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[The kinetics of vaccine antibodies against tetanus toxoid, diphtheria toxoid, measles virus, poliomyelitis virus and pneumococcus after allogeneic and autologous bone marrow transplantation and revaccination. 3: The kinetics of vaccine antibodies against tetanus toxoid and diphtheria toxoid after allogeneic and autologous bone marrow transplantation and combined revaccination against diphtheria and tetanus].

The 3rd part of the paper deals with the results of a combined revaccination against diphtheria and tetanus in a group of 25 children after allogeneic bone marrow transplantation (BMT) with and without graft versus host disease (GvHD) and after autologous transplantation. It can be shown that in the allogeneic transplanted groups with and without GvHD it is possible to build up a tetanus and diphtheria antitoxin titre in a safe protective cause by a 2nd basic immunisation consisting of 3 single vaccinations starting about 9 to 12 months later. For autologous transplanted children only 1 to 2 vaccinations at a later term than for the allogeneic transplanted children may possibly be sufficient.

Bone Marrow Transplantation

[The microbiological cancer test--further studies with experimental mouse tumor tetanus and wound tetanus].

A re-evaluation of the specificity of the tumour-tetanus assay of the mouse was performed by analysing the wound-tetanus assay under comparable test conditions. This was achieved by injecting 1 X 10(6) viable Ehrlich carcinoma cells admixed with 1 X 10(2) tetanus spores subcutaneously, in a 0.1 ml dose volume or, 1 X 10(2) tetanus spores suspended in 5% CaCl2 solution, respectively. By comparison, these two groups of mice developed about the same tetanus mortality rates, however, following tetanus antitoxin therapy with 3 doses of 100 IU each day on days 0, 4 and 7 after infection, clinical signs of late tetanus exclusively belonged to tumour bearing animals. This typical tetanus behaviour may be explained by a spatial-temporal association between growing tetanus rods and proliferating cells of warm-blooded animals. In this manner tumour tissue can be differed from wound granulomatous tissue by way of permanently cloning stem cells.

Animals

Affinity chromatography of tetanus toxin, tetanus toxoid, and botulinum A toxin on synaptosomes, and differentiation of their acceptors.

125I-labelled tetanus toxin and 125I-labelled botulinum A neurotoxin are known to be specifically bound to brain synapotosomes. In order to discriminate between active toxin and inactive admixtures present in the starting material or arising during iodination, synaptosome columns were prepared using bromacetylcellulose and/or kieselgur (Celite) as carriers. Both types of columns absorb the toxins from low ionic strength medium and release them if the pH and ionic strength are raised. Botulinum toxin was eluted with lower ionic strength than tetanus toxin, and could be freed from nontoxic admixtures. Analysis by affinity chromatography disclosed partially toxoided tetanus toxin in both labelled and unlabelled toxin samples. High concentrations of formaldehyde (0.5%) destroyed both toxicity and affinity to the synaptosomes of tetanus toxin. Low concentrations of formaldehyde (0.05%) yielded a derivative of low toxicity which was still however less firmly, bound to synaptosomes. Tetanus and botulinum toxin differ by their acceptors. Whereas unlabelled botulinum toxin is unable to compete with labelled tetanus toxin, unlabelled tetanus toxin slightly competes with botulinum toxin. Both labelled toxins display anomalous binding behavior in that they cannot be displaced completely even with a large excess of unlabelled toxin.

Affinity Labels

Tetanus toxin induced actions on spinal Renshaw cells and Ia-inhibitory interneurones during development of local tetanus in the cat.

