THE PHENOMENA OF ANTITOXIN FORMATION 6l 



ceptibility of the animal ; and when they have passed off a small 

 amount of antitoxin will be found in the blood, and the animal 

 will, as a rule, be found to be less susceptible to the action of the 

 toxin than before, so that the injection of the same dose will 

 produce less reaction, both local and general. 



This, however, is not always the case, and careful research 

 leads us to the belief that the appearance of immunity is preceded 

 by a period of hypey sensitiveness, in which the animal betrays a 

 greatly increased susceptibility to the action of the toxin, and this 

 in spite of the fact that it may contain quite large quantities of 

 antitoxin in its blood. Thus it happens not infrequently that 

 after a horse has passed successfully through the early stages 

 of immunization to diphtheria toxin, and has developed far more 

 antitoxin than is necessary to neutralize the doses of toxin with 

 which it is being treated, it yet will die after the injection of an 

 amount which it would appear must be immediately rendered inert 

 as soon as it came into contact with the plasma. Such cases have 

 been reported from the Pasteur Institute, Behring and Kitashima, 

 and others, and by Brieger for tetanus. In the latter an immunized 

 horse died after an injection of tetanus toxin with the typical 

 symptoms of tetanus intoxication, and after death its blood con- 

 tained much free antitoxin. The phenomenon has probably been 

 witnessed by most observers who have been engaged in the manu- 

 facture of antitoxin, though it has become much less frequent since 

 the introduction of modern methods for the early treatment of 

 animals. It is an exceedingly puzzling one, and we shall leave 

 its further interpretation until later ; here it is sufficient to say 

 that Behring's theory of the occurrence of a stage in which the 

 tissues are hypersensitive to the toxin is well established. 



The difficulty of immunizing the small animals of the laboratory 

 to these toxins appears to depend in large measure on the marked 

 development of hypersensitiveness. Thus Behring and Kitashima 

 found that they could kill a guinea-pig with ^J^ of the " minimal 

 lethal dose" of tetanus toxin, if this amount were divided into 

 several doses and given at suitable intervals, and similar facts 

 have been recorded by others. 



The most striking proof of the occurrence of hypersensitiveness 

 in the process of immunization has been investigated by Behring, 

 who pointed out that normal horses show no local effects from the 

 injection of small quantities of tetanus toxin ; their connective 

 tissues are insusceptible to its action. As the animal becomes 



