Immunopharmacology. Proceedings of The Third International Pharmacological Meeting July 24–30, 1966 PDF
Preview Immunopharmacology. Proceedings of The Third International Pharmacological Meeting July 24–30, 1966
ii PROCEEDINGS OF THE FIRST INTERNATIONAL PHARMACOLOGICAL MEETING, STOCKHOLM, 22-25 AUGUST, 1961 Vol. 1 Part 1: Plenary Session Part 2: Pharmacological Control of Release of Hormones Including Antidiabetic Drugs Vol. 2 Effects of Drugs on Synthesis and Mobilization of Lipids Vol. 3 New Aspects of Cardiac Glycosides Vol. 4 Drugs and Membranes Vol. 5 Methods for the Study of Pharmacological Effects at Cellular and Subcellular Levels Vol. 6 Metabolic Factors Controlling Duration of Drug Action Vol. 7 Modern Concepts in the Relationship between Structure and Pharmacological Activity Vol. 8 Pharmacological Analysis of Central Nervous Action Vol. 9 Part 1: Bradykinin and Vaso-dilating Polypeptides Part 2: Pharmacology of the Lung Vol. 10 Abstracts PROCEEDINGS OF THE SECOND INTERNATIONAL PHARMACOLOGICAL MEETING PRAGUE, 20-23 AUGUST, 1963 Vol. 1 Pharmacology of Conditioning, Learning and Retention Vol. 2 Biochemical and Neurophysiological Correlation of Centrally Acting Drugs Vol. 3 Pharmacology of Cholinergic and Adrenergic Transmission Vol. 4 Drugs and Enzymes Vol. 5 Pharmacology of Cardiac Function Vol. 6 Pharmacology of Smooth Muscle Vol. 7 Pharmacology of Oriental Plants Vol. 8 Evaluation of New Drugs in Man Vol. 9 Recent Advances in the Pharmacology of Toxins Vol. 10 Oxytocin, Vasopressin and their Structural Analogues Vol. 11 Drugs and Respiration PROCEEDINGS OF THE THIRD INTERNATIONAL PHARMACOLOGICAL MEETING SAO PAULO, 24-30 JULY, 1966 Vol. 1 Mode of Action of Anti-Parasitic Drugs Vol. 2 Pharmacology of Reproduction Vol. 3 Clinical Pharmacology Vol. 4 Mechanisms of Drug Toxicity Vol. 5 77?^ Control of Growth Processes by Chemical Agents Vol. 6 Drugs in Relation to Blood Coagulation, Haemostasis and Thrombosis Vol. 7 Physico-Chemical Aspects of Drug Action Vol. 8 Salt and Water Balance Vol. 9 Pharmacology and Pain Vol. 10 Rapporst Entre les Actions Pharmacologiques des LM.A.O. et Leurs Effets chez V Homme Vol. 11 Immunopharmacology Immunopharmacology Edited by H. O. SCHILD University College London 000 ©©[ROdHSG 1 — 5£> [Ff}m[^iM®My®©iMi <S8> TT 'OU-S rACWHDA R OINDY U6S1 9T6H PERGAMON PRESS O X F O RD L O N D ON • E D I N B U R G H • N EW Y O RK T O R O N TO - S Y D N E Y* P A R I S - B R A U N S C H W E IG Pergamon Press Ltd., Headington Hill Hall, Oxford 4 & 5 Fitzroy Square, London W.l Pergamon Press (Scotland) Ltd., 2 & 3 Teviot Place, Edinburgh 1 Pergamon Press Inc., 44-01 21st Street, Long Island City, New York 11101 Pergamon of Canada, Ltd., 6 Adelaide Street East, Toronto, Ontario e Pergamon Press (Aust.) Pty. Ltd., Rushcutters Bay, Sydney, New South Wales Pergamon Press S.A.R.L., 24 rue des Ecoles, Paris 5 Vieweg & Sohn GmbH, Burgplatz 1, Braunschweig Copyright © 1968 Pergamon Press Ltd. First edition 1968 Library of Congress Catalog Card No 67-19416 08 003269 9 LISTOF AUTHORS BENACERRAF, B. Department of Pathology, New York University, School of Medicine New York, N.Y., U.S.A. BROCKLEHURST, W. E. Edinburgh University, Medical School, Edinburgh, U.K. BRODER, I. Department of Medicine and Pharmacology, University of Toronto, Toronto, Canada COCHRANE, C. G. Scripps Clinic and Research Foundation Division of Experimental Pathology, La Jolla, California, U.S.A. DAVID, J. R. Department of Medicine, New York University School of Medicine, New York, N.Y., U.S.A. FRAY, ANTOINETTE Chaire de Medecine Experimentale, College de France, Paris, France GOTH, A. Department of Pharmacology, The University of Texas, Southwestern Medical School, Dallas, Texas, U.S.A. GREAVES, M. W. Department of Pharmacology, University College, London, England HALPERN, B. Chaire de Medecine Experimentale, College de France, Paris, France HAYASHI, H. Department of Pathology, Kumamoto University Medical School, Kumamoto, Japan ISHIZAKA, K. Children's Asthma Research Institute and