In the earlier experiments on smaller animals the potency of the toxin was modified for the first injections, but in preparing antitoxin for therapeutical purposes the toxin is used in its unaltered condition, the horse being the animal usually employed.
Applies only to the bacterium or toxin used in its production.
Then we have the property of adaptation, in which the negative reaction may be changed into a positive; a given toxin may at first repel the cell, but by a gradual process the cell becomes accustomed to such a toxin and will move towards it.
By growing this bacillus in broth a toxin is formed which remains in solution and can be separated from the bacilli themselves by filtration.
Of such are tetanus and diphtheria, now known to be due to the establishment from without of a local microbic infection, from which focus a toxin is diffused to the nervous matter.
Though an enormous of amount of work has been done on the subject, no important bacterial toxin has as yet been obtained in a pure condition, and, though many of them are probably of proteid nature, even this cannot be asserted with absolute certainty.
It is probable that the kidneys also have an internal secretion, and that the great oedema sometimes found in kidney disease is rather due to the action of some proteid body resembling in its effects the streptococcus anti-toxin, than to accumulation of water due to imperfect action of the kidney.
Indirectly or physiologically; or it may act directly on the toxin, i.e.
This toxin-containing broth is injected into a horse in increasing doses, just as in the case of the serpent venom, and after the resistance of the horse has been much increased it is bled into sterilized vessels and the blood is allowed to coagulate.
The antitoxic serum when injected enttinoxic previously to the toxin also confers immunity (passive) against it; when injected after the toxin it has within certain limits a curative action, though in this case its dose requires to be large.
The unit of antitoxin in Ehrlich's new standard is the amount requisite to antagonize i oo times the minimum lethal dose of a particular toxin to a guinea-pig of 250 grm.
(a) The action of antitoxin on toxin, as tested by neutralization effects, takes place more quickly in concentrated than in weak solutions, and more quickly at a warm (within certain limits) than at a cold temperature.
Kanthack and Cobbett, that in certain instances the toxin can be made to pass through a gelatine membrane, whereas the antitoxin cannot, its molecules being of larger size.
In view of the fact that antitoxin has a direct action on toxin, we may say that theoretically this may take place in one of two ways.
It may produce a disintegration of the toxin molecule, or it may combine with it to produce a body whose combining affinities are satisfied.
His view as to the dual composition of the toxin molecule has already been mentioned, and it is evident that if the haptophorous or combining group has its affinity satisfied by union with antitoxin, the toxin will no longer combine with living cells, and will thus be rendered harmless.
One other important fact in support of what has been stated is that a toxin may have its toxic action diminished, and may still require the same amount of antitoxin as previously for neutralization.
There is, however,, still dispute with regard to the exact nature of the union of toxin and antitoxin.
This result, which is usually known now as the " Ehrlich phenomenon," was explained by him on the supposition that the " toxin " does not represent molecules which are all the same, but contains molecules of different degrees of combining affinity and of toxic action.
Arrhenius, who hold that the union of toxin and antitoxin is comparatively loose, and belongs to the classof reversible actions, being comparable in fact with the union of a weak acid and base.
If such were the condition there would always be a certain amount both of free toxin and of free antitoxin in the mixture, and in this case also considerably more than a dose of toxin would have to be added to a " neutral mixture " before the amount of free toxin was increased by a dose, that is, before the mixture became lethal.
Still another view, advocated by Bordet, is that the union of toxin and antitoxin is rather of physical than of strictly chemical nature, and represents an interaction of colloidal substances, a sort of molecular deposition by which the smaller toxin molecule becomes entangled in the larger molecule of antitoxin.
Toxins may thus become so closely keyed into their corresponding atom groups, as for instance in tetanus, that they are no longer free to combine with the antitoxin; or, again, an antitoxin injected before a toxin may anticipate it and, preventing its mischievous adhesion, dismiss it for excretion.
Immunity against toxins also became a subject of investigation, and the result was the discovery of the antitoxic action of the serum of animals immunized against tetanus toxin by E.
In recent years the relations of toxin and antitoxin, still obscure, have been the subject of much study and controversy.
So that when a " toxin " is spoken of, a mixture with other organic substances is usually implied.
A " dry toxin " is thus obtained, though still in an impure condition.
It has been found, for example, that a toxin may pass through such a filter while an antitoxin may not.
With regard to toxin formation the following general statements may be made.
Thus, to mention examples, diphtheria toxin produces inflammatory oedema which may be followed by necrosis; dead tubercle bacilli give rise to a tubercle-like nodule, &c. Furthermore, a bacillus may give rise to more than one toxic body, either as stages in one process of change or as distinct products.
Thus paralysis following diphtheria is in all probability due to a different toxin from that which causes the acute symptoms of poisoning or possibly to a modification of it sometimes formed in specially large amount.
Attempts to get a pure toxin by repeated precipitation and solution have resulted in the production of a whitish amorphous powder with highly toxic properties.
