Antigenicity of purified glutaraldehyde-treated cholera toxoid administered orally.
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The antigenicity of orally administered glutaraldehyde-treated cholera toxoid was investigated in healthy volunteers. Fourteen volunteers ingested two or three 2-mg doses of toxoid with saline, with the doses spaced at 28-day intervals. Thirteen other volunteers received comparable toxoid doses with NaHCO3 and milk to neutralize gastric acid. Increments in circulating antitoxin levels were used to assay the antigenicity of oral toxoid. Antitoxin was measured by adrenal cell, rabbit skin permeability factor, and passive hemagglutination assays in sera collected on days 0, 28, 35, 56, 63, and 84 after primary immunization. Adrenal cell and rabbit skin assays exhibited identical sensitivity in detecting antitoxin rises in the 27 vaccinees (19/27) and were significantly more sensitive than passive hemagglutination (11/27) (P less than 0.03). Volunteers who ingested toxoid with NaHCO3 and milk had a higher rate of seroconversion (77%) than those who received toxoid with saline (64%); they also had earlier rises in antitoxin titer and consistently higher geometric mean titers on all days tested. These studies demonstrate that purified cholera toxoid is antigenic in humans after oral administration. The possible role of oral toxoid in enhancing the protective effect of killed whole-cell vaccines can now be investigated. (+info)
Lack of J chain inhibits the transport of gut IgA and abrogates the development of intestinal antitoxic protection.
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Recent publications have provided confusing information on the importance of the J chain for secretion of dimeric IgA at mucosal surfaces. Using J chain-deficient (J chain-/-) mice, we addressed whether a lack of J chain had any functional consequence for the ability to resist challenge with cholera toxin (CT) in intestinal loops. J chain-/- mice had normal levels of IgA plasma cells in the gut mucosa, and the Peyer's patches exhibited normal IgA B cell differentiation and germinal center reactions. The total IgA levels in gut lavage were reduced by roughly 90% as compared with that in wild-type controls, while concomitantly serum IgA levels were significantly increased. Total serum IgM levels were depressed, whereas IgG concentrations were normal. Following oral immunizations with CT, J chain-/- mice developed 10-fold increased serum antitoxin IgA titers, but gut lavage anti-CT IgA levels were substantially reduced. However, anti-CT IgA spot-forming cell frequencies in the gut lamina propria were normal. Anti-CT IgM concentrations were low in serum and gut lavage, whereas anti-CT IgG titers were unaltered. Challenge of small intestinal ligated loops with CT caused dramatic fluid accumulation in immunized J chain-/- mice, and only 20% protection was detected compared with unimmunized controls. In contrast, wild-type mice demonstrated 80% protection against CT challenge. Mice heterozygous for the J chain deletion exhibited intermediate gut lavage anti-CT IgA and intestinal protection levels, arguing for a J chain gene-dosage effect on the transport of secretory IgA. This study unequivocally demonstrates a direct relationship between mucosal transport of secretory SIgA and intestinal immune protection. (+info)
Similarities between the pathogenesis of and immunity to diphtheria and pertussis: the complex nature of serum antitoxin-induced immunity to these two diseases.
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Despite data from animal studies, seroepidemiological surveys, and controlled clinical trials, skepticism persists about immunity to pertussis conferred by serum IgG neutralizing antibodies (antitoxin). This is largely prompted by the absence of a "protective" level of antitoxin. Examination of the similarities between the pathogenesis and immunity to pertussis and diphtheria provides an explanation for this dilemma. As with pertussis, diphtheria toxoid vaccination confers only approximately 70% immunity on an individual basis, individuals with protective levels of antitoxin may contract diphtheria, and about 50% of the entire population, especially adults, have less than protective levels of antitoxin. The virtual disappearance of diphtheria followed vaccination of the entire population with diphtheria toxoid, which blocked transmission of toxigenic Corynebacterium diphtheriae and thus reduced the pathogen to almost undetectable levels. The individual and community-based immunity induced by diphtheria toxoid, we hypothesize, is similar to that of pertussis and pertussis toxoid. (+info)
Shigellosis and Escherichia coli diarrhea: relative importance of invasive and toxigenic mechanisms.
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Shigellae and dysentery-like Escherichia coli must invade the epithelium of the colon to cause disease which can present as dysentery, diarrhea, or both. This paper addresses the possible role of a Shigella dysenteriae-like (Shiga-like) toxin in the pathogenesis of shigellosis and E. coli diarrheal diseases. The possibility for such a role is suggested by the following observations: 1) diarrhea, considered to be a result of secretion of water by the small bowel, is frequently observed in shigellosis, a large bowel disease. 2) Even though shigellae do not invade the jejunum of monkeys fed Shigella flexneri, jejunal secretion is seen in animals with diarrhea. 3) The Shiga toxin of S. dysenteriae has enterotoxic activity and other serotypes of shigellae produce Shiga-like toxins. 4) E. coli 015 RDEC-1 causes a diarrheal disease and frequently death in young rabbits. This organism neither produces E. coli enterotoxins nor is it invasive, but it may produce low levels of a Shiga-like toxin. (+info)
The sigma ligand, igmesine, inhibits cholera toxin and Escherichia coli enterotoxin induced jejunal secretion in the rat.
