210 THE PRINCIPLES OF IMMUNOLOGY 



condition the opposite of prophylaxis they named it anaphylaxis. As 

 a result of the reports of accidents following the use of diphtheria 

 antitoxin, Rosenau and Anderson investigated the problem experi- 

 mentally and found that the danger lies in the serum rather than in its 

 content of antitoxin. They demonstrated that the reaction is specific 

 for the protein employed, that the period of " incubation " is about six 

 days and that once established the sensitive state persists for many 

 months with but slight reduction in intensity. In the same year, 1906, 

 Otto entirely independently published similar findings in Ehrlich's 

 laboratory as the result of an interview between Ehrlich and Theobald 

 Smith. Smith had noted that animals used for the titration of diph- 

 theria antitoxin were subsequently extremely sensitive to horse serum. 

 Otto, accordingly, employed the name Theobald Smith phenomenon. 

 Of somewhat similar significance, but for the time without the same 

 direct application to medicine, were the investigations of Arthus, who 

 in 1903 published a study in which he showed that if repeated sub- 

 cutaneous injections of protein are given, the fourth and subsequent 

 injections may lead to severe local reactions which may go on to 

 gangrene. If a later injection is given intravenously death may result. 

 Arthus also recognized the specificity of the reaction. The year 1906 

 marked the beginning of a period of widespread investigation 

 of anaphylaxis. Much has been learned in regard to the mechanism 

 of the process, but the fundamental principles are still in the form 

 of hypotheses. 



The Sensitization. The substances necessary for the demonstra- 

 tion of anaphylaxis are proteins. These need not contain all the amino- 

 acids, for Wells has shown that certain vegetable proteins, zein, hordein, 

 gliadin, lacking " one or more such amino-acids as glycocoll, tryptophane 

 or leucine produce typical reactions " and Abderhalden claims to have 

 demonstrated anaphylaxis with a compound polypeptid made up of four- 

 teen amino-acid molecules, which include only two of the amino-acids, 

 leucine and glycocoll. The sensitizing substance is extremely thermo- 

 resistant. Wells finds that proteins such as casein and ovo-mucin 

 which are not heat coagulable are active after heating to 100 C. and 

 Besredka has found that if a coagulable protein is so diluted as to 

 prevent coagulation it withstands temperatures up to 120 C. Rosenau 

 and Anderson found that if the protein be in the dry state it may be 

 heated to 170 C. for ten minutes and upon re-solution will serve for 

 the production of anaphylaxis. Heat or chemical agents which render 

 the protein insoluble destroy its sensitizing properties. Trypsin diges- 

 tion has the same effect. Gay and Adler reported that upon frac- 

 tioning serum with ammonium sulphate the euglobulin contains the 

 sensitizing substance, but not that substance which intoxicates at the sec- 

 ond injection. Kato, however, finds that the globulins possess the largest 

 content of both sensitizing and intoxicating substances. Bogolomez 

 and subsequently Meyer claimed that anaphylaxis could be produced 

 with lipoids but this has failed of confirmation in the hands of Wilson 

 and of White and others ; it is not generally accepted. The chief dif- 