In anaesthetized cats the activities of Renshaw cells (RCs) and Ia-inhibitory interneurones (IaINs) were recorded during the accumulation of tetanus toxin in the spinal cord following injection into the gastrocnemius muscle. The early response of the RCs increased during the period of development of local tetanus. With some cells there was a subsequent decrease in the early response in later periods of the observation time (16-44 hrs after intramuscular injection). The effects on the spontaneous activity of the RCs were in good correspondence to those on the early response. The hyperactivity of the RCs is proposed to be mediated mainly via disinhibited cholinergic gamma-motoneurones using muscarinic postsynaptic receptors. The "pause" which follows the early response and the recurrent inhibition of IaINs was not reduced during the development of local tetanus. These results indicate that the central action of tetanus toxin in local tetanus does not consist of a general loss of postsynaptic inhibition. It is suggested that tetanus toxin acts mainly on synaptic elements of the alpha- and gamma-motoneurones or on presynaptic nerve terminals in their vicinity. In later periods of disturbing influence on the cholinergic transmission at Renshaw cells seems to occur.

Animals

Active immunization against tetanus in guinea-pigs. An attempt to evaluate "rapid immunization" with tetanus vaccine.

The effect of 3 schedules for tetanus vaccination on the immunity developed by guinea-pigs was investigated, using 1.5 Lf adsorbed tetanus toxoid injected subcutaneously. The following injection schedules were used: a) 5 injections: initially and after 3, 7, 10, and 13 days; b) 3 injections:: initially and after 2 and 4 weeks; c) 2 injections: initially and after 4 weeks. Blood samples were taken after 1, 2, 3, 4, 6, and 8 weeks and the titres of tetanus antitoxin were recorded. No significant difference in the titres was observed within 2 weeks. Immunity was also tested by challenge with different amounts of tetanus toxin after 1 week, 10 days, 2, 3, and 8 weeks. A tendency to a higher immunity with schedule a) was observed after 10 days to 2 weeks; thereafter no acceleration of immunity could be shown. The results indicate that frequent injections over a short period of time do not establish rapid immunity against tetanus.

Animals

Active immunization against tetanus in man. III. Antibody response to vaccine injections in the presence of therapeutic doses of human tetanus immune globulin. a record of five cases.

The tetanus antitoxin titres of five tetanus cases treated with 6,000-45,000 IU of human immune globulin and 2-4 doses of adsorbed tetanus toxoid were followed during 1 year. A typical response to the second injection of toxoid might be masked by the passively administered antibodies. The rise in titre after the third injection of toxoid was of the same magnitude as in patients receiving only active immunization. Hence the possible impediment by large doses of human immune globulin does not seem to play any practical role in complete immunization with three doses of tetanus toxoid.

Adolescent

[Changes in anti-tetanus antibodies under sero-toxoid therapy. Study in 50 patients with tetanus].

A study concerning changes in anti-tetanus antibody (ATA) levels in 50 patients with tetanus following the injection of antitetanic serum of equine origin and of toxoid, the first dose of the latter being given 24 hours after the administration of serum and the others at intervals of 5 to 7, 15 and 30 days. Repeated estimation of ATA demonstrated, regardless of the toxoid dose protocol adopted, that levels did not reach 0.1 IU/ml on the 30th day and that they only rose late. By contrast, after a booster, the increase was the same as that seen in subjects who had not acquired tetanus. The various factors which may underly defective active immunisation during the acute phase of tetanus are discussed. Heterologue serum therapy, which has been held responsible, cannot be considered to be a responsible factor since patients who did not receive serum behaved in exactly the same way as those who had. By virtue of this "gap" in the acquisition of immunity, the use of heterologue serum is recommended to neutralise any remaining circulating toxin as rapidly as possible.

Age Factors

Active immunization against tetanus in man. II. Combined active and passive prophylaxis with human tetanus immune globulin.

19 Persons were actively immunized with adsorbed tetanus toxoid and were simultaneously given tetanus immune globulin of human origin, TIG(H), in doses of 500-1500 IU. Their antitoxin titres were followed for 1 year. Seven persons were given only TIG(H), 500 IU and 1500 IU and their antitoxin titres were followed for 3 months to 1 year. For comparison, 30 military recruits were actively immunized with adsorbed tetanus toxiod according to common practice. Their antitoxin titres were followed for 1 year. The response to complete active immunization could not be demonstrated to be impaired by passive immunization, when 500 IU or 1500 IU OF TIG(H) were given simultaneously with toxoid. The titres were in accordance with those achieved by active immunization of the recruits.

