MODE OF PRODUCTION OF ANTITOXINS 529 



should be noted in connection with this controversy that there are 

 two questions which may be independent of each other, namely, 

 (1) does the "toxin" in any particular case represent a single 

 substance or several 1 ? (2) What is the nature of the combination 

 of any one constituent substance and its anti-substance is it 

 reversible or is it not ? It may be said that it is practically 

 impossible to explain, the facts with regard to diphtheria toxin 

 on the hypothesis of a single substance, even if this should have 

 its combining and toxic actions equally weakened ; " toxoids " in 

 Ehrlich's sense must in our opinion be supposed. Then there is 

 an important fact established by Danysz and by v. Dungern, 

 namely that the amount of toxin neutralisable by a given amount 

 of antitoxin is different according as the toxin is added in several 

 moieties or all at once in the latter case the amount of toxin 

 neutralisable is greater. There seems no explanation of this 

 according to the view of Madsen and Arrhenius, as the same state 

 of equilibrium ought to be reached in the two cases, that is, the 

 amounts of toxin neutralised should be the same. 



An important t'ai-tnr in the union of toxin and antitoxin is 

 the time necessary for the union to be complete. Morgenroth 

 lias shown that in the case of diphtheria toxin this is considerable, 

 about twenty-four hours. Up to this time, mixtures of toxin 

 and antitoxin, \\hrn injected intravenously, show decreasing 

 degrees of toxicity according to the time they have kept. On 

 the other hand, when the subcutaneous method of injection is 

 used the time interval has no effect, and this he considers to be 

 due to a catalytic action of the tissues which accelerates the 

 union of the two substances. A striking phenomenon, which 

 apparently points to the reversibility of the combination, was 

 noted by Behring in the case of diphtheria toxin, and afterwards 

 studied l>y Madsen and by Otto and Sachs in the case of 

 botulismus toxin, namely, that when a mixture of toxin and 

 antitoxin was found to be neutral on injection, a fraction of the 

 mixture might produce toxic phenomena or even death. This 

 wa* apparently due to dissociation of the toxin in the greater 

 dilution, and in favour of this being the case Otto and Sachs 

 found that when the mixture was allowed to stand for twenty- 

 ton! 1 hours, so that combination was complete, the phenomenon 

 no longer occurred. It was shown by Morgenroth and by Muir 

 independently that the union of a hasinolytic immune-body with 

 tin- onvspondinu; red corpuscle was of reversible nature, and 

 tin- latter observer found that in this case the union was not 

 increased in iirnmess after twenty-four hours. There is little 

 doubt that there are varying degrees of firmness of union of an 



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