Equine Clinical Immunology

Equine Clinical Immunology

To Nora and Robin. To my family, friends and mentors who shared their support all the way.

Equine Clinical Immunology Edited by MedVet, MSc, PhD, Associate Professor of Large Animal Medicine,, USA

This edition first published 2016 2016 by John Wiley & Sons, Inc. Editorial offices: 1606 Golden Aspen Drive, Suites 103 and 104, Ames, Iowa 50010, USA The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Blackwell Publishing, provided that the base fee is paid directly to the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license by CCC, a separate system of payments has been arranged. The fee codes for users of the Transactional Reporting Service are ISBN-13: 978-1-1185-5887-4 / 2016 Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Equine clinical immunology / [edited by]. p. cm. Includes bibliographical references and index. ISBN 978-1-118-55887-4 (cloth) 1. Horses Immunology. 2. Horses Diseases. I. Felippe, M. Julia B. (Maria Julia B.), editor. [DNLM: 1. Horse Diseases immunology. 2. Immune System Diseases veterinary. 3. Immunotherapy veterinary. SF 951] SF951.E5423 2016 636.1'0896079 dc23 2015019958 A catalogue record for this book is available from the British Library. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Set in 9.5/12pt MinionPro-Regular by Thomson Digital, Noida 1 2016

Contents Contributors, ix Preface, xi 1 The Immune System, 1 1.1 Definition, 1 1.2 The organs of the immune system, 1 1.3 The immune cells and soluble molecules, 2 1.4 B and T cell activation in lymphoid tissues, 6 1.5 When the immune response goes wrong, 9 References, 10 2 The Immune System of the Young Horse, 11 Rebecca L. Tallmadge 2.1 Definition, 11 2.2 Equine immune system development, 11 2.3 Unique susceptibilities and disorders of young horses, 16 2.4 Vaccinology teaches about neonatal immunity, 18 References, 18 3 The Immune System of the Older Horse, 23 Amanda A. Adams and David W. Horohov 3.1 Definition, 23 3.2 Clinical conditions associated with aging, 23 3.3 Immunosenescence and vaccination, 23 3.4 Nutrition in enhancing immunity in the old horse, 26 3.5 Conclusion, 27 References, 27 4 Anaphylaxis, 31 Rolfe M. Radcliffe 4.1 Definition, 31 4.2 Signalment and clinical signs, 31 4.3 Immunologic mechanisms and etiologic associations, 32 4.4 Diagnostics, 33 4.5 Treatment, 34 4.6 Prevention, 36 4.7 Prognosis and clinical outcomes, 37 References, 37 5 Allergy, 39 Bettina Wagner 5.1 Definition, 39 5.2 Culicoides hypersensitivity, 39 5.3 Urticaria, 43 5.4 Recurrent airway obstruction, 44 References, 44 6 Immune-Mediated Cytopenias, 47 Thomas J. Divers 6.1 Definition, 47 6.2 Immune-mediated hemolytic anemia, 47 6.3 Immune-mediated thrombocytopenia, 50 6.4 Immune-mediated neutropenia, 53 References, 54 7 Bullous Diseases of the Skin and Mucosa, 55 Jeanine Peters-Kennedy and Rebecca E. Ruby 7.1 Definition, 55 7.2 Immune-mediated bullous dermatoses, 55 7.3 Pemphigus complex, 57 7.4 Cutaneous adverse drug reactions, 61 7.5 Erythema multiforme, 62 7.6 Lupus erythematosus, 64 References, 65 8 Serum Sickness, 69 Lais R.R. Costa 8.1 Definition, 69 8.2 Signalment and clinical signs, 69 8.3 Immunologic mechanisms and etiologic associations, 69 8.4 Diagnostics, 71 8.5 Treatment and prevention, 71 References, 72 v