Adult

Effect of fragmentation of tetanus immune globulin (human) on neutralization of tetanus toxin.

The effect of fragmentation produced by plasmin digestion of tetanus immune globulin (human) on the neutralization of tetanus toxin was determined. Based on a mouse test, there was a significant reduction in neutralizing potency when fragmentation to 3.5 S material reached or exceeded 20% suggesting a threshold for antibody fragmentation beyond which the resulting decrease in antibody potency would result in serious disease. Because this threshold is not known for man, the use of fragmented globulin for the prevention or treatment of tetanus should be avoided until additional data are available on its neutralizing potency and efficacy.

Animals

Treatment of tetanus in the horse by injections of tetanus antitoxin into the subarachnoid space.

In 40 horses with tetanus, large doses of tetanus antitoxin (TAT) were injected into the subarachnoid space. In all the horses that recovered, the disease stabilized immediately after the injection. The results (77.5% recovery) were much better than in a previous series of horses with tetanus (50% recovery), in which TAT was injected either intravenously, intramuscularly, or in the epidural space.

Animals

[Immune status after tetanus vaccination. Possibilities and indications for a quantitative rapid determination of tetanus antibodies in human serum].

Active and passive immunization against tetanus is one of the most used vaccination procedures in our population. Detection of size and duration of protection till now failed due to expensive methods. Counter-Immuno-Electrophoresis (CIE) is presented as a simple and non-expensive method with adequate sensitivity, and allows to obtain data concerning immunity of tetanus-immunized persons in almost any case. Rarely positive results as to antitoxin level are obtainable only by more sensitive methods. Further detection methods, and examinations of tetanus-immunity of "problem patients" showing immunofailure and of collectives immunized on various schedules will be reported later.

Child

The estimation of the survival rate of tetanus-intoxicated mice. A model for screening anti-tetanus drugs.

The estimation of the survival rate of tetanus-intoxicated mice is suggested to be a useful animal model for assaying the anti-tetanus potency of drugs. This model was tested with the four central depressants phenobarbitone, chlorpromazine, diazepam and halothane. In agreement with their clinical value, diazepam appeared to be the most, phenobarbitone the least effective agent.

Animals

[Kinetics of vaccine antibodies to tetanus toxoid, diphtheria toxoid, measles virus, poliomyelitis virus and pneumococci after allogenic and autologous bone marrow transplantation and booster immunization. 1: The kinetics of vaccine antibodies to tetanus toxoid after allogenic and autologous bone marrow transplantation].

Today BMT belongs to the established methods of treatment in haematology and oncology. Because of the constant increase of healthy long-term survivors after BMT the problem of immunological reconstitution and eventual possible late effects gets more and more importance. One problem, which til now has been few attention paid to, is that of the protection by vaccination after BMT. We report on the kinetics of the tetanus-antitoxin in 20 patients after allogeneic or autologous BMT and demonstrate the influence of a graft-versus-host disease and its therapy on the antibody kinetics. In the group of allogeneic transplanted children without a GvHD the tetanus-antitoxin titers felt below their detection range after a time of about 8 months whereas in the group with GvHD this effect already occurred after nearly 4 months. The autologous transplanted patients have a positive antibody level til the time of 20 months after BMT. As a consequence of the lost protection by vaccination after BMT follows the necessity of revaccinations respectively of boostering after immunological reconstitution.

Adolescent

Intraaxonal and extraaxonal transport of 125I-tetanus toxin in early local tetanus.

