Pediatric and Adolescent Medicine
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1 Pediatric Immunology
2 Pediatric and Adolescent Medicine Vol. 3 Series Editor D. Branski, Jerusalem KARGER Basel Freiburg Paris London New York. New Delhi Bangkok Singapore Tokyo Sydney
3 Pediatric Immunology Volume Editors Z. Spirer, Tel Aviv CM. Roifman, Toronto, Ont. D. Branski, Jerusalem 10 figures and 16 tables, 1993 KARGER Basel Freiburg Paris London New York. New Delhi Bangkok Singapore Tokyo Sydney
4 Pediatric and Adolescent Medicine Successor to 'Modern Problems in Paediatrics' and 'Monographs in Paediatrics' Library of Congress Cataloging-in-Publication Data Pediatric immunology / volume editors, Z. Spirer, CM. Roifman, D. Branski. (Pediatric and adolescent medicine; vol 3) Includes bibliographical references and index. 1. Immunologic disorders in children. I. Spirer, Z. II. Roifman, CM. (Chaim M.) III. Branski, D. [DNLM: 1. Immunologic Diseases - in infancy & childhood. 2. Immunologic Diseases - in adolescence.] ISBN Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. <t> Copyright 1993 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland) Printed on acid-free paper. ISBN
5 Contents Preface VII Doherty, P.J.; Roifman, C.M. (Toronto, Ont.): Functions and Disorders of the T-Cell System: Thymic Failure to Select CD8+ Cells Results in a Selective Cellular Immune Deficiency Etzioni, A. (Haifa); Douglas, S.D. (Philadelphia, Pa.): Microbial Phagocytosis and Killing in Host Defense Rechavi, G.; Mandel, M. (Tel-Hashomer): Principles of Autoimmunity in Pediatric Practice Slavin, S. (Jerusalem): New Developments in Bone Marrow Transplantation Spirer, Z.; Eilat, E. (Tel Aviv): Neonatal Immunity Stiehm, E.R.; Roberts, R.L. (Los Angeles, Calif.): Adolescent Immunity: Immune Deficiency in Adolescents Nagler, A.; Engelhard, D. (Jerusalem); Good, R.A. (St. Petersburg, Fla.): Immunity to Infection Landor, M.; Rubinstein, A. (Bronx, N.Y.): Human Immunodeficiency Virus Infection in Children Levy, J. (Beer-Sheva); Wilmott, R.W. (Cincinnati, Ohio): Defense Mechanisms of the Respiratory Tract Elson, C.O. (Birmingham, Ala.); Freier, S. (Jerusalem): The Clinical Spectrum of Immune Aberrations in the Intestine Bujanover, Y. (Tel Aviv); Mieli-Vergani, G.; Mowat, A. (London): The Contribution of the Liver to Immunity Passwell, J.H. (Tel Aviv): Bacterial Immunization Roifman, C.M. (Toronto, Ont.): High-Dose Intravenous Immune Serum Globulin Replacement in Hypogammaglobulinemia: Optimal Replacement and Individualization of Dosing Regimens Handzel, Z.T.; Buchner, V.c. (Rehovot): Stress and the Immune Response Subject Index
6
7 Preface The last decade has witnessed dramatic growth in the scientific foundations of pediatric clinical immunology, especially in the field of molecular biology. The structure of antibodies being clarified, the genetic control of antibody production has been sketched out. The mechanisms of antigenic stimulation and how an antigen is rendered immunogenic have been delineated, and the correlation between structure and function of the various branches of the immune response have been described. Our knowledge about the T-cell receptor and the role of the major histocompatibility complex in normal and abnormal regulation of immune functions has grown geometrically. New techniques in immunogenetics have brought remarkable progress in the mapping of genes involved in immunodeficiency syndromes. This progress is particularly evident in some of the sex-linked immunodeficiency diseases, where prenatal diagnosis is now possible. The discovery of new cell surface molecules and the development of monoclonal antibodies to them has considerably advanced the diagnosis of certain diseases involving the immune system. A large number of cytokines - important mediators and regulators of the immune response - have been described and purified and their genes cloned. Their discovery moved immunology into a new era with the promise of novel diagnostic and therapeutic modalities. The mechanisms of the phagocytic and bactericidal action of PMN and macrophages have been elucidated, and in some disorders the molecular basis of the defect has been explained. A salient example is the chronic granulomatous diseases in which new vistas in diagnosis, prenatal diagnosis and therapy were opened. Other important achievements were the discovery of a new class of molecule - the adhesion molecules - and the syndromes of leukocyte adhesion deficiency.
