212 THE PRINCIPLES OF IMMUNOLOGY 



marked in intravenous injection and exhibit decreasing severity in the 

 order named. Besredka estimates that by the use of serum, approxi- 

 mately equivalent reactions may be produced by intravenous injections 

 of 0.05 to o.i c.c., intrathecal injections of 0.066 to 0.125 c.c. and intra- 

 peritoneal injections of 5.0 to 6.0 c.c. Subcutaneous injections in experi- 

 mental animals rarely produce severe or fatal reactions. 



When used for the intoxicating dose the proteins are subject to the 

 same physical and chemical agents as have been discussed in connec- 

 tion with the sensitizing injection. The statement of Gay and Adler 

 that the sensitizing agent is contained in the globulin fraction of serum 

 and the intoxicating agent in the whole serum and albumin fractions 

 is not generally accepted and has recently been contradicted by Kato. 

 Kato found that guinea-pigs sensitized to any of the serum fractions 

 respond to intoxicating doses of any of the fractions but most strongly 

 to that fraction to which they were sensitized. The aging of serum 

 has an important influence. The toxicity of fresh serum decreases 

 rapidly during the first ten days of preservation to about half its 

 original power. A slight decrease occurs during the first two 

 months, after which the deterioration is extremely gradual. Besredka 

 has found that a serum twenty years old produced anaphylactic shock 

 in a sensitized animal. Uhlenhuth states that he has produced ana- 

 phylactic shock with proteins from mummies. 



The selection of the route of intoxicating injection depends on the 

 character of the protein; the intravenous route is undesirable with 

 solid proteins and even with bacteria because thrombosis and embolism 

 confuse the picture of anaphylaxis. The minimal intoxicating dose is 

 larger than the minimal sensitizing dose in the ratio of about 100 to i. 

 Wells has obtained fatal reactions with 0.000,001 gram crystallized 

 egg-white. Fatal reactions are rarely obtained with less than 0.025 c.c. 

 serum and, as a rule, 0.05 c.c. to o.i c.c. is required. We find that for 

 laboratory demonstrations the use of 0.05 c.c. serum given subcu- 

 taneously for sensitization and o.i c.c. fresh serum given intravenously 

 practically always produces fatal reactions. Of great importance is the 

 fact that there is considerable individual variation not only in the 

 sensitivity of the experimental animals but also in the sera employed 

 for experiments. Wells has stated that blood serum contains so many 

 substances that it is in reality an " extract of the animal " ; hence 

 variations such as are found in serum are not present in pure iso- 

 lated proteins. 



The Reaction. The phenomena of the reaction may be discussed 

 under three heads, the objective manifestations, the morbid anatomical 

 changes and the functional disturbances. The reaction may be imme- 

 diate or delayed, depending upon the sensitiveness of the animal, the 

 size and mode of administration of the toxic dose and the state of 

 deterioration of the intoxicating substance. The immediate reaction 

 is called anaphylactic shock. In the guinea-pig the objective manifesta- 

 tions include rubbing of the nose, ruffling of the fur, evacuation of 

 urine and feces, spasmodic movements of increasing severity, including 



