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Differences in the ultrastructure of basophils in the bone marrow reflect transition from early to late stages of cell development. Mast cells in the trachea, stomach and duodenum lack such developmental changes, but one cell encountered in mitosis indicates a low rate of replication by apparently mature cells. Mast cells differ from basophils in shape and in the structure, shape, and position of the nucleus. The Golgi complex clearly participates in granulogenesis in early basophils but not in late basophils or mast cells, and in mast cells appears associated with rough coated vesicles and mitochondria. In basophils precursor granules mature into a homogeneous granules population. The more numerous, smaller, rounder, granules of the mast cells differ also in varying widely in structure and not evidencing a clear maturational sequence. Increased density of mast cell granules apparently correlates with decreased size and increased indentation by a lucent focus and with the presence of lucent vacuoles in the cytoplasm. Laminated, crystal-like foci replacing the thread-like component in the periphery of some granules appear rigid and resist the indentation deforming the granule elsewhere. Mast cells of the adult differ from those of fetal guinea pigs in lacking the concentric lamination and having more dense granules. Many mast cells reveal several small, dense bodies which apparently constitute a second granule type, and often occupy the lucent indentation of the large granule.

Cromolyn (Lomudal, Intal, Aarane) plays an important role in the modern therapy of bronchial asthma. Its combination with a betastimulator activating the cyclic AMP of the mast cells, inhibiting their degranulation and developing an antiallergic activity directly on the bronchioles, leads to an optimal antianaphylactic synergy; indeed, Cromolyn inhibits the mast cells phosphodiesterase (which inactivates the cyclic AMP) and therefore protects the mast cell against the degranulation (like the betastimulators) and prevents synergistically the release of asthma mediators.

Adult Oesophagostomum columbianum populations were larger in sheep fed low-protein diets than in adequately fed animals. Diet did not influence the numbers of larva which became established in sheep. Sheep fed high-protein diets eliminated more worms and were more immunologically competent than poorly fed animals. More encapsulated larvae, showing arrested development, were found in adequately fed sheep than in those fed low-protein diets. Adult O. columbianum produced eggs at an earlier time after infection in poorly fed sheep than worms in well fed sheep. More eggs/female worm were produced in sheep on a low-protein diet compared with the number of eggs produced in well fed hosts over the last week of the infection. The effects of immunity on the behaviour of the worm in both host diet groups is discussed.There was a greater cellular proliferation in the intestines of infected adequately fed sheep than in infected animals on low-protein diets. These changes were most pronounced in the large intestine where the adult parasites were found. The macrophage-lymphocyte series of cells underwent hyperplasia in well fed animals but these changes were reduced, particularly among the plasma cells, in sheep fed low-protein diets. Increased mucin and mast cell counts were observed in sheep on high-protein, but not in hosts on low-protein diets: the intestinal populations of eosinophil and globule leucocytes were also reduced in poorly fed sheep.The relationship of these various cellular reactions and their effect on the protective immunity of sheep to O. columbianum is discussed. It was concluded that the increased susceptibility of protein deprived sheep to O. columbianum infections was associated with malfunctions of the innate immunity of the gut, involving decreased peristalsis and failure of the mucin cell response, and with reduction of the adaptive immune response which was reflected by impoverished lymphocyte and plasma cell reactions, and possibly with poor cooperation between sensitized lymphocytes, antibodies and the mast cell-granulocyte effector mechanisms in protective immunity.

Alpha-chymotrypsin (CT) was modified chemically and physically by the treatments with diisopropyl fluorophosphate, L-(l-tosylamide-2-phenyl) ethylchloro-mcthylkctone, hydrogen peroxide and heat. After these treatments, CT lost or decreased both the enzymic activity and ability of releasing histamine from rat mast cells. Ca++ was essential for histamine release by CT, while it enhanced only slightly the enzymic activity. Process of histamine release by CT could be separated into two stages: CT-dependent but not Ca++-dependent, and Ca++-dependent but not CT-dependent. The activated stale of mast cells produced by CT decayed rapidly at 37°C in the absense of Ca++, but these cells responded to Ca++ by adding CT once again, suggesting reconstitution of cell membrane structure affected by CT. Isoproterenol, epinephrine, prostaglandin E1, and dibutyryl-cyclic AMP (0.01–0.1 mM) did not inhibit release of histamine induced by CT. Neither theophylline (0.01–0.1 mM) alone nor the combinations of these cyclic AMP-active agents with theophylline inhibited the release of histamine. But, in the presence of papaverine (0.01–0.1 mM) a marked, dose-dependent inhibition was observed. These data suggest that 1) release of histamine by CT from rat mast cells is causally related to its hydrolytic activity, 2) this activity causes a reversible change on mast cell membrane which probably facilitates Ca++-influx through the cell membrane, and 3) there arc subtle differences among CT, compound 48/80 and antigens concerning the effect of cyclic AMP-active agents in histamine-releasing mechanisms in mast cells.

The domain of anaphylaxis in the atrium and oviduct is described and modeled. Mast cells are identified as the primary source of histamine in atrial and tubal anaphylaxis. The granules in the mast cells of these tissues carry ionically bound histamine which is readily released following the loss of granules from the cell. The extent to which histamine is released is shown to depend on the kinetics of sensitization and challenge. For any bulk phase concentration of antibody there is a single concentration of antigen which maximizes histamine release. A mechanism of mediator cell activation is proposed which is based on optimum stimulation of the mast cell membrane.