8 Preface VIII The precision of the new diagnostic modalities changed the concept of strict classification to identification by cellular, humoral and phagocytic components. It became clear that the classical syndromes were only the tip of the iceberg of'incomplete'-combined immunodeficiences, and that dissonance in one branch of a system, normally working in total harmony, disrupts the 'symphony' of the entire system. Increasing sophistication as well as enhanced reliability, precision and simplicity have changed the face of diagnostic modalities. ELISA, in situ hybridization, PCR, high affinity antibody estimation, T-cell quantitation, and characterization of the subpopulations of lymphocytes are only a few examples of these modalities. Better understanding ofthe antigen-antibody interaction and the molecular basis of antibody production has led to the possibility of vaccinations against agents like HIB, pneumococci and meningococci. While they give hope that these serious infections will soon disappear, new infections are appearing. As the AIDS epidemic spread, research led within a short time to the characterization and isolation of the HIV viruses, the description of the clinical spectrum of pediatric AIDS, and the delineation of the precise mechanisms of virus-lymphocyte interaction. These developments offer hope for an effective AIDS vaccine. Bone marrow transplantation is proving successful in a growing variety of immunodeficiency disorders. The development of monoclonal antibodies to various cell surface receptors on the lymphocytes enables bone marrow transplantatio~ from unrelated donors and helps prevent and treat graftversus-host disease. Gammaglobulin has been used routinely for years as replacement therapy in immunodeficiency disorders. In fact, this decade belongs to intravenous gammaglobulin, which has proved helpful in immunodeficiency and in a variety of diseases with important immunoregulatory or immunomodulatory aspects. To name a few: Kawasaki disease, autoimmune disorders, infectious diseases, and viral and bacterial diseases including AIDS. The outcome of extreme preterm babies also improved under this therapy. However, despite the rapid accumulation of knowledge in basic immunology and the major advances made in clinical diagnostic methodology, the therapeutic modalities available today remain limited. Cytokines hold potential therapeutic promise. Recombinant interferon gamma is helpful in some variants of CGD and appears beneficial in the prevention of severe neonatal infections. Interferon alpha is widely used in chronic hepatitis Band C. The discovery that IL-4 plays an important role in IgE synthesis may soon be used as a therapeutic tool in severe allergic
9 Preface IX diseases. New molecular-biology intervention modalities for the treatment of asthma and other atopic diseases are on the horizon, including gamma interferon, soluble IL-4 receptor, specific IgE receptor antagonists and soluble rcam-i. Inhibition of some cytokine activities by antagonists promises to be an important therapeutic advance in infectious, autoimmune and malignant diseases. An example is the use of corticosteroid to inhibit the inflammatory cascade in bacterial meningitis. This book is not intended as a basic course in pediatric immunology. Rather, it focuses on new developments in some important areas of this exciting specialty. Each chapter is the product of an international collaborative effort of clinical pediatric immunologists who address the topics oft and B cells, phagocytosis, new bacterial vaccines, AIDS, gammaglobulin, transplantation, and immunity to infection. New insights are brought on the role of the liver in immunity, and the immunology of the gut and respiratory tract. A chapter is devoted to the important role of neuroendocrine influences in the immune system - the field of stress and immunity. Convinced that the immune system is a saga of development and maturation with critical periods - intrauterine, neonatal and adolescence - we include chapters on neonatal and adolescent immunity. We hope this book will stimulate basic and clinical investigations aimed at further broadening our knowledge and providing answers to questions that occupy and preoccupy the physician and the researcher. Z. Spirer, MD CM. Roijman, MD D. Branski, MD
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