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ANAPHYLAXIS

Novartis Foundation Symposium 257

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The Novartis Foundation is an international scienti¢c and educational charity (UK Registered Charity No. 313574). Known until September 1997 as the Ciba Foundation, it was established in 1947 by the CIBA company of Basle, which merged with Sandoz in 1996, to form Novartis. The Foundation operates independently in London under English trust law. It was formally opened on 22 June 1949.

The Foundation promotes the study and general knowledge of science and in particular encourages international co-operation in scienti¢c research. To this end, it organizes internationally acclaimed meetings (typically eight symposia and allied open meetings and 15^20 discussion meetings each year) and publishes eight books per year featuring the presented papers and discussions from the symposia. Although primarily an operational rather than a grant-making foundation, it awards bursaries to young scientists to attend the symposia and afterwards work with one of the other participants.

The Foundation’s headquarters at 41 Portland Place, London W1B 1BN, provide library facilities, open to graduates in science and allied disciplines. Media relations are fostered by regular press conferences and by articles prepared by the Foundation’s Science Writer in Residence. The Foundation o¡ers accommodation and meeting facilities to visiting scientists and their societies.

Information on all Foundation activities can be found at http://www.novartisfound.org.uk

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ANAPHYLAXIS

Novartis Foundation Symposium 257

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Copyright& Novartis Foundation 2004 Published in 2004 by John Wiley & Sons Ltd,

The Atrium, Southern Gate, Chichester PO19 8SQ, UK National 01243 779777 International (+44) 1243 779777

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or http://www.wiley.com All Rights Reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1T 4LP, UK, without the permission in writing of the Publisher. Requests to the Publisher should be addressed to the Permissions Department, John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester,West Sussex PO19 8SQ, England, or emailed to permreq@wiley.co.uk, or faxed to (+44) 1243 770620.

This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the Publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought.

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Novartis Foundation Symposium 257 ix+296 pages, 33 ¢gures, 18 tables

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library ISBN 0 470 86114 2

Typeset in 101

2on 1212pt Garamond by DobbieTypesetting Limited, Tavistock, Devon.

Printed and bound in Great Britain by T. J. International, Padstow, Cornwall.

This book is printed on acid-free paper responsibly manufactured from sustainable forestry, in which at least two trees are planted for each one used for paper production.

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Contents

Symposium on Anaphylaxis, held atthe Novartis Foundation, 25^27 February 2003 Editors: Gregory Bock (Organizer) and Jamie Goode

This symposium is based on a proposal made by Johannes Ring

Stephen Galli Chair’s introduction 1

Johannes Ring, Knut Brockowand Heidrun Behrendt History and classi¢cation of anaphylaxis 6

Discussion 16

Debra Stern,Waltraud Eder, Gina Tebow, I. Carla Lohman, Elisa Soprana, Charlotte Braun-Fahrlnder, Josef Riedler, Dennis Nowak, ErikaVon Mutius and the ALEX Study Group, Marilyn Halonenand Donata Vercelli

RethinkingTh2 antibody responses and allergic sensitization 25 Discussion 37

General discussion I 45

Henry Metzger The high a⁄nity receptor for IgE, FceRI 51 Discussion 59

Lawrence B. Schwartz E¡ector cells of anaphylaxis: mast cells and basophils 65 Discussion 74

Richard Strait, Suzanne C. Morrisand Fred D. Finkelman Cytokine enhancement of anaphylaxis 80

Discussion 91

General discussion II 98

David B. K. Golden Patterns of anaphylaxis: acute and late phase features of allergic reactions 101

Discussion 110

Richard S.H. Pumphrey Fatal anaphylaxis in the UK, 1992^2001 116 Discussion 128

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Gianni Marone, Maria Bova, Aikaterini Detoraki, Anna Maria Onorati, FrancescaW. Rossiand Giuseppe Spadaro The human heart as a shock organ in anaphylaxis 133

Discussion 149

General discussion III 157

Hugh A. Sampson Food-induced anaphylaxis 161 Discussion 171

Holger Mosbech Anaphylaxis to insect venom 177 Discussion 188

Malcolm Fisher Anaphylaxis to anaesthetic drugs 193 Discussion 202

General discussion IV 207

Elliott C. Lasser The radiocontrast molecule in anaphylaxis. A surprising antigen 211