vi Contents 9 Vasculitis, 73 James S. W. Prutton and Nicola Pusterla 9.1 Definition, 73 9.2 Signalment and clinical signs, 73 9.3 Immunologic mechanisms and etiologic associations, 73 9.4 Diagnostics, 75 9.5 Treatment, 75 9.6 Thrombophlebitis, 75 9.7 Pastern and cannon leukocytoclastic vasculitis, 76 9.8 Drug-induced vasculitis, 76 9.9 Photo-activated vasculitis (photodynamic drugs), 77 9.10 Strongylus vulgaris, 77 9.11 Equine granulocytic anaplasmosis, 77 9.12 Equine viral arteritis, 78 9.13 Equine herpesvirus-1, 78 9.14 African horse sickness, 78 References, 79 10 Purpura Hemorrhagica, 83 Laszlo M. Hunyadi and Nicola Pusterla 10.1 Definition, 83 10.2 Signalment and clinical signs, 83 10.3 Immunologic mechanisms and etiologic associations, 83 10.4 Diagnostics, 84 10.5 Treatment and prevention, 85 References, 86 11 Glomerulonephritis, 87 11.1 Definition, 87 11.2 Signalment and clinical signs, 87 11.3 Immunologic mechanisms and etiologic associations, 87 11.4 Diagnostics, 88 11.5 Treatment and prognosis, 88 References, 88 12 Inflammatory and Immune-Mediated Muscle Disorders, 91 Sian Durward-Akhurst and Stephanie J. Valberg 12.1 Definition, 91 12.2 Infarctive purpura hemorrhagica, 91 12.3 Rhabdomyolysis associated with Streptococcus equi, 93 12.4 Immune-mediated myositis in Quarter Horse-related breeds, 94 12.5 Systemic calcinosis, 96 12.6 Uncharacterized immune-mediated and inflammatory myopathies, 97 12.7 Sarcocystis myositis, 97 References, 98 13 Granulomatous Diseases, 101 Lais R.R. Costa 13.1 Definition, 101 13.2 Signalment and clinical signs, 101 13.3 Immunologic mechanisms and etiologic associations, 101 13.4 Diagnostics, 104 13.5 Treatment and prevention, 105 13.6 Types of cell-mediated hypersensitivity reactions, 105 References, 110 14 Chronic Inflammatory Bowel Disease, 113 Gillian A. Perkins 14.1 Definition, 113 14.2 Signalment and clinical signs, 113 14.3 Immunologic mechanisms and etiologic associations, 113 14.4 Diagnostics, 115 14.5 Treatment and prognosis, 116 References, 117 15 Recurrent Uveitis, 121 Brian C. Gilger 15.1 Definition, 121 15.2 Signalment and clinical signs, 121 15.3 Immunologic mechanisms and etiologic associations, 121 15.4 Diagnostics, 123 15.5 Treatment and prevention, 124 15.6 Prognosis and clinical outcomes, 124 References, 125 16 Recurrent Airway Obstruction and Summer Pasture-Associated Obstructive Pulmonary Disease, 127 Michela Bullone and Jean-Pierre Lavoie 16.1 Definition, 127 16.2 Signalment and clinical signs, 127 16.3 Immunologic mechanisms and etiologic associations, 128 16.4 Diagnostics, 134 16.5 Treatments and prevention, 136 References, 137

Contents vii 17 Inflammatory Airway Disease, 145 Mathilde Leclère and Jean-Pierre Lavoie 17.1 Definition, 145 17.2 Signalment and clinical signs, 145 17.3 Immunologic mechanisms and etiologic associations, 145 17.4 Types of bronchoalveolar lavage fluid inflammation and cytokine profile, 147 17.5 Links between IAD and heaves, 148 17.6 Links between IAD and EIPH, 148 17.7 Diagnostics, 148 17.8 Treatment and prevention, 149 17.9 Prognosis and clinical outcomes, 150 References, 150 18 Inflammation, Endotoxemia and Systemic Inflammatory Response Syndrome, 153 Erin L. McConachie and Kelsey A. Hart 18.1 Definition, 153 18.2 Signalment and clinical signs, 154 18.3 Immunologic mechanisms and etiologic associations, 155 18.4 Multi-systemic response triggered by inflammatory mediators, 157 18.5 Diagnostics, 160 18.6 Treatment, 162 18.7 Prognosis and clinical outcome, 166 References, 166 19 Leukemia, 173 Tracy Stokol 19.1 Definition, 173 19.2 Classification of leukemias, 173 19.3 Specialized diagnostic techniques for leukemia, 173 19.4 Chronic leukemia, 175 19.5 Acute leukemia, 177 References, 179 20 Lymphoma, 181 SallyAnne L. Ness 20.1 Definition, 181 20.2 Signalment and clinical signs, 181 20.3 Forms of equine lymphoma, 182 20.4 Immunologic mechanisms and etiologic associations, 183 20.5 Diagnostics, 183 20.6 Classification of lymphomas, 185 20.7 Prognosis and treatment, 186 20.8 Monitoring, 189 References, 189 21 Immunodeficiencies, 193 21.1 Definition, 193 21.2 Classification of immunodeficiencies, 194 References, 202 22 Immunologic Testing, 205 22.1 Definition, 205 22.2 Types of immunologic testing, 205 References, 211 23 Non-steroidal Anti-inflammatories, 213 Michelle H. Barton 23.1 Definition, 213 23.2 Non-steroidal anti-inflammatory drugs, 213 References, 228 24 Immunosuppressive Therapy, 237 24.1 Definition, 237 24.2 Types of immunosuppressive drugs, 237 References, 240 25 Immunomodulators, 243 Elizabeth G. Davis 25.1 Definition, 243 25.2 Immunologic mechanisms, 243 25.3 Commercially available immunostimulants for use in horses, 244 References, 249 26 Immunoglobulin Therapy, 251 Elizabeth G. Davis 26.1 Definition, 251 26.2 Immunologic mechanisms, 251 References, 254 27 Plasmapheresis, 257 Nathan M. Slovis 27.1 Definition, 257 27.2 Methods for preparing plasma products, 257 27.3 Apheresis, 258 27.4 Therapeutic plasmapheresis, 258 27.5 Complications of therapeutic plasmapheresis, 260 References, 260