The present study has established, that cows suitably immunized with either DNP-edestin (DNP-Ed), di-DNP-gramicidin-J [(DNP)2-Gram], respectively, or p-azobenzenearsonate-Ed (ABA-Ed) synthesized and secreted reaginic antibodies (IgE) into colostrum. Whereas ABA-Ed failed to elicit more than a low response, there was however a persistent and increased antibody synthesis between 10 and 56 days after priming with DNP-Ed. Bivalent and multivalent DNP haptens differing in molecular size, degree of substitution, and rigidity were compared for their effectiveness in eliciting Prausnitz-Küstner (P-K) reactions in either newborn colostrum-deprived calves or in those 4 wk of age. The sensitization with reaginic anti-DNP antibody has been accomplished either by feeding colostrum of the immunized dam or by intradermal injection of reaginic serum or colostral whey. It could be demonstrated that equimolar doses of the bivalent α,N-(ϵ,N-DNP-aminocaproyl-)-ϵ,N-DNP-L-lysine and the multivalent dinitrophenylated bovine serum albumin were equally effective in eliciting reactions in skin sites provided that a high affinity antibody was used for sensitization. By contrast, the comparatively rigid, bivalent hapten, (DNP)2-Gram consistently failed to induce comparable reactions. Furthermore, it was clearly shown that optimal distances of determinant groups on the haptenic molecule are a prerequisite for positive P-K reactions, since α,ϵ,N-bis-DNP-lysine failed to induce comparable reactions. Concurrent sensitization of skin sites with reaginic anti-DNP and anti-ABA antibodies provides the final proof that cross-linking of two adjacent reaginic molecules on the mast cell surface by a bivalent hapten is required for effective elicitation of immediate-type reactions. This has been accomplished by utilizing the bivalent ϵ,N-DNP-α,N-[(4-hydroxy-3-azobenzenearsonic acid)-phenacetyl]-L-lysine (DNP-ABA) carrying noncross-reactive haptenic groups, which was consistently effective in eliciting P-K reactions in doubly but never in singly sensitized skin sites. It is apparent from the results that equimolar doses of monovalent haptens could completely inhibit the response to DNP-ABA. The present studies finally establish that mast cells of newborn colostrum-deprived calves lack IgE molecules on their surface. Thus, mast cells of newborn calves may be unique, to investigate the molecular mechanisms involved in immediate-type reactions more precisely.

We have used ferritin-conjugated divalent and monovalent anti-Ig antibodies to study simultaneously, histamine secretion and the ultrastructural distribution and redistribution of Ig receptors on rat peritoneal mast cells. We conclude that (a) divalent anti-Ig is required for both receptor redistribution and for calcium-dependent degranulation and histamine release, (b) divalent anti-Ig induces patching and pinocytosis but not capping of Ig molecules, (c) neither capping nor pinocytosis are required for triggering and if clustering is necessary, then less than 10 Ig molecules are required per cluster, and (d) degranulation (and histamine release) is not an all or none response of the mast cell.

1. 1. There are marked differences between mammalian species in the tissue distribution of heparin, histamine, mast cells, anaphylactic symptoms yet a surprising parallelism between these parameters. Heparin and sulfated mucopolysaccharides are responsible for the histological label of mast cells—metachromasia with toluidine blue. 2. 2. Heparin has now been shown to be a series of polymers of a hexasaccharide composed of two disaccharides of α1,4 linked 2 sulfoiduronic—2,6 disulfoglucosamine, and one of β1,4 linked glucuronic—2,6 disulfoglucosamine. 3. 3. Anticoagulant activity is not a constant activity of heparins and is only one of a number of biological activities of heparin due to its ability to react with enzymes, hormones, etc. 4. 4. Heparin must be defined by its chemical structure. This can be made an operational definition by using electrophoresis, allowing rapid quantitative examination of heparin and sulfated mucosaccharides. 5. 5. Heparin and histamine are found both in mast cells and in other locations. 6. 6. Feeding olive oil to rats releases histamine to increase intestinal lymph flow. 7. 7. Simultaneous release of heparin liberating diamine oxidase demonstrates heparin can act as a modulator of histamine function. 8. 8. The difference in concentration for histamine between mast cell and extracellular fluid is about 10 5 . 9. 9. Padawer (1974) suggested that the mast cell granule functions as an ion exchanger in tissues. 10. 10. It is proposed that three levels of histamine and heparin function are to be recognized. The free agents (as transmitter and modulator) are released close to the site of action. Combined in an insoluble complex in the granules inside the mast cell, they serve an ion exchange function. Introduction of pathogenic agents or influences can release the granules so that they come in contact with extracellular Na 2+ . This releases histamine, heparin, etc. and produces heterostatic effects.

This study was designed to determine the presence of cell-bound histamine and mast cells, if any, in the lung and skin of nonhuman primate fetuses and neonates. The results indicate that cell-bound histamine can be detected in both tissues of the rhesus monkey fetus by 60 days of gestation, the earliest age examined, at levels that are 2% to 3% of levels present in yearling animals. Levels increase markedly during the last life mo of gestation; however, at birth, levels are only 12% to 46% of those observed in the yearling and are lower than levels observed at 150 days of gestation. Mast cell numbers in lung and skin of the fetus closely parallel histamine content.