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Following our 1 demonstration that the giving off of toxic products by the liver is the physiologically dominant initial factor in canine anaphylaxis, we have begun a study of chemical changes in the canine liver during anaphylactic shock. Among other things, we have followed the changes in hepatic glycogen.NORMAL LIVERSThe normal canine liver has a fairly constant glycogen content. Stained by Best's carmin method, the parenchyma is usually seen to be fairly well filled with red granules. The granules are usually largest and most numerous in the central portions of the hepatic lobules. Occasionally a narrow peripheral zone is free from granules.Quantitative glycogen determinations were made by the official method adopted by the American Agricultural Chemists. From a 300 gm. normal canine liver, from 16 to 20 gm. of glycogen could usually be isolated by this method, after fifteen minutes' ether anesthesia.SHOCK LIVERSLivers were removed

In previous papers it was shown that characteristic anaphylactic contractions of the urinary bladder 1 and of the gastro-intestinal tract2 do not take place in dehepatized anaphylactic dogs. The conclusion was drawn that the typical anaphylactic contractions of these organs are due to chemical products (hepatic anaphylatoxins) explosively formed or liberated by the anaphylactic liver, products having a histamin-like effect on smooth muscles. We have obtained additional evidence in support of this conclusion by hepatic transplantation and blood transfusion tests.LIVER TRANPLANTATIONSAs a preliminary to transplantation experiments, it is shown that primary reactions between specific foreign protein and anaphylactic blood are in themselves insufficient to produce appreciable anaphylactic reactions in normal canine tissues. If a normal dog is exsanguinated as completely as possible and transfused from an anaphylactic donor, the dog will usually show no recordable anaphylactic reactions on immediate intravenous injection with specific foreign protein. This negative

In a previous paper 1 it was shown that a sharp contraction of the urinary bladder takes place during the first two minutes of typical canine anaphylactic shock. It was further shown that this characteristic bladder contraction does not take place in dehepatized anaphylactic dogs. The conclusion was drawn that the typical anaphylactic bladder contraction is due to chemical products (hepatic anaphylatoxins), explosively formed or liberated by the anaphylactic liver, products having a histamin-like effect on the urinary bladder. The present paper presents additional evidence of the existence of this anaphylactic hepatic internal secretion, based on a study of the effects of dehepatization on the anaphylactic reactions of the gastro-intestinal tract.GASTRO-INTESTINAL REACTIONS IN INTACT ANAPHYLACTIC DOGSTo demonstrate gastro-intestinal reactions, segments of the digestive tract were inflated with Ringer's solutions at a pressure of about 10 mm. of mercury. The pressure changes within these segments during anaphylactic shock were

To the Editor:—The following report from the Research Council is endorsed for publication by the Executive Council of the Association for the Study of Allergy.Ray M. Balyeat, M.D., Oklahoma City.Harry S. Bernton, M.D., Washington, D. C.William W. Duke, M.D., Kansas City, Mo.Richard A. Kern, M.D., Philadelphia.Albert H. Rowe, M.D., San Francisco.George Piness, M.D., Los Angeles, Chairman.Warren T. Vaughan, M.D., Richmond, Va.,Secretary.Antiallergic therapy is a carefully thought out and conscientious attempt to apply current immunologic theories to the prevention, alleviation and cure of hereditary and acquired hypersensitiveness and allied clinical conditions.Statistics show that no immunologic theory of the past three decades has been more than 5 per cent clinically efficient (Manwaring, W. H., and Krueger, A. P.: Laboratory-Endorsed Therapeutic Agents, The

Current serum diagnosis and serum therapy are based on the assumption that specific serum antibodies are chemically identical with the specific immune substances of the living body.Without this assumption, test tube reactions would be of questionable diagnostic interpretation and specific antiserums might be illogical prophylactic and therapeutic agents.The clinical success of certain antitoxins is evidence though not proof of the approximate identity of these antitoxins with their precursors in living tissues. But the failure of most other proposed antiserums suggests that this identity is not the universal rule. We have recently obtained experimental evidence in support of such nonidentity by a comparison of passive sensitization by cross-circulation, blood transfusion and serum transfer. PASSIVE SENSITIZATION BY CROSS-CIRCULATION AND BLOOD TRANSFUSION If a cross-circulation is made between a hypersensitive dog and a normal dog of approximately the same weight, and the blood of the two animals allowed to mix freely

