ANAPHYLAXIS 409 



of normal sera would seem to depend upon a mechanism similar to 

 that of other anaphjlactic phenomena. 



Toxin Tiy per susceptibility, which is often acquired by animals 

 in the course of immunization with diphtheria and tetanus toxin, is 

 usually classified with anaphylaxis, indeed is often cited as the 

 earliest observation of this phenomenon. However, it is by no 

 means clear that the two conditions are actually analogous, since in 

 the case of the toxins we are dealing with antigens which are not only 

 toxic in themselves, but against which neutralizing antibodies are 

 formed in the reacting animal. This last fact alone would separate 

 toxin hypersusceptibility sharply from true protein-anaphylaxis in 

 that entirely different reacting-mechanisms seem to be called into 

 play by the two varieties of antigen. It will be necessary, therefore, 

 to discuss toxin hypersusceptibility at some length. 



Probably the earliest authentically recorded observation is that 

 of von Behring, 77 who determined, both for diphtheria and tetanus 

 toxins, that animals once inoculated with these poisons were oc- 

 casionally more sensitive to them subsequently than were normal 

 animals. He spoke of "Gift Ueber empfindlichkeit" as a property 

 acquired by reason of a preceding injection, and the observation was 

 further developed by Knorr 78 in 1895, and by v. Behring himself, 

 in collaboration with Kitashima 79 a few years later. These writers 

 showed that guinea pigs which are treated repeatedly with small 

 doses of diphtheria toxin may, under certain circumstances, not only 

 fail to show immunity, but may even develop a susceptibility in- 

 creased to such an extent that doses far too small to injure a normal 

 animal will cause their death. Again, in the case of diphtheria toxin 

 similar observations were made upon horses by both Salomonsen and 

 Madsen, 80 and by Kretz. 81 The last-named worker observed that 

 horses that had been immunized with diphtheria toxin would often 

 react to neutral mixtures of toxin and antitoxin by which normal 

 horses were unaffected. This so-called "paradox phenomenon' 7 was 

 much discussed, and many theories advanced to explain it, a most 

 ingenious adaptation of the side-chain theory being applied to it by 

 Kretz 82 and by Wassermann. 83 They assumed that the partial im- 

 munization in such treated animals had in truth induced the forma- 

 tion of excessive receptors; that, in the stages of hypersusceptibility, 

 however, these receptors had not yet been cast off from the cells. In 



77 Von Behring. Deutsche med. Woch., 1893. 



78 Knorr. Quoted from Otto, "Dissertation," Marburg-, 1895. 



79 Von Behring u. Kitashima. Berlin, klin. Woch., 1901. 



80 Salomonsen et Madsen. Ann. de I'Inst. Past., 1897. 



81 Kretz. Quoted from Otto in "Kolle u. Wassermann Handbueh," Er- 

 ganzungsband 2, p. 232. 



82 Kretz. Zeitschr. f. Heilkunde, 1902. 



83 Wassermann. "Kolle u. Wassermann Handbueh/'" Vol. 4, 479. 