Discussion 224

General discussion V Fatal course of Vespula venom immunotherapy: pretreatment withdrawal of the b blocker may have been involved 226 F. Estelle R. Simons Epinephrine (adrenaline) in the ¢rst-aid, out-of-hospital

treatment of anaphylaxis 228 Discussion 243

Donald Y. M. Leung,William R. Shanahan Jr, Xiu-Min Liand

Hugh A. Sampson New approaches for the treatment of anaphylaxis 248 Discussion 260

Anne Mu•oz-Furlong Patient’s perspective and public policy regarding anaphylaxis 265 Discussion 274 Final discussion 276 Index of contributors 286 Subject index 288 vi CONTENTS

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Participants

K. Frank Austen Department of Medicine, Brigham and Women’s Hospital, Smith Building, Room 638, One Jimmy Fund Way, Boston, MA 02115, USA Heidrun Behrendt ZAUM (Zentrum Allergie und Umwelt), GSF/TUM,

Klinik und Poliklinik fˇr Dermatologie und Allergologie , TU Mˇnchen, Biedersteiner Strasse 29, D-80802 Mˇnchen, Germany

Aikaterini Detoraki(Novartis Foundation Bursar) Laboratory of Radiology, 31 Cornarou Square, Heraklion, Greece

Gerald Dubois Novartis Horsham Research Centre,Wimblehurst Road, Horsham RH12 5AB, UK

Franz Kricek Novartis Forschungsinstitut, Brunner Strasse 59, A-1235 Vienna, Austria

Fred Finkelman Research Service (151), Cincinnati VAMC, 3200 Vine Street, Cincinnati, OH 45220, USA

Malcolm Fisher IntensiveTherapy Unit, Royal North Shore Hospital, St Leonards, NSW 2065, Australia

Stephen Galli(Chair) Department of Pathology, L-235, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA Hannah Gould Randall Centre for Molecular Mechanisms of Cell Function,

GKT School of Biomedical Sciences, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK

David Golden Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA

Erhard H˛lzle Department of Dermatology, City Hospital Oldenburg, Dr-Eden-Str. 10, D-26133 Oldenburg, Germany

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Elliott C. Lasser 8081 Calle del Cielo, LaJolla, CA 92037, USA

Tak H. Lee Department of Asthma and Allergy, Guy’s Hospital, GKT School of Medicine, 5th Floor,Thomas Guy House, London SE1 9RT, UK

Donald Leung National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206, USA

Donald MacGlashan Jr Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA

Gianni Marone University of Naples Federico II School of Medicine,

Department of Clinical Immunology & Allergy,Via S. Pansini 5, Napoli, 80131, Italy

Henry Metzger NIAMS/NIH, Building 10, Room 9N228, 10 Center Drive MSC 1820, Bethesda, MD 20892-1820, USA

Holger Mosbech National University Hospital, Allergy Unit 4222, DK-2100 Copenhagen O«, Denmark

Ulrich Mˇller Medizinische Klinik, Spital Bern Ziegler, Morillonstr. 75^91, CH-3001 Bern, Switzerland

Anne Mu•oz-Furlong Food Allergy & Anaphylaxis Network, 11781 Lee Jackson Hgwy, Suite 160, Fairfax,VA 22033, USA

Hiroshi Ohtsu Department of Cellular Pharmacology, Tohoku University School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan Rosetta Pedotti Immunology and Muscular Pathology Unit, National

Neurological Institute ‘‘C. Besta’’,Via Celoria, 11, 20133 Milan, Italy

Richard Pumphrey Immunology Department, St Mary’s Hospital, Hathersage Road, Manchester M13 OJH, UK

Johannes Ring Klinik und Poliklinik fˇr Dermatologie und Allergologie am Biederstein, TU Mˇnchen, Biedersteiner Strasse 29, D-80802 Mˇnchen, Germany

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Hugh Sampson Ja¡e Food Allergy Institute, Department of Paediatrics, Division of Allergy and Immunology, Mount Sinai School of Medicine, Box 1198, One Gustave L Levy Place, NewYork, NY 10029, USA

