All the above-mentioned observations led to no special investigations as to their cause. In 1903, Arthus noticed abscess formation, necrosis and sloughing following several injections of horse serum in immediately adjacent parts of the skin in rabbits (“Arthus’ phenomenon”). Theobald Smith, in 1904, observed the death of guinea-pigs following properly spaced injections of horse serum. This subject was investigated by Otto and by Rosenau and Anderson in this country and about the same time von Pirquet and Schick were making a study of serum rashes mentioned above. The publications of these men led to a widespread study of the subject of injections of foreign proteins. It is now a well-established fact that the injection into an animal of a foreign protein--vegetable, animal or bacterial, simple or complex--followed by a second injection after a proper length of time leads to a series of symptoms indicating poisoning, which may be so severe as to cause the death of the animal. Richet’s term “anaphylaxis” has been applied to the condition of the animal following the first injection and indicates that it is in a condition of supersensitiveness for the protein in question. The animal is said to be “sensitized” for that protein.[25] The sensitization is specific since an animal injected with white of chicken’s egg reacts to a second injection of chicken’s egg only and not pigeon’s egg or blood serum or any other protein. The specific poisonous substance causing the symptoms has been called “anaphylotoxin” though what it is, is still a matter of investigation. It is evident that some sort of an antibody results from the first protein injected and that it is specific for its own antigen. A period of ten days is usually the minimum time that must elapse between the first and second injections in guinea-pigs in order that a reaction may result, though a large primary dose requires much longer. If the second injection is made within less time no effect follows, and after three or more injections at intervals of about one week the animal fails to react at all, it has become “immune” to the protein. Furthermore, after an animal has been sensitized by one injection and has reacted to a second, then, if it does not die from the reaction, it fails to react to subsequent injections. In this latter case it is said to be “antianaphylactic.”