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BACKGROUND: Cholera toxin, and Escherichia coli heat labile (LT) and heat stable (STa) enterotoxins induce small intestinal secretion in part by activating enteric nerves. Igmesine is a novel sigma receptor ligand that inhibits neurally mediated secretion. AIMS: To assess the antisecretory potential of igmesine in cholera toxin, LT, and STa induced water and electrolyte secretion using an in vivo rat model of jejunal perfusion. METHODS: After pretreatment with igmesine, 0.03-10 mg/kg intravenously, jejunal segments of anaesthetised, adult male Wistar rats were incubated with cholera toxin (25 microg), LT (25 microg), or saline. Jejunal perfusion with a plasma electrolyte solution containing a non-absorbable marker was undertaken. In some cases 200 microg/l STa was added to the perfusate. After equilibration, net water and electrolyte movement was determined. In additional experiments rats received igmesine, intravenously or intrajejunally, after exposure to cholera toxin. RESULTS: Cholera toxin induced net water secretion was inhibited by 1 mg/kg igmesine (median -120 versus -31 microl/min/g, p<0.001). LT and STa induced secretion were also inhibited by 1 mg/kg igmesine (-90 versus -56, p<0.03; and -76 versus -29, p<0.01, respectively). Igmesine reduced established cholera toxin induced secretion. CONCLUSION: The sigma ligand, igmesine, inhibits neurally mediated enterotoxigenic secretion. Its ability to inhibit established secretion makes it an agent with therapeutic potential. (+info)
Vitronectin and its fragments purified as serum inhibitors of Staphylococcus aureus gamma-hemolysin and leukocidin, and their specific binding to the hlg2 and the LukS components of the toxins.
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Staphylococcal gamma-hemolysin and leukocidin are bi-component cytolysins, consisting of LukF (or Hlg1)/Hlg2 and LukF/LukS, respectively. Here, we purified serum inhibitors of gamma-hemolysin and leukocidin from human plasma. Protein sequencing showed that the purified inhibitors of 62, 57, 50 and 38 kDa were the vitronectin fragments with truncation(s) of the C-terminal or both N- and C-terminal regions. The purified vitronectin fragments specifically bound to the Hlg2 component of gamma-hemolysin and the LukS component of leukocidin to form high-molecular-weight complexes with them, leading to inhibition of the toxin-induced lysis of human erythrocytes and human polymorphonuclear leukocytes, respectively. Intact vitronectin also showed inhibitory activity to the toxins. The ability of gamma-hemolysin and leukocidin to bind vitronectin and its fragments is a novel function of the pore-forming cytolysins. (+info)
Monoclonal antibodies against the Androctonus australis hector scorpion neurotoxin I: characterisation and use for venom neutralisation.
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A series of monoclonal antibodies (mAbs) specific for the alpha-neurotoxin I (Aah I) from the venom of the dangerous Androctonus australis hector scorpion were obtained using carrier protein-coupled toxin. Competitive RIA, receptor assays and mouse toxicity tests were performed to characterise mAbs in terms of affinity and neutralisation. Cross-reactivity studies and two-site ELISA results allowed some classification of mAbs into three groups. One mAb, 9C2, was particularly interesting since it recognised the parent toxin I with a K(D) of 0.15 nM and was also reactive with toxins of the same immunological group. Its ability to neutralise the toxic effect of the parent toxin and the venom fraction has been investigated. This anti-Aah I mAb 9C2, associated with anti-Aah II mAb 4C1, provides a valuable tool to neutralise the toxicity of the venom. (+info)
Combining phage display and molecular modeling to map the epitope of a neutralizing antitoxin antibody.
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Crotoxin is a potent presynaptic neurotoxin from the venom of the rattlesnake Crotalus durissus terrificus. It is composed of the noncovalent and synergistic association of a weakly toxic phospholipase A2, CB, and a nontoxic three-chain subunit, CA, which increases the lethal potency of CB. The A-56.36 mAb is able to dissociate the crotoxin complex by binding to the CA subunit, thereby neutralizing its toxicity. Because A-56.36 and CB show sequence homology and both compete for binding to CA, we postulated that A-56.36 and CB had overlapping binding sites on CA. By screening random phage-displayed libraries with the mAb, phagotopes bearing the (D/S)GY(A/G) or AAXI consensus motifs were selected. They all bound A-56.36 in ELISA and competed with CA for mAb binding, although with different reactivities. When mice were immunized with the selected clones, polyclonal sera reacting with CA were induced. Interestingly, the raised antibodies retained the crotoxin-dissociating effect of A-56.36, suggesting that the selected peptides may be used to produce neutralizing antibodies. By combining these data with the molecular modeling of CA, it appeared that the functional epitope of A-56.36 on CA was conformational, one subregion being discontinuous and corresponding to the first family of peptides, the other subregion being continuous and composed of amino acids of the second family. Phage-displayed peptides corresponding to fragments of the two identified regions on CA reacted with A-56.36 and with CB. Our data support the hypothesis that A-56.36 and CB interact with common regions of CA, and highlight residues which are likely to be critical for CA-CB complex formation. (+info)