Publisher Summary

This chapter discusses the immunological basis of anaphylaxis in tissues of a particular experimental animal species. Each species responds to anaphylactic shock with a syndrome derived from an immunological response common to all, but in which the final manifestations have certain features that are species specific. This involves determining the relative involvement of reactions of antigen with fixed tissue antibody and the reactions between antigen and antibody circulating in the blood. In the dog, anaphylaxis causes the release of histamine and heparin from the liver and possibly bradykinin from plasma. In the rabbit, anaphylaxis is a blood rather than a tissue phenomenon. It is accompanied by the release of histamine, serotonin, and an unidentified anticoagulant. In the guinea pig, lung anaphylaxis causes the release of histamine, SRS-A, and an unidentified anticoagulant as well as traces of serotonin. In the rat, the chemical mediators of anaphylaxis are unknown, but histamine and serotonin are probably not involved. In the mouse, it is likely but not yet conclusively established that serotonin is a chemical mediator of anaphylaxis in the whole animal and also the anaphylactic contraction of uterus.

Anaphylaxis in the dog

Anaphylaxis was discovered by Portier and Richet in dogs receiving sub-lethal doses of a glycerin extract of a certain species of sea anemone.1 Animals survived a small sub-lethal dose of the extract, but if the same dose was repeated three weeks to a month afterwards the animals became severely ill and died. The symptoms were described as severe prostration, emesis, and bloody diarrhœa. Since it appeared to Richet that he had induced a condition which was the reverse of immunity he invented the term “anaphylaxis” to describe it.

Later on, largely as a result of the work of Arthus2 it was shown that Richet’s phenomenon could be developed in the dog when the injected material was a non-toxic protein-like serum protein or egg albumin, and that the resulting hypersensitivity could be explained on an immunological basis involving the formation of antibodies.

It became rapidly established that the main physiological effect of anaphylaxis in the dog was a steep fall in systemic blood pressure.3 Other workers showed that exclusion of the abdominal organs by ligatures of the thoracic aorta and inferior vena cava just above the diaphragm could prevent shock, while ligatures on the stomach, intestines, kidneys, adrenals or spleen had no protective action.4 Stagnation of blood in the liver and portal circulation and reduction in spleen and, kidney volume were reported.5 It was also shown that anaphylactic shock could be prevented if the liver is excluded from the circulation by an Eck fistula.6, 7 Weil8, 9, 10 made extensive studies of the liver as the shock organ and concluded that the stagnation of blood in the liver and hepatic portal circulation was quantitative enough to explain the fall in blood pressure. In one of his experiments he discovered that 61·5 per cent of the total circulating blood had been retained by the liver. He described the liver of the dog in anaphylactic shock as tremendously swollen and cyanotic. When sectioned he noted that the cut surfaces bled profusely. In his opinion the gastro-intestinal symptoms described by Richet were secondary features resulting from stagnation of blood in the hepatic circulation.

During the next decade further interesting facts about anaphylaxis in the dog continued to appear in the literature. Marked reductions in the number of leucocytes (leukopenia) and platelets (thrombocytopenia) circulating in the blood were described.11 Mainwaring and his colleagues12 transfused the liver of sensitised dog from the circulation of either a normal or eviscerated dog. They were able to demonstrate a fall in systemic blood pressure and rise in intracystic pressure following injection of antigen. They also demonstrated the release from sensitised liver by antigen of a chemical substance with hypotensive and smooth muscle stimulating properties.

It was in 1932 that Dragstedt and Gebaur-Fulnegg found that the thoracic duct lymph of a dog subjected to anaphylactic shock contained a smooth muscle stimulating substance, which they could not distinguish from histamine.13 This substance was stable to boiling in acid, was inactivated by coupling with diazotised sulphanilic acid and exhibited the same pharmacological actions as histamine upon isolated guinea pig ileum and cat blood pressure preparations. Later, Dragstedt and Mead14 recovered the same substance from the circulation immediately after antigen injection and were able to show that its pharmacological actions were destroyed by histaminase. These findings were later confirmed,15 when it was also shown that histamine is an extremely diffusable substance. The concentration of released histamine should be calculated not upon the circulating blood volume of the dog (15 per cent of its body weight) but on its total body fluids (67 to 70 per cent of its body weight). This rapid disappearance of histamine out of the circulation provided an explanation for the earlier but unsuccessful experiments of Weil,10 who had attempted to establish the existence of a chemical mediator of anaphylaxis by transfusing into a normal dog, a large volume of blood taken from a second dog which had died in anaphylaxis.

Evidence for the discharge of histamine from dog liver in anaphylactic shock was presented by Ojers, Holmes and Dragstedt in 1941.16 Before the antigen was injected (in this case horse serum) a piece of liver was removed, washed in saline, blotted dry and weighed. It was then extracted for histamine. Twenty minutes after antigen administration a second piece of liver was removed and similarly treated. The paired histamine estimations showed considerable reductions as a result of anaphylaxis. In one experiment the histamine content of a liver fell from 60 to 6 micrograms per gram of tissue. This was equivalent to an overall liberation into the circulation from the liver of 2·3 mg. of histamine base.

The mechanism by which such large amounts of histamine are released in dog liver was derived from an analysis of other features of anaphylactic shock in this species. One characteristic feature of anaphylaxis in the dog is an increase in the clotting time. This was noted by early workers2, 3 but it was not until 1925 that Howell17 suggested it might be due to heparin release. Other workers demonstrated a deficiency in fibrinogen, platelets, and prothrombin as a cause of the incoagulability18 and the dependence of the effect on heparin release.19 Finally in 1941, Jacques and Waters isolated heparin in a crystallisable form from the blood of dogs subjected to anaphylactic shock. Its origin was the mast cells in the connective tissue of the liver: a fact which assumed great importance some 11 years later when Riley and West provided the first evidence that mast cell granules contain both heparin and histamine.21

The degranulation of mast cells in the liver of the dog undergoing anaphylactic shock has been confirmed and it is often inferred that the degranulated or disrupted mast cells are the source of the histamine released. Akasu and West167 have recently reported an extensive study of mast cell changes during anaphylaxis in the dog. The histamine and serotonin (5-hydroxytryptamine 5HT) contents of a large number of dog tissues were compared with their mast cell content. Whereas the liver contains many mast cells and much histamine and serotonin, it was discovered that the skin and ears contain many mast cells and much histamine but are deficient in serotonin. Histamine liberators like compound 48/80 and tubocurarine administered intravenously caused mast cell damage in the skin and ears but much less damage to mast cells in the liver. When anaphylactic shock was induced, extensive mast cell damage occurred in the liver, but there was little or no histamine release in the skin and ears and negligible mast cell damage. Dogs which were sensitised to two antigens were simultaneously desensitised to both by a challenge dose of one of them. This suggests that both types of antibody are held at the same site. Administering a chemical liberator immediately before antigen injection caused the expected release of histamine and mast cell damage in the skin and ears and liver.

A subsequent dose of antigen then had no effect, suggesting the prior...