Advances in Veterinary Science and Comparative Medicine Edited by C. E. Cornelius California Primate Research Center University of California, Davis Davis, California R. R. Marshak New Bolton Center University of Pennsylvania Kennett Square, Pennsylvania E. C. Melby SmithKline Beecham Animal Health Products Research and Development West Chester, Pennsylvania Advisory Board Kalman Perk André Rico Irwin Arias Bennie Osburn W. Jean Dodds Advances in Veterinary Science and Comparative Medicine Volume 35 Iirtmunomodulation in Domestic Food Animals Edited by Frank Blecha Department of Anatomy and Physiology College of Veterinary Medicine Kansas State University Manhattan, Kansas and Bernard Charley Station de Recherches de Virologie et d'Immunologie Moléculaires Institut National de la Recherche Agronomique Centre de Recherches de Jouy-en-Josas Jouy-en-Josas, France Academic Press, Inc. Harcourt Brace Jovanovich, Publishers San Diego New York Boston London Sydney Tokyo Toronto This book is printed on acid-free paper. @ COPYRIGHT © 1990 BY ACADEMIC PRESS, INC. All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. ACADEMIC PRESS, INC. San Diego, California 92101 United Kingdom Edition published by ACADEMIC PRESS LIMITED 24-28 Oval Road, London NW1 7DX LIBRARY OF CONGRESS CATALOG CARD NUMBER: 53-7098 ISBN 0-12-039235-6 (alk. paper) PRINTED IN THE UNITED STATES OF AMERICA 90 91 92 93 9 8 7 6 5 4 3 2 1 CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors' contributions begin. PAUL E. BAKER, Immunex Research and Development, Seattle, Wash­ ington 98101 (181) 1 H. BIELEFELDT-OHMANN, Veterinary Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W0, Canada (215) FRANK BLECHA, Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506 (3, 231) BERNARD CHARLEY, Station de Recherches de Virologie et d'Immu- nologie Moléculaires, Institut National de la Recherche Agrono­ mique, Centre de Recherches de Jouy-en-Josas, 78350 Jouy-en-Josas France(3) KRISTIAN DALSGAARD, Animal Biotechnology Research Center, State Veterinary Institute for Virus Research, Lindholm, DK-4771, Kalve- have, Denmark (121) ROBERT DANTZER, Psychobiologie des Comportements Adaptatifs, In­ stitut National de la Recherche Agronomique and, Institut National de la Santé et de la Recherche Médicale, 33077 Bordeaux, France (283) KEVAN P. FLAMING, Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, Iowa 50011 (21) R. A. FREY, Department of Anatomy and Physiology, College of Veteri­ nary Medicine, Kansas State University, Manhattan, Kansas 66506 (255) 1 Present address: Menzies School of Health Research, Casuarina, Darwin, Australia. ix X CONTRIBUTORS BYRON GALLIS, Immunex Research and Development, Seattle, Wash­ ington 98101 (181) LUUK HILGERS, Duphar Β. V., Animal Division, Veterinary Vaccines, Weesp, Holland (121) PARVIZ JAFARI, Immunobiological Laboratories, Inc., New York, New York 10018 (161) MARCUS E. KEHRLI, JR., Metabolic Diseases and Immunology Research Unit, National Animal Disease Center, USDA-Agricultural Re­ search Service, Ames, Iowa 50010 (103) KEITH W. KELLEY, Laboratory of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801 (283) DAVID NEMAT KHANSARI, Immunobiological Laboratories, Inc., New York, New York 10018 (161) CHARLES MALISZEWSKI, Immunex Research and Development, Seattle, Washington 98101 (181) S. R. MARTINOD, Biovet Unit, Ciba-Geigy Ltd., Centre de Recherches Agricoles, St. Aubin, Switzerland (215) JOHN J. MCGLONE, Department of Animal Science, Texas Tech Univer­ sity, Lubbock, Texas 79409 (307) P. J. QUINN, Department of Veterinary Microbiology and Parasitology, University College Dublin, Ballsbridge, Dublin 4, Ireland (43) P. G. REDDY, Department of Anatomy and Physiology, College of Veter­ inary Medicine, Kansas State University, Manhattan, Kansas 66506 (255) JAMES A. ROTH, Department of Veterinary Microbiology and Preven­ tive Medicine, Iowa State University, Ames, Iowa 50011 (21, 103) GERARD TROUVE, SEPPIC, Lacaze Basse, F-81105 Castres Cedex, France (121) FOREWORD Immunology is one of the newest and most important basic and applied biological sciences. The impact immunology has had on agriculture, bio­ logical sciences, human and veterinary medicine, and elsewhere is re­ markable considering its very short history. Although observations on disease resistance and host defense were recorded as early as the 13th century, it has only been during the present century and specifically the last 50 years, that information has been generated to provide the basis for the present day specialty of immunology. Increased awareness of mecha­ nisms involved in immunity have come from studies on cellular and molecular aspects of immunity. Thece studies have also