Table Of ContentAdvances 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
