134 ANAPHYLAXIS, ALLERGY OR HYPERSENSITIVENESS 
alien for the blood/ is without visible effect upon the animal, but 
leads to its sensitization to the specific protein. The sensitizing 
agent is variously referred to as a sensitizer, sensibilisinogen , or ana- 
phylactogen, and may be effective in very small doses. Rosenau 
and Anderson- were able to sensitize guinea-pigs with one-millionth 
of a cubic centimeter of horse serum; Wells'* has sensitized the same 
animal with one-twenty-millionth of a gram of crystallized egg albu- 
men. Usually 0.001 to 0.1 cc. of serum given intraperitoneally, is an 
effective sensitizing dose. In general, anaphylactogens are always 
proteins; those which are deficient in aromatic amino-acids will not 
sensitize. Proteins deficient in non-aromatic amino-acids, on the 
contrary, usually induce sensitization. It is essential that the ana- 
plylactogen be soluble and injected without previous denaturization. 
Coagulable proteins, consequently, rendered insoluble by heat or 
otherwise, do not sensitize. In this connection, the "racemized egg 
albumen," prepared by Dakin, and found to be without anaphy lacto- 
genic properties by Ten Broeck'* is of significance. 
A latent period intervenes between the initial injection of the 
animal with the sensitizing protein and the development of the state of 
sensitization. On the average, this is about ten to fourteen days. 
Gay and Southard^ showed, however, that the time necessary to 
effect sensitization depends somewhat upon the size of the sensitizing 
dose, larger amounts requiring longer periods than small amounts. 
White and Avery '^ have found that an approximate relation exists 
between the minimum sensitizing and the maximum intoxicating dose, 
larger amounts of protein being required on reinjection to elicit a 
reaction when the sensitizing dose is very small, and vice versa. Sensi- 
tization once established may persist for a very long time. Rosenau 
and Anderson^ found guinea-pigs sensitive to a single injection of horse 
serum after two years. 
Reinjection of the Homologous Protein.— Repeated injections of the 
homologous protein spaced at intervals less than ten days do not, 
as a rule, cause symptoms of acute anaphylaxis— after a third or a 
fourth injection, however, there frequently appears at the site of the 
first injection, and then succeeding injection sites, a swelling, usually 
indurated and more or less edematous, which may lead to extensive 
necrosis and sloughing. These local reactions, the so-called Arthus^ 
phenomenon, are closely related phylogenetically to the anaphylactic 
symptoms described below. 
If the second parenteral injection is made after sensitization is 
established— usually after ten to fourteen days— symptoms follow 
1 In general, blood-alien proteins are more effective anaphylactogens than tissue- 
alien proteins. 
2 Bull. No. 29, 1906, and No. 36, 1907, Hygienic Laboratory, Washington, D. C. 
3 Clinical Pathology, 2d ed, 1914, p. 180. ■> Jour Biol. Chem., 1914, 17, 369. 
6 Jour. Med. Res., 1908, 18, 407. " Jour. Infec. Dis., 1913, 13, 103. 
7 Bull. No. 50, 1909, Hygienic Laboratory. 
s Compt. rend. Soc. Biol., 1903, 55, 817; 1906, 60, 1143. 