provided informa­ tion required to develop methods and products for controlling or regulat­ ing the immune response. Immunomodulation, which involves increasing and/or decreasing immune responses, is essential to improve protective immunity and reduce immune mediated disease (e.g., allergy, autoim­ munity). The ability to modulate the immune response for the purpose of en­ hanced resistance to a wide range of pathogens is an important goal of the immunologist and microbiologist. The ability to modulate immunity for the benefit of the host would provide cost effective products for use in food animals. Vaccine technology has improved significantly since it was first introduced, however, constantly changing requirements in food animal production require additional changes, and further improvement in the development and delivery of vaccines are necessary to reduce disease losses not controlled by current vaccines. Protection from complex dis­ eases, especially those affecting young animals where the immune system has not reached maturity, will require methods and products that cur­ rently do not exist. Improvement of vaccines will require new adjuvants. Adjuvant technology has improved with the discovery of new chemicals, synthetics, and natural products, but much work remains to be done to find optimal cost effective and acceptable products. The discovery of the role that cytokines play in immunomodulation provides an opportunity, through genetic engineering technology, to use certain cytokines as ad­ juvants in food animals. An increased understanding of their role in the immune system will lead to the most appropriate use of cytokines for enhancing disease resistance. Understanding the interaction of the immune system with various xi xii FOREWORD organ systems is important for the development of an effective immune response. One system receiving attention because of its influence on im­ munity is the neuroendocrine system. Stress from a variety of factors, especially from management practices of food producing animals, pro­ foundly affects the immune system. It has been known for years that temperature changes, shipping, and crowding have profound effects on increased susceptibility to disease. Some of the effects are undoubtedly related to exposure to new or high concentrations of pathogens, but also of importance are the modulating effects of stress on immunity. An under­ standing of the interaction between neuroendocrine function and immu­ nity will lead to management practices that have the effect of enhancing immunity to various infectious diseases and providing information on proper timing of vaccination for optimal protective immunity. The role nutrition plays in modulation of the immune system is also of great interest, especially as it relates to food animal production. Nutrients can significantly effect the development and/or maintenance of the im­ mune system, therefore, optimal nutrition is a requirement for optimal immunity to be realized. Under certain circumstances immunomod­ ulation can be achieved through nutritional therapy. It is critical to understand that immunity can be enhanced or suppressed with the use of certain nutrients in the diet or given by injection. The specific nutrients and the range of levels must be known to ensure that nutrition is not having a negative impact on disease resistance, but instead ensuring optimal or enhanced immunity. This book for the first time provides valuable information on mecha­ nisms of immunologic control and on the possible methods and products that can be used to modulate the immune response of animals. It also provides a detailed description of the numerous factors that effect an immune response and how management of these factors can be used to the advantage or disadvantage of food animal production. RONALD D. SCHULTZ SCHOOL OF VETERINARY MEDICINE UNIVERSITY OF WISCONSIN-MADISON PREFACE The purpose of this volume is to compile recent developments in the immunology and regulation of the immune response in domestic food animals. Given the rapid rate of progress in the field, this is a difficult task; we feel however, that it is a necessary one. The subject of this book concerns the regulation of the immune response in food animals and means of enhancing that response to decrease suscep­ tibility to disease. The book is divided into four parts. Part I provides an overview of the basic concepts of immunomodulation and the rationale for manipulating the immune response in food animals. Part II contains information on immunopotentiation using chemicals and a thorough dis­ cussion of adjuvant use. The molecular biology and in vivo use of cytokines in food animals is presented in Part Π.