to the cytosol by internalization of the hybrid antibody-toxin complex. Internalization by endocytosis of a hybrid antibody-toxic subunit has been strikingly enhanced by the use of secondary monoclonal antibody reagents alone or in conjunction with other biomodifier reagents. For example, use of a second monoclonal antibody specific for ricin A chain to which ricin B chain (binding subunit) is chemically coupled results in selective and synergistic cell kill of targeted cancer cells. In vitro studies involving temporally staggered exposure of the cells to the individual components (primary hybrid antibody, toxin, and secondary antitoxin monoclonal antibody biomodifier) have been performed in a manner allowing maintenance of cytotoxic efficacy. It is concluded that sequential administration of these immunotherapeutic components, individually nontoxic, is a feasible strategy to develop an effective immunotherapeutic treatment of human prostate carcinoma.

Animals↗
PubMed2005

Kid cleaves specific mRNAs at UUACU sites to rescue the copy number of plasmid R1.

Stability and copy number of extra-chromosomal elements are tightly regulated in prokaryotes and eukaryotes. Toxin Kid and antitoxin Kis are the components of the parD stability system of prokaryotic plasmid R1 and they can also function in eukaryotes. In bacteria, Kid was thought to become active only in cells that lose plasmid R1 and to cleave exclusively host mRNAs at UA(A/C/U) trinucleotide sites to eliminate plasmid-free cells. Instead, we demonstrate here that Kid becomes active in plasmid-containing cells when plasmid copy number decreases, cleaving not only host- but also a specific plasmid-encoded mRNA at the longer and more specific target sequence UUACU. This specific cleavage by Kid inhibits bacterial growth and, at the same time, helps to restore the plasmid copy number. Kid targets a plasmid RNA that encodes a repressor of the synthesis of an R1 replication protein, resulting in increased plasmid DNA replication. This mechanism resembles that employed by some human herpesviruses to regulate viral amplification during infection.

Base Sequence↗
PubMed2003

Crystal structure of the plasmid maintenance system epsilon/zeta: functional mechanism of toxin zeta and inactivation by epsilon 2 zeta 2 complex formation.

Programmed cell death in prokaryotes is frequently found as postsegregational killing. It relies on antitoxin/toxin systems that secure stable inheritance of low and medium copy number plasmids during cell division and kill cells that have lost the plasmid. The broad-host-range, low-copy-number plasmid pSM19035 from Streptococcus pyogenes carries the genes encoding the antitoxin/toxin system epsilon/zeta and antibiotic resistance proteins, among others. The crystal structure of the biologically nontoxic epsilon(2)zeta(2) protein complex at a 1.95-A resolution and site-directed mutagenesis showed that free zeta acts as phosphotransferase by using ATPGTP. In epsilon(2)zeta(2), the toxin zeta is inactivated because the N-terminal helix of the antitoxin epsilon blocks the ATPGTP-binding site. To our knowledge, this is the first prokaryotic postsegregational killing system that has been entirely structurally characterized.

Amino Acid Sequence↗
PubMed1989

Endocytosis from coated pits of Shiga toxin: a glycolipid-binding protein from Shigella dysenteriae 1.

Evidence is presented that endocytosis is involved in the transport to the cytosol of the cytotoxin from Shigella dysenteriae 1, Shiga toxin, which acts by removal of a single adenine residue in 28-S ribosomal RNA. Inhibition of endocytosis by ATP depletion of the cells prevented toxin uptake. Exposure of HeLa S3 and Vero cells to toxin at low extracellular pH, where translocation to the cytosol, but not endocytosis is inhibited, allowed the toxin to accumulate in a compartment where it was protected against antibodies to the toxin. Upon transfer of the cells to normal medium endocytosed toxin entered the cytosol. Electron microscopical studies of cells exposed at 0 degrees C to a toxin-horseradish peroxidase (HRP) conjugate, or to unconjugated toxin followed by horse antitoxin antibodies and then protein G-gold, revealed that the Shiga toxin binding sites were randomly distributed on the cell surface, without any preference to, for example, coated pits. In contrast, when cells were exposed to toxin at 37 degrees C, the binding sites were preferentially localized in coated pits. The Shiga-HRP conjugate was also seen in endosomes, lysosomes, and in the Golgi region. Endocytosis by the coated pit/coated vesicle pathway was selectively inhibited by acidification of the cytosol. Under these conditions, both the uptake of toxin-HRP conjugates and intoxication of the cells were inhibited. Evidence from the literature as well as our own results suggest that Shiga toxin binding sites are glycolipids. Thus, Shiga toxin appears to be the first example of a lipid-binding ligand that is endocytosed from coated pits.

Ammonium Chloride↗