The question has, however, been raised whether the toxin is really itself a proteid, or whether it is not merely carried down with the precipitate.
There is of course the possibility in this case that the toxin was a proteid, but was in so small amount that it escaped detection.
These facts show the great difficulty of the problem, which is probably insoluble by present methods of analysis; the only test, in fact, for the existence of a toxin is its physiological effect.
According to this view, then, a part at least of the directly toxic substance is produced in the living body by enzymes present in the so-called toxin obtained from the bacterial culture.
It is also to be noted that, as in the case of poisons of known constitution, each toxin has a minimum lethal dose which is proportionate to the weight of the animal and which can be ascertained with a fair degree of accuracy.
It consists in all probability of disturbance, by means of the chemical affinities of the toxin, of the highly complicated molecules of living cells.
In other cases such changes cannot be detected, and the only evidence of their occurrence may be the associated symptoms. The very important work of Ehrlich on diphtheria toxin shows that in the molecule of toxin there are at least two chief atom groups - one, the " haptophorous," by which the toxin molecule is attached to the cell protoplasm; and the other the " toxophorous," which has a ferment-like action on the living molecule, producing a disturbance which results in the toxic symptoms. On this theory, susceptibility to a toxin will imply both a chemical affinity of certain tissues for the toxin molecule and also sensitiveness to its actions, and, furthermore, non-susceptibility may result from the absence of either of these two properties.
It is to be noted that there is no fixed relation between toxin production and bacterial multiplication in the body, some of the organisms most active as toxin producers having comparatively little power of invading the tissues.
Again, in certain cases the toxin has a special affinity for certain tissues.
In the development of toxin-immunity the doses, small at first, are gradually increased in successive inoculations; or, as in the case of very active toxins, the initial injections are made with toxin modified by heat or by the addition of various chemical substances.
The serum of the animal is tested from time to time against a known amount of toxin, i.e.
Weight, the indication that the toxin has been antagonized being that a fatal result does not follow within five days after the injection.
(b) Antitoxin acts more powerfully when injected along with the toxin than when injected at the same time in another part of the body; if its action were on the tissue-cells one would expect that the site of injection would be immaterial.
If, however, toxin be mixed with antitoxin for some time, it can no longer be passed through, presumably because it has become combined with the antitoxin.
He found, however, that if he took the largest amount of toxin which was just neutralized by a given amount of antitoxin, much more than a single dose of toxin had to be added before a single dose was left free.
We are probably safe in saying, however, that the molecules of a toxin are not identical but vary in the degree of their combining affinities, and also in their toxic action, and that, while in some cases the combination of anti-substances has been shown to be reversible, we are far from being able to say that this is a general law.
Its serum in course of time is found to contain something (antitoxin) which has the power of neutralizing the toxin secreted by the organism when parasitical upon the body.
But the evidence in favour of the view that tapeworms normally excrete toxin into the body of their host in such amount as to occasion disease is not generally accepted as conclusive.
Little is known of its toxic action; only a weak toxin has been obtained from cultures.
The serum is then removed and its anti-toxic power tested by ascertaining the amount necessary to counteract a given amount of active toxin in a guinea-pig of a certain size, the standard weight being three hundred grammes.
Yersin has prepared a serum from horses in the same way as diphtheria anti-toxin, and this is said to have a curative action during the attack.
In fact, a splitting appears to take place in the process of secretion somewhat resembling that which takes place in the formation of a toxin and anti-toxin.
We do not know at present if any corresponding anti-toxin or antitrypsin, as we may term it, is returned into the lymphatics or blood from the gland, but the pancreas, which in addition to secreting trypsin secretes a diastatic ferment forming sugar from starch, pours this into the intestine and secretes at the same time a glycolytic ferment which breaks up sugar, and this latter passes into the blood by way of the lymphatics.
Or the toxin may be precipitated with other organic substances, purified to a certain extent byre-solution, re-precipitation, &c., and desiccated.
It may also be mentioned that many toxins have now been obtained by growing the particular organism in a proteid-free medium, a fact which shows that if the toxin is a proteid it may be formed synthetically by the bacterium as well as by modification of proteid already present.
A third method is by injections of the separated toxins of a bacterium, the resulting immunity being not only against the toxin, but, so far as present knowledge shows, also against the living organism.
In order that the immunity may reach a high degree, either the bacterium in a very virulent state or a large dose of toxin must ultimately be used in the injections.
So far as bacterial immunity is concerned, the anti-serum exerts its action either on the toxin or on the bacterium itself; that is, its action is either antitoxic or anti-bacterial.
The term " antitoxic " signifies that serum has the power of neutralizing the action of the toxin, as is shown by mixing them together outside the body and then injecting them into an animal.
For example, if 'co doses of toxin were neutralized by a unit of antitoxin (v.
It may be stated that while in certain instances the union of toxin and antitoxin may be reversible, all the facts established cannot be explained on this simple hypothesis of reversible action.