Ι Finally, Part IV discusses physio­ logically regulated immunomodulation, including nutritional modulation of the immune response and neuroendocrine-immune interactions. Our task of compiling this book was made easier by the willingness of the authors to provide timely, concise reviews of their areas of expertise. We are sincerely grateful to each author for the time and energy that was required to prepare their contribution. FRANK BLECHA BERNARD CHARLEY xiii ADVANCES IN VETERINARY SCIENCE AND COMPARATIVE MEDICINE, VOL. 35 Rationale for Using Immunopotentiators in Domestic Food Animals 1 FRANK BLECHA* AND BERNARD CHARLEY * Department of Anatomy and Physiology, College of Veterinary Medicine, 1 Kansas State University, Manhattan, Kansas 66505, and Station de Recherches de Virologie et d'Immunologie Moléculaires Institut National de la Recherche Agronomique, Centre de Recherches de Jouy-en-Josas, 78350 Jouy-en-Josas, France I. Introduction II. Why Are Immunomodulators Needed? III. Specific versus Nonspecific Immunomodulation A. The Neonatal Period B. Stress-Induced Immunosuppression C. Pathogen-Induced Immunosuppression IV. Summary References I. Introduction Prevention and treatment of disease are primary concerns of every­ one involved in the production of domestic food animals. Producers, veterinarians, and production animal specialists, such as nutritionists and reproductive physiologists, can all cite specific economic endpoints that are directly related to the incidence and intensity of disease in food production animals. Indeed, even the consumer of animal agricultural products is greatly affected by the cost of maintaining an abundant supply of healthy food animal products. Consequently, much effort and expense are directed toward minimizing the incidence of disease in domestic food animals. One means of decreasing the impact of disease in food animals is increasing the animal's ability to withstand infec­ tions. 3 Copyright © 1990 by Academic Press, Inc. All rights of reproduction in any form reserved. 4 FRANK BLECHA AND BERNARD CHARLEY Regulation of the immune response is extremely complex. Neverthe­ less, we are slowly beginning to understand how the immune system, indeed the whole animal, orchestrates the body's response to an invad­ ing pathogen. With the knowledge, however incomplete, of how the immune system responds to disease-causing organisms, we can devise ways of intervening in the regulation of the immune system, particu­ larly by modulating the host's immune response. Immunomodulation, as the term implies, can be used to designate either a suppression or an augmentation of an immune response. The necessity and capability of suppressing the function of the immune system are well recognized in such areas as organ transplantation and autoimmune disorders. However, in general, medically induced immuno­ suppression is not a practical concern in domestic food animals. Conversely, augmentation of immunity has received much attention in domestic food animals and provides a means of increasing the host's resistance to disease. Various chemicals and biological substances have been used and evaluated as immunomodulators in domestic food animals and will be discussed in the following chapter of this book. Other synonyms for immunomodulators that are frequently used in­ clude immunostimulators, immunopotentiators, immunotherapeutic agents, and biological response modifiers. II. Why Are Immunomodulators Needed? Vaccination of domestic food animals against economically impor­ tant pathogens is effective and has increased the efficiency of food animal production. However, even with the successes attained in food animal production through vaccination programs, tremendous eco­ nomic losses still occur in animal agriculture that are directly related to the health of the animal. Two important examples of diseases that still cause large economic losses, bovine respiratory disease and mastitis, will be used to illustrate this point. Respiratory disease of cattle continue to present a serious economic burden to the producer. The annual economic loss to the North Ameri­ can cattle industry from bovine respiratory disease has been estimated to range from $250 million to $1 billion (Babiuk et al, 1987). The etiology of bovine respiratory disease is very complex and multifacto­ rial; the interactions of viruses, bacteria, and stress greatly contribute to the disease process (Loan, 1984). Vaccines against viruses and bac­ teria involved in bovine respiratory disease are available and used. However, bovine respiratory disease still accounts for 65% of the health problems and deaths among feedlot cattle (Edwards, 1987). In addition