The distribution of radioactivity in the sciatic nerve, the spinal ganglia, the ventral roots and the spinal cord was studied by means of histoautoradiography after injection of 125I-labelled tetanus toxin into gastrocnemius muscles of cats. In the sciatic nerve the major part of the radioactivity was found in the epineurium, but some axons also contained radioactivity. In the ventral root the radioactivity was strictly confined to a few axons; no radioactivity was found in other parts of the ventral root. In the spinal cord the radioactivity was confined to a few motoneurones where it was found in the soma as well as in the dendrites. Transient cooling of the ventral roots prevented the ascent of radioactivity into the spinal cord. Colchicine and vinblastine, after local application to the sciatic nerve, reduced the amount of radioactivity found in the ventral roots and in the spinal cord. However, the same effect was also obtained but to a lesser degree with lumicolchicine. It is concluded that the intraaxonal compartment is involved in the neural ascent of tetanus toxin into the spinal cord.

Animals

Anti-tetanus toxoid antibodies in intravenous gamma globulin: an alternative to tetanus immune globulin.

The levels of anti-tetanus toxoid IgG antibodies were measured in 29 lots of intravenous gamma globulin (IVIG). The antibody levels varied from 4 to 90 IU/mL (geometric mean, 18.6; 90% confidence interval, 9.7-35.7). The variation from manufacturer to manufacturer accounted for most of the observed differences among lots; there was relatively little variability among multiple lots from a single manufacturer. IVIG may be an acceptable alternative to horse or human tetanus immune globulin.

Antibodies, Bacterial

Safety and immunogenicity of acellular pertussis vaccine, combined with diphtheria and tetanus as the Japanese commercial Takeda vaccine, compared with the Takeda acellular pertussis component combined with Lederle's diphtheria and tetanus toxoids in two-, four- and six-month-old infants.

A double blind, randomized, controlled trial compared the safety and immunogenicity of an acellular pertussis vaccine formulated at Lederle using the Takeda acellular pertussis component combined with Lederle diphtheria and tetanus toxoids vaccines (APDT), with the commercially available Japanese Takeda vaccine (APDT-T/J) as a three-dose series to 2-, 4-, and 6-month-old children. Sera were analyzed for antibody to pertussis antigens: lymphocytosis-promoting factor; filamentous hemagglutinin; 69-kDa outer membrane protein; pertussis agglutinogens; neutralizing antibodies to LPF; and to diphtheria and tetanus toxoids. Information concerning local reactions and systemic events were collected daily for 10 days postimmunization. The overall reaction rate was low for both groups. There were no reactions that contraindicated subsequent vaccine and no serious adverse events. For local reactions statistically significant differences between the groups were seen only for a greater incidence of induration in the APDT group at 2 months (12% vs. 0%, P < 0.01), and at 4 months (8% vs. 0%, P = 0.4) compared to the APDT-T/J group. Of the few systemic reactions the only statistically significant difference between the vaccine groups was a greater incidence of fretfulness in the APDT group after the initial immunization (12% vs. 2%, P = 0.05). There were no statistically significant differences in the immune response between the two vaccines at the 7-month visit. We conclude that APDT is equivalent to the commercially available Takeda vaccine (APDT-T/J).

Antibodies, Bacterial

Structure of tetanus toxin. Demonstration and separation of a specific enzyme converting intracellular tetanus toxin to the extracellular form.

Protease activity has been demonstrated in culture supernatants of Clostridium tetani at various stages of fermentation. Gel chromatography of the concentrated filtrates revealed the presence of three enzymatically active fractions eluting at separate positions off the column. The smallest protease was found to "nick" the single chain intracellular tetanus toxin, producing the extracellular, two-chain structure of the molecule. As little as 3 ng of active protease were sufficient to cleave 50 microgram of intracellular tetanus toxin, suggesting that this enzyme is responsible for the observed structural change of the toxin molecule during its release into the culture medium. By comparison, the second protease, eluting at an intermediate position, exhibited only marginal activity towards intracellular toxin. The third, largest, enzyme was not active under the conditions of the assay. However, the latter protease effectively hydrolyzed low molecular weight histidyl peptides, and it is concluded that this enzyme is similar to the one described by Miller, P.A. Gray, C.T., and Eaton, M.D. (1960) J. Bacteriol. 79, 95-102. The properties of the partially purified enzymes, including their differential behavior towards a number of protease inhibitors, are reported.

Clostridium tetani