Hospital, Denver, Colorado, U.S.A. LEVINE, B. B. Department of Medicine, New York University School of Medicine, New York, N.Y., U.S.A. MONGAR, J. L. Department of Pharmacology, University College, London, England M 0 LLER-EBERHARD, J. Scripps Clinic and Research Foundation, Division of Experimental Pathology, La Jolla, California, U.S.A. vii viii LIST OF AUTHORS OVARY, Z. Department of Pathology, New York University School of Medicine, New York, N.Y., U.S.A. ROTSCHILD, A. M. Department of Pharmacology, Faculty of Medicine, Ribeirao Preto, Brazil SCHILD, H. O. Department of Pharmacology, University College, London, England STORB, URSULA Chaire de Medecine Experimental, College de France, Paris, France UNGAR, G. Baylor University, College of Medicine, Houston, Texas, U.S.A. UVNAS, B. Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden WARD, P. A. Scripps Clinic and Research Foundation, Division of Experimental Pathology, La Jolla, California, U.S.A. WlLLOUGHBY, D. A. Department of Pathology, St. Bartholomew's Hospital, London, England PREFACE THIS volume contains the proceedings of a symposium on Immunophar- macology held at Sao Paulo, Brazil, on 26 July 1966, in conjunction with the Illrd International Pharmacological Congress. The symposium expresses the close relations between pharmacology and immunology, relations which are likely to become even closer as the nature of the substances mediating hypersensitivity reactions gets further elucidated. Part I of this volume deals with immunoglobulins responsible for hyper- sensitivity reactions and with the mechanisms of these reactions; part II with pharmacological mediators of immediate and delayed hypersensi- tivity and Arthus reactions and with soluble factors released by the action of antigen on sensitized lymphocytes. Part III contains a single paper on the subject of penicillin allergy. I have been entrusted with the organization of the symposium together with Dr. Benacerraf and am most grateful to the participants for their lucid contributions and for providing the manuscripts in good time. I also wish to thank Dr. Radan Capek, Prague, for helping with the editing and print- ing of the volume. H. O. SCHILD ix PROPERTIES OF IMMUNOGLOBULINS WHICH MEDIATE THE RELEASE OF VASOACTIVE AMINES IN EXPERIMENTAL ANIMALS* BARUJ BENACERRAF Department of Pathology New York University School of Medicine New York, N.Y. RECENT studies on the heterogeneity of immunoglobulins have revealed that several mammalian species including man produce a special immuno- globulin capable of sensitizing host tissues for systemic, local, and under certain experimental circumstances, in vitro anaphylactic reactions. This immunoglobulin type will be referred to as "anaphylactic antibody". Its biological properties are a consequence of its capacity to combine with certain target cells (probably tissue mast cells) so that subsequent contact with a specific antigen initiates a series of events which cause the release of vasoactive agents. The anaphylactic antibodies are characteristic of the species in which they have been produced since they can only mediate and transfer anaphylactic reaction within this species or to closely related species. It is a general observation that anaphylactic antibodies cannot sensitize unrelated species. However, mammalian anaphylactic antibodies can nevertheless be classified into main types according to their physico- chemical properties and some of thei(r 1b)io2logical pro perti()es.3 T,he 4anaphy- lactic antibodies of the guinea pig ' and mouse are very similar and have been called y\ immunoglobulin(s. 5)Th,ey6 diff(er) 7app rec)ia(bl8y from () 9 the anaphylactic antibodies of the rat, rabbit, dog and man which will be referred to as the "reaginic type" of anaphylactic antibody. * This work was supported by United Public Health Service Grants AI 2094 and AI 04983 and by the Health Research Council of the City of New York under contract no. 1-138. 3 4 B. BENACERRAF I. ANAPHYLACTIC ANTIBODIES OF THE GUINEA PIG AND MOUSE, L ITMMUNOGLOBULINS A. The guinea pig.