viii Contents 28 Principles of Vaccination, 263 Noah D. Cohen and Angela I. Bordin 28.1 Definition, 263 28.2 Efficacy and effectiveness of vaccines, 263 28.3 Safety of vaccines, 271 28.4 Key knowledge-gaps in equine vaccinology, 273 28.5 Protocols for vaccination, 275 References, 276 29 Types of Vaccines, 279 Angela I. Bordin and Noah D. Cohen 29.1 Definition, 279 29.2 Immunologic mechanisms, 279 29.3 Immune responses to vaccination, 282 29.4 Routes of vaccination, 284 29.5 Adjuvants and vaccine delivery systems, 285 29.6 Important diseases with unavailable effective vaccines, 285 References, 286 30 Transplantation Immunology, 289 Rebecca L. Tallmadge 30.1 Definition, 289 30.2 Equine MHC genes: genomic organization and variation, 289 30.3 Determining equine MHC haplotypes, 290 30.4 Immunosuppression and engraftment, 291 30.5 Graft rejection, 292 30.6 Current transplantation applications, 293 References, 294 31 Mesenchymal Stem Cell Therapy, 297 Gerlinde R. Van de Walle, Catharina De Schauwer and Lisa A. Fortier 31.1 Definition, 297 31.2 Regenerative functions of mesenchymal stem cells, 297 31.3 Immunologic mechanisms and associations, 298 31.4 Sources of equine mesenchymal stem cells, 299 31.5 Characterization of equine mesenchymal stem cells, 300 31.6 Applications of equine mesenchymal stem cells in equine regenerative medicine, 302 References, 306 32 Hematopoietic Stem Cell Transplantation, 311 32.1 Definition, 311 32.2 Hematopoietic stem cell sources, 311 32.3 Pre-transplantation conditioning, 313 32.4 Post-transplantation immunosuppression, 313 32.5 Hematopoietic stem cell transplantation in the horse, 313 References, 315 Index, 317

Contributors Amanda A. Adams, PhD Department of Veterinary Science Gluck Equine Research Center University of Kentucky Lexington, Kentucky Michelle H. Barton, DVM, PhD, Department of Large Animal Medicine University of Georgia Athens, Georgia Angela I. Bordin, DVM, MS, PhD Department of Large Animal Clinical Sciences and Biomedical Sciences Texas A&M University College Station, Texas Michela Bullone, DVM, MSc Département de Sciences Cliniques Faculté de Médecine Vétérinaire Université de Montréal Montréal, Canada Noah D. Cohen, VMD, MPH, PhD, Department of Large Animal Clinical Sciences and Biomedical Sciences Texas A&M University College Station, Texas Lais R.R. Costa, MedVet, MS, PhD,, Diplomate ABVP Mississippi State University Mississippi State, Mississippi Elizabeth G. Davis, DVM, PhD, Kansas State University Manhattan, Kansas Catharina De Schauwer, DVM, PhD, Diplomate ECAR Department of Obstetrics, Reproduction, and Herd Health Ghent University, Belgium Merelbeke, Belgium Thomas J. Divers, DVM, Diplomate ACVIM, Diplomate ACVECC Sian Durward-Akhurst, BVMS Department of Veterinary Population Medicine University of Minnesota St. Paul, Minnesota, MedVet, MSc, PhD, Lisa A. Fortier, DVM, PhD, Diplomate ACVS Brian C. Gilger, DVM, MS, Diplomate ACVO, Diplomate ABT North Carolina State University Raleigh, North Carolina Kelsey A. Hart, DVM, PhD, Department of Large Animal Medicine University of Georgia Athens, Georgia David W. Horohov, PhD Department of Veterinary Science Gluck Equine Research Center University of Kentucky Lexington, Kentucky Laszlo L. Hunyadi, DVM, MS, PhD Veterinary Medical Teaching Hospital UC-Davis School of Veterinary Medicine University of California Davis, California ix