Lawrence Schwartz Division of Rheumatology, Allergy and Immunology, Virginia Commonwealth University, Box 980263, Richmond,VA 23298, USA Estelle Simons Department of Paediatrics & Child Health, University of

Manitoba, 504DJohn Buhler Research Centre (Brodie Building), 727 McDermot Avenue,Winnipeg, Manitoba R3E 3P5, Canada

DonataVercelli Functional Genomics Laboratory, Arizona Respiratory Center, The University of Arizona, PO Box 245030, Tucson, AZ 85724, USA

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Chair’s introduction

Stephen J. Galli

Department of Pathology, L-235, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA

When I give an introductory lecture on anaphylaxis to medical students, I usually start with the story of a child in our neighbourhood who had a peanut allergy. While he was at a friend’s home he was served ice cream. He read the ingredients on the carton, and saw that peanuts weren’t mentioned. However, on his ¢rst mouthful he realized from the rapid onset of symptoms that peanuts must have been included. He was rushed to the emergency room, but there apparently was a delay before he received epinephrine (adrenaline) and he died. It turned out that while peanuts in fact were not listed on the carton, they were in the candy bar that was mentioned in the ice cream’s ingredients. This phenomenon, anaphylaxis, a catastrophic and sometimes fatal allergic reaction to an otherwise innocuous substance, represents arguably the most grotesque imbalance between the cost and bene¢t of an immune response.

As Johannes Ring will tell us in detail, it turns out that observations of anaphylaxis extend far back in antiquity. For example, it is thought that Pharaoh Menes died from a reaction to a wasp sting some 4500 years ago. More recently, about 100 years ago, in an attempt to develop an anti-toxin to the venom of the Portuguese man-of-war (Physalia physalis), Charles R. Richet and Paul Jules Portier instead discovered anaphylaxis. They named the phenomenon anaphylaxis, taking ‘phylaxis’ from the Greek for ‘immunity’ or ‘protection’, and, according to one account, adding the ‘ana’ simply to make the term euphonic. This history is detailed in Estelle Simon’s wonderful book The Ancestors of Allergy (Simons 1994). Apparently, receiving the Nobel Prize can induce paroxysms of modesty in those so honoured. Richet wrote that, ‘The discovery of anaphylaxis is not at all the result of deep thinking, but of simple observation, almost accidental. It had no other merit than that of not refusing to see the facts which presented themselves before me completely evident.’

Since the original descriptions of anaphylaxis in the scienti¢c literature 100 years ago, our understanding of this phenomenon has come a long way. There is no doubt that the activation of mast cells is a key event in many forms of anaphylaxis, and many investigators deserve credit for elucidating the mechanisms responsible for such mast cell (and basophil) activation in response

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to environmental substances. Several investigators made important contributions to the discovery and characterization of the critical antibody isotype involved in anaphylactic reactions in humans, that was ultimately named IgE (Bennich et al 1968), including Kimishige and Teruko Ishizaka (Ishizaka et al 1966), S. G. O. (Gunnar) Johansson and Hans Bennich (1967) and Denis Stanworth (Stanworth et al 1967). Henry Metzger, who is a participant at this symposium, is responsible for de¢ning the receptor for IgE as a single molecular entity (Metzger 1992) and he and Jean-Pierre Kinet cloned and characterized the genes for the three components of the tetrameric high a⁄nity receptor for IgE, FceRI (Metzger 1992, Turner & Kinet 1999). It is now known that the aggregation of the receptor, FceRI, induces the activation of the mast cell, resulting in the release of diverse mediators, many of which can induce the pathophysiology of anaphylaxis (Metzger 1992, Turner & Kinet 1999).