The development of a rational theory as to the origin, nature and physiologic rôle of specific antibodies that will be a reliable and permanent guide to clinical diagnosis and biologic therapy can come only from detailed knowledge of the fate of antigens in the animal body. One must know, for example, the topographic distribution of different antigens in normal organs, tissues and body fluids, the modifications in distribution as influenced by dosage and portals of entry, and the modifications due to pathologic conditions and to previous and concurrent sensitization and immunization. Above all, it is necessary to know the successive chemical changes in each antigen in immunologically important organs, tissues and body fluids until its final destruction, elimination or incorporation in the body.Thus far, few attempts have been made to supply the necessary data. I have thought that it might be of value, therefore, to study the initial chemical

The liver is the first organ for which a function of internal secretion was predicted by Claude Bernard. Our knowledge of hepatic physiology is so scanty, however, that modern textbooks on endocrinology rarely mention the liver as a possible site of hormone formation. We have recently obtained experimental evidence that, at least under certain pathologic conditions, the liver forms or liberates internal chemical products markedly influencing the physiologic activity of other organs. We believe that these internal hepatic products are of clinical significance, and that they play a rôle in the action of therapeutic agents.Cannon,1 Asher 2 and others have obtained experimental evidence that internal hepatic products influence the activity of the myocardium. Our evidence of an internal hepatic secretion is based on a study of the effects of hepatic exclusion on the reactions of the urinary bladder in canine anaphylaxis.ANAPHYLACTIC REACTION IN THE URINARY BLADDERIn

An important unsolved problem in immunology is the identification of the organs or tissues responsible for the formation of immune hormones or antibodies. The identification of these tissues may conceivably lead to successful therapeutic methods in diseases in which the essential antibodies do not appear in the circulating blood in sufficient quantities for successful serum treatment.The identification of these tissues has been attempted by numerous workers. Various tissues have been removed surgically from experimental animals, or destroyed in these animals by physical or chemical agents, and the animal's power to produce antibodies has been compared with that of normal controls. No organ or tissue has thus far been found, however, whose removal or destruction will prevent the formation of antibodies, or reduce antibody formation sufficiently to warrant the conclusion that the organ or tissue in question is the essential or sole site of antibody formation.Since not all tissues

The experimental laboratory stands as the first buffer between suggested curative agents and their clinical application. A hundred instinctive "hunches" may be tested in order that three or four may be endorsed for clinical trial. Any therapeutic agent thus endorsed, however, now faces a second buffer, a mathematical law of clinical probability. For many suggested agents the mathematical probability for or against clinical success is readily calculated. CALCULATED PROBABILITY WITH VACCINES AND ANTISERUMS Three decades of clinical experience with laboratory-endorsed vaccines and antiserums give ample data from which to calculate the probability coefficient for this class of therapeutic agents. Hundreds of theoretically logical, laboratory-endorsed vaccines and antiserums have been tried by clinicians; 95 per cent of them have been thrown into the clinical discard.An impartial mathematician would conclude from this that our fundamental immunologic theories and current experimental laboratory methods assay less than 5 per cent clinically verifiable truth.

One of the debated questions in immunology is the relation of acquired hypersusceptibility to acquired immunity. Is hypersusceptibility an expression of an incompletely developed immunity, being possibly even a necessary integral part of the immunity mechanism? Or are the two processes wholly unrelated, independent expressions of toxic injury and bodily adaptation to foreign products?Among serologists, the debate has narrowed down to a question of the identity or nonidentity of the specific precipitin and the so-called specific sensitizing antibody. Several observers have noted that the power of a rabbit antiserum to produce passive sensitization in guinea-pigs varies with its precipitin titer. Others have noted that in rabbits active sensitization is synchronous with the appearance of a certain definite amount of precipitin in the serum. Many serologists therefore believe that the sensitizing antibody and precipitin are identical, and that small amounts of precipitin give hypersusceptibility, larger amounts conferring immunity.We have

Contrasted with our wealth of knowledge concerning changes in blood plasma and in tissue lymph during immunization, the almost total lack of knowledge concerning possible immunologic adaptations in fixed tissues is a striking fact. Nevertheless, there is reason to believe that immunologic adaptation of fixed tissues plays an important rôle in bodily resistance, the dominant rôle in the immunity against certain infectious disseases.1 Adequate knowledge of fixed tissue changes in immunity may in time give therapeutic methods as valuable as the methods that have thus far resulted from serum study.Practically the only physiologic studies so far made of immune tissues are a few tests of the reactions of isolated smooth muscle and isolated lungs of immune guinea-pigs. Perfused free from circulating antibodies, these tissues are apparently identical, physiologically, with anaphylactic tissues.2 This has led to the tentative generalization that bodily adaptations in immunity probably consist of the