—Although the guinea pig has been an animal of choice for the study of local and systemic anaphylactic reactions ever since the discovery of these phenomena, characterization of the specific guinea pig immunoglobulin which mediates these reactions has only been accomplished in the past few years. This has been achieved independently by two groups of workers in the United States and in England. Benacerraf, Ovary, and Bloch observed that antisera of guinea pigs immunized with hapten-protein conjugates contain two populations of prec1i, pit)at1ing0 anti- bodies directed against the same antigenic determinant/ These two antibodies differ in their electrophoretic mobility on agar gel and starch block electrophoresis. They were identified as yi and y 2 antibodies. White, Jenkins and Wilkinson made similar observations with antisera of g(u)i2nea pigs immunized with egg albumin in complete Freund's adjuvant. Both groups reported that the faster migrating y x but not y2 antibodies are able to sensitize guinea pigs for passive cutaneous anaphylaxis (PCA) and for systemic anaphylaxis. y 2 antibodies are able to block specifically PCA reactions provoked by y± antibodies with the same immunological specificity provided a sufficient excess is used. Contrasting with their ability to mediate anaphylactic reactions, y± guinea-pig antibodies are not able to fix complement in the presence of antigen, nor to sensitize antigen coated erythrocytes for lysis by complement. Complement fixation was shown to be a property of the slower migrating y 2 immunoglobulins.These two antibo(d)y1 types were shown to have approximately 7S sedimentation constants. Immunological analysis of y x and y2 guinea-pig antibodies with rabbit antisera against these immunoglobulins and their papain- fragments revealed that y x and y2 antibodies are identical with respect to their L chains and their Fd fragments, which c(on1 st2i tu1t)e 31the4 Fab frag- ment containing the antibody combining site. ' ' However, these two immunoglobulins differ completely in the portion of their H chains contributing to the Fc fragments. These structural differences are not sur- prising and contribute to explain the different biological properties of these two antibody classes, since it has been clearly demonstrated that the chemical structures respon(1s5ib)le for biological activities of antibodies, ( )1 6 such as complement fixation, and passive anaphylactic sensitization, are indeed located on the Fc fragment of 7S immunoglobulins. Although the level of yi immunoglobulins is usually much lower in the serum of unimmunized guinea pigs than the level of y 2 immunoglobulins, PROPERTIES OF IMMUNOGLOBULINS 5 specific immu(n)liz7ation will cause a very high level of y± antibodies to be synthesized. Immunization with protein antigens, in complete adju- vants containing mycobacteria, st(im 1u)la2tes the synthesis of comparable quantities of y2 and y\ antibodies ' although the respective amount of these two imm(un)1og8lobulins formed differs somewhat with the type of antigens used. Immunization without adjuv(a)1nts stimulates the forma- tion of yi immunoglobulin almost exclusively. It can be stated, therefore, that anaphylactic antibody of the guinea pig is one of its two most preva- lent immunoglobulins and for this reason it has been possible to obtain it in sufficient amounts, relatively pure, to allow its characterization and the study of its physical properties. The anaphylactic properties of guinea pig y± antibodies whether in th(e 12)9 0 serum or purified are unaffected by heating to 56°C from 30 min to 4 fir, ' a treatment which is known to (d)e7stroy the activity of human, rat and rabbit anaphylactic antibodies. Alkylation and reduction under con(- )2 1 ditions known to completely inactivate human anaphylactic antibodies reduced the skin sensitizing activity of guinea pig purified y± antihapten antibodies only slightly. Because of their important differences in electric charge, guinea pig y± and y 2 immunoglobulins can be easily separated either by