As it turns out, IgE does not only ‘sensitize’ or ‘prime’ mast cells (and basophils) to undergo activation and to release mediators when the cells encounter the antigen for which that IgE has speci¢city. IgE also has the ability, independent of its antigen speci¢city, to enhance signi¢cantly the e¡ector function of these cells. Two groups reported that there is a strong positive correlation in humans between levels of circulating IgE and levels of surface expression of FceRI on blood basophils (Conroy et al 1977, Stallman et al 1977, Malveaux et al 1978). In 1985, using RBL (rat basophil leukaemia) cells, two groups reported that the presence of IgE in the media could cause a modest increase in the number of FceRI expressed on these cells, by inhibiting the elimination of the receptor from the cell surface (Furuichi et al 1985, Quarto et al 1985). Subsequently, Don MacGlashan’s group (Hsu & MacGlashan 1996) and my group (Yamaguchi et al 1997) reported that this IgE-dependent enhancement of FceRI surface expression can be quite striking, quantitatively, in non-neoplastic in vitro-derived (Hsu & MacGlashan 1996, Yamaguchi et al 1997) or in vivo-derived (Yamaguchi et al 1997) mouse mast cells, and that this phenomenon has signi¢cant functional consequences. These include enhancing the capacity of the cells to bind more IgE, and thereby potentially to express sensitivity to an expanded panel of unrelated antigens, lowering the antigen concentration necessary to activate the cells, increasing the amounts of mediators released by the cells at a given concentration of antigen, and, at least in mouse mast cells, rendering the cells able to release additional products (including interleukin 4) that may not be detectably released by cells that express lower amounts of the receptor.

It is now clear that the basic ¢ndings regarding the IgE-dependent enhancement of FceRI surface expression, and its functional consequences, ¢rst established in the mouse system, also occur in humans (Kawakami & Galli 2002, MacGlashan et al 1997, Yamaguchi et al 1999). The implications of these ¢ndings are that subjects with high levels of IgE, and therefore with high levels of expression of FceRI on

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the surface of mast cells and basophils, have key e¡ector cells of anaphylaxis, namely, mast cells and basophils, that are primed to be more exquisitely sensitive to antigen, and to release larger amounts of mediators in response to antigen challenge, than are those in subjects with lower levels of IgE.

Thus, in the approximately 100 years since the description of anaphylaxis by Richet and Portier, it has become possible to outline a classical pathogenic sequence in the production of this reaction: once a subject produces IgE to a speci¢c antigen, IgE-bearing mast cells (located in the tissues) and basophils (in the circulation) can recognize and undergo activation in response to that antigen upon its systemic distribution, and then can rapidly release large amounts of diverse mediators, resulting in the expression of signi¢cant pathology in multiple organ systems (Wasserman 2001).

However, a number of important issues are as yet unsettled, and several of these will be addressed in the discussions at this meeting. As we will hear, there is not yet an international consensus on the classi¢cation and nomenclature of anaphylaxis, especially when one considers those expressions of the disorder that re£ect the activation of mast cells and other e¡ector cells independently of IgE. Even if one considers only those examples of anaphylaxis that result from antigen-dependent activation of mast cells and basophils, it is not clear, in humans, whether some forms of this disorder may include a signi¢cant role for antibody isotypes other than IgE. In mice, by contrast, it is well known that either IgE or IgG1 antibodies, acting via FceRI or FceRIII, respectively, can induce potentially fatal anaphylactic reactions (Miyajima et al 1997, Strait et al 2002).

Are mast cells and basophils the only signi¢cant cellular sources of mediators in anaphylaxis? How do we explain the acute as opposed to late stages of the reaction? Why do only some individuals develop this kind of reactivity, and to what extent does this re£ect genetic, as opposed to environmental, factors? Finally, what more can be done to discover improved treatments for this disorder, and, in the area of public policy, to use e¡ectively what we already know about the causes, management and treatment of anaphylaxis to improve, and in some cases, to save, the lives of those a¥icted with this devastating condition?

I expect that these questions, and other important topics in the ¢eld of anaphylaxis, will be addressed in detail by the speakers at this symposium. Each of the formal presentations will be followed by extensive periods of discussion. In addition, there also will be several general discussions throughout the meeting that will permit us to look at some of the major topics in more detail.

I will close these opening remarks by reminding us of the important contributions to this ¢eld of Mary Hewitt Loveless. Mary Loveless earned her undergraduate and medical degrees at Stanford and went on to perform her work on immunity and allergy in New York. By showing that injections of extracts of the venom sacs of stinging insects (Hymenoptera) could essentially cure patients of

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