x Contributors Jean-Pierre Lavoie, DMV, Département de Sciences Cliniques Faculté de Médecine Vétérinaire Université de Montréal Montréal, Canada Mathilde Leclère, DMV, PhD, Département de Sciences Cliniques Faculté de Médecine Vétérinaire Université de Montréal Montréal, Canada Erin L. McConachie, DVM, Department of Large Animal Medicine University of Georgia Athens, Georgia SallyAnne L. Ness, DVM, Gillian A. Perkins, DVM, Jeanine Peters-Kennedy, DVM, Diplomate ACVP, Diplomate ACVD Department of Biomedical Sciences Jamie W. Prutton, BVSc, MRCVS, Veterinary Medical Teaching Hospital UC-Davis School of Veterinary Medicine University of California Davis, California Nicola Pusterla, DVM, PhD, Department of Medicine and Epidemiology UC-Davis School of Veterinary Medicine University of California, Davis, California Rolfe M. Radcliffe, DVM, Diplomate ACVS, Diplomate ACVECC Rebecca E. Ruby, BVSc, MS Department of Biomedical Sciences Nathan M. Slovis, DVM, CHT, Hagyard Equine Medical Institute Lexington, Kentucky Tracy Stokol, BVSc, PhD, Diplomate ACVP (Clinical Pathology) Department of Population Medicine and Diagnostic Sciences Rebecca L. Tallmadge, PhD Stephanie J. Valberg, DVM, PhD, Department of Veterinary Population Medicine University of Minnesota St. Paul, Minnesota Gerlinde R. Van de Walle, DVM, PhD Baker Institute for Animal Health Bettina Wagner, DVM, Dr.vet.med. habilitation Department of Population Medicine and Diagnostic Sciences

Preface The major motivation for gathering the information in this book was to highlight the field of clinical immunology using accessible and applied approaches for students and practitioners with interest in furthering horse health. The topics covered include developmental immunology, immunodeficiencies, inflammation, hypersensitivity reactions, immune-mediated diseases, oncology, vaccinology, transplantation, and regenerative medicine. These areas cover both routine and advanced equine clinical cases. Clinical immunology is grounded on the history of infectious disease outbreaks in humans and animals but this is just the beginning. A dysfunctional immune system has been associated with the pathophysiology of tissue damage, poor healing, and cancer, involving one or multiple organs. Organ-specific specialties investigate diseases that one way or another implicate the immune system, and much of the gathered clinical immunology knowledge and principles come from these basic applied studies. Natural immunodeficiencies have taught us about mechanisms of immune response and immunity. In addition, the growing fields of transplantation and regenerative medicine attempt to explore the connection and involvement of the immune system with their success in cell and tissue restoration. The chances of an effective treatment increase with our ability to diagnose and understand the mechanisms of disease. Working as a large animal internist in a referral hospital, and as a clinical immunologist with emphasis in immunodeficiencies, I am reminded about the broad participation of the immune system in the cause and/or effect of the great majority of diseases. However, it is at the primary care level that clinical immunology offers the most significant contributions to patient care, when the curiosity of a clinician brings questions about the role of the immune system in a clinical context, and allows the early considerate intervention before tissue damage ensues. Inspiration is the fuel for moving forward and, in the planning of this book, I got mine from my patients and students throughout the years. Some of my patients came with aberrant susceptibility to infections or excessive inflammatory response, and my students were curious about explanations for the cause and approaches for treatment. My inspiration also came from the pioneers in the studies of equine clinical immunology, who identified and characterized the first primary immunodeficiency of the horse, shared their discoveries on developmental immunology of the fetus and foal, described the mechanisms of endotoxemia, and created the critical reagents and diagnostic tools for basic and applied research of the immune system of the horse. Although we have achieved answers to many of our questions, the gaps are still considerable, and much work is ahead of us in order to better define diseases, promote healing and, ultimately, ensure prevention. I hope this book inspires you in pursuing knowledge and training in clinical immunology. xi