preparat(iv)2e 2zone electrophoresis^ or by chromatography on DEAE cellulose. In order to differentiate guinea pig y± immunoglobulins from the IgA ( )2 3 antibodies, which are characterized by a high content of carbohydrates, hexose analysis of both y x and y2 (g)u2in2ea pig antibodies were made and these were found to be identical. Since the placental membranes of some animals select certain maternal antibodies for transmission to the fetus and exclude others, passage of y\ and y 2 immunoglobulins from mother to fetus was investigated. Both immunoglobulin types are trans- mitted to the young by active(ly )2or0 passively immunized pregnant moth- ers in comparable amounts. Thus the site on the Fc fragment of these two immunoglobulin types which is involved in placental membrane transport in this species is present in both types of guinea pig antibodies. B. The mouse.—The immunoglobulins of the mouse have been well investigated and the following types have bee(n )i2de4ntified: IgM, IgA, and two IgG's also referred to as y 2A and y2B. Besides (th)2ese5 immunoglo- bulins, the mouse produces also a y± immunoglobulin which appears to b e (2id3 e4n)t2ica5l in many respects with the guinea pig y± immunoglobu- lin. ' ' The y1 mouse antibodies have a faster electrophoretic mobility than mouse y2 antibodies, although this difference is not as marked as in the guinea pig, which renders the separation of yi from y 2 mouse immu- 6 B. BENACERRAF noglobulins more difficult. Mouse y± antibodies have been shown to be the only immunoglobulin class capable of transferring passive cutaneous anaphylaxis in the mouse and can be consi3d, e)re4d therefore to be the ana- phylactic immunoglobulin of the species/ Mouse y± is also a 7S immu- noglobulin. It is found in the serum in lesser amounts than y 2 immuno- globulins but it is synthesized in large quantities following specific immu- nization. Similarly to guinea pig y± immunoglobulins, mouse anaphylactic antibodies appea(r) 3not to lyse antigen coated erythrocytes in the presence of complement. Mouse y x immunoglobulins are synthesized in sufficient amounts to be characterized and to allow their physicochemical properties to be investigated. The anaphylactic antibody of the mouse is somewhat more sensitive than that of the guinea p(ig) 3 to reduction and alkylation but equally resistant to heat at 56°C. In summary both mouse and guinea pig produce in large amounts a 7S immunoglobulin type with somewhat faster mobility than their re- spective 72 antibodies. These y± globulins possess distinct antigenic deter- minants on the Fc fragment of their respective H chains. They mediate anaphylactic reactions in their respective species. They are also similar in some of their biological characteristics. Both require a relatively short latent period for passive cuta(n)2eo6us anaphylactic sensitization(, )2v7arying from one hour in the mouse, to 3 to 5 hr in the guinea pig and they bind to the skin for a very short period of time. Greatly decreased reac- tions( a2 re 6)o2bs7erved after 24 hr in the mouse and after 48 hr in the guinea pig. ' These sensitizing characteristics are quite different from those of the anaphylactic antibodies of the rat, the rabbit, the dog and man which bind much more strongly to the skin of their respective species. They are the result of a comparatively lesser affinity of the mouse and guinea pig 71, anaphylactic antibodies for their respective target cells. In spite of their numerous similarities, the y x immunoglobulins of the guinea pig and the mouse are characteristic of their respective species as neither species can be sensitized by the yi antibodies of the other species. II. ANAPHYLACTIC ANTIBODIES OF THE RAT, THE RABBIT AND THE DOG, "REAGENIC TYPE" The anaphylactic antibodies of these three species are very similar and resemble closely in their physicochemical and biological properties the human reagin. They can be considered therefore to belong to a distinct immunoglobulin class.
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