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IMMUNODEFICIENT ODENTS A Guide to Their mmunobiology, Husbandry, and Use Committee on Immunologically Compromiser! Rodents Institute of Laboratory Animal Resources Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1989

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NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NW Washington, DC 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council? whose members are drawn from the councils of the National Academy of Sciences, National Academy of Engineering, and Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regarc! for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, National Academy of Engineering, and Institute of Medicine. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Frank Press is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Robert M. White is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and upon its own initiative to identify issues of medical care, research, and education. Dr. Samuel O. Thier is president of the Institute of Medicine. The National Research Council was established by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Frank Press and Dr. Robert M. White are chairman and vice-chairman, respectively, of the National Research Council. This project was funded primarily by the U.S. Department of Health and Human Services (DHHS) through contract number NO1-CM-57644 with the National Cancer Institute. Addi- tional funding was provided by the National Science Foundation (NSF) through grant number BSR-8716373. Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the committee and do not necessarily reflect the views of DHHS or NSF, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Library of Congress Catalog Card No. 89-12387 ISBN 0-309-03796-4 Copyright it) 1989 by the National Academy of Sciences Printed in the United States of America

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COMMITTEE ON IMMUNOLOGICALLY COMPROMISED RODENTS Fred W. Quimby (Chairman), Center for Research Animal Resources, New York State College of Veterinary Medicine, Cornell University Melvin J. Bosma, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania Robert A. Good, All Childrens Hospital, St. Petersburg, Florida Carl T. Hansen, Veterinary Resources Branch, Division of Research Services, National Institutes of Health, Bethesda, Maryland David D. Myers, Research Animal Resources Center, Memorial Sloan- Kettering Cancer Center, New York, New York Conrad B. Richter, Division of Laboratory Animal Medicine, Duke University Medical Center John B. Roths, The Jackson Laboratory, Bar Harbor, Maine Henry H. Wortis, Department of Pathology, Tufts University School of Medicine Invited Participants David E. Briles, The University of Alabama at Birmingham Muriel T. Davisson, The Jackson Laboratory, Bar Harbor, Maine Gabriel Fernandes, University of Texas Health Science Center, San Antonio Margaret C. Green, Emeritus, The Jackson Laboratory, Bar Harbor Maine Dennis L. Guberski, University of Massachusetts Medical School Hedi Haddada, Institut de Recherches Scientifiques sur le Cancer, Villejuif, France Hans J. Hedrich, Central Institute for Laboratory Animal Breeding, Hannover, Federal Republic of Germany Masahisa Kyogoku, Department of Pathology, Tohoku University School of Medicine, Sendai, Japan Priscilla W. Lane, The Jackson Laboratory, Bar Harbor, Maine Jennifer L. Lasky, Department of Pathology, New York University Medical Center Edward H. Letter, The Jackson Laboratory, Bar Harbor, Maine Sandy C. Marks, ,Jr., University of Massachusetts Medical School Thomas H. Roderick, The Jackson Laboratory, Bar Harbor, Maine Leonard D. Shultz, The Jackson Laboratory, Bar Harbor, Maine . . .

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G. Jeanette Thorbecke Medical Center Sara E. Walker, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri , Department of Pathology, New York University Staff Dorothy D. Greenhouse, Senior Program Officer Judith Grumstrup-Scott, Consulting Editor The Institute of Laboratory Animal Resources (ILAR) was founded in 1952 under the auspices of the National Research Council. Its mission is to provide expert counsel to the federal government, the biomedical research community, and the public on the scientific, technological, and ethical use of laboratory animals within the context of the interests and mission of the National Academy of Sciences. ILAR promotes the high-quality humane care of laboratory animals; the appropriate use of laboratory animals; and the exploration of alternatives in research, testing, and teaching. 1V

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INSTITUTE OF LABORATORY ANIMAL RESOURCES COUNCIL Steven P. Pakes (Chairman), University of Texas Southwestern Medical Center, Dallas June R. Aprille, Tufts University Melvin W. Balk, Charles River Laboratories, Inc., Wilmington, Massachusetts Douglas M. Bowden, University of Washington, Seattle Thomas }. Gill III, University of Pittsburgh School of Medicine Alan M. Goldberg, School of Hygiene and Public Health, The Johns Hopkins University Fred W. Quimby, New York State College of Veterinary Medicine, Cornell University J. Wesley Robb, School of Medicine, University of Southern California William H. Stone, Department of Biology, Trinity University COMMISSION ON LIFE SCIENCES Bruce M. Alberts (Chairman), University of California, San Francisco Perry L. Adkisson, Texas A&M University Francisco 'T. Ayala, University of California, Irvine J. Michael Bishop, University of California Medical Center, San tranclsco Freeman ,l. Dyson, The Institute for Advanced Study, Princeton, New Jersey Nina V. Fedoroff, Carnegie Institution of Washington, Baltimore Maryland Ralph W. F. Hardy, Boyce Thompson Institute for Plant Research, Ithaca, New York Richard J. Havel, Cardiovascular Research Institute, University of California School of Medicine, San Francisco Leroy E. Hood, California Institute of Technology Donald F. Hornig, Harvard University School of Public Health Ernest G. Jaworski, Monsanto Company, St. Louis, Missouri Simon A. Levin, Ecosystems Research Center, Cornell University, Ithaca, New York Harold A. Mooney, Stanford University v

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Steven P. Pakes, University of Texas Southwestern Medical Center, Dallas Joseph E. Rall, National Institutes of Health, Bethesda, Maryland Richard D. Remington, University of Iowa Paul G. Risser, University of New Mexico, Albuquerque Richard B. Setlow, Brookhaven National Laboratory, Upton, New York Torsten N. Wiesel, Rockefeller University V1

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Preface In 1974 the Institute of Laboratory Animal Resources, National Research Council, convened the Committee on Care and Use of the "Nude" Mouse to prepare guidelines for maintaining, breeding, and rearing mice homozy- gous for the autosomal recessive mutation "nude." These mice, which have thymic aplasia and a developmental defect in hair growth, are difficult to maintain because of their severely compromised T-cell immunity and, con- sequently, their lack of resistance to many microbial diseases. With their increasing use as animal models, especially in the fields of immunology, oncology, and infectious diseases, it was recognized that guidelines were needed to ensure the production and maintenance of healthy animals. The committee's 1976 report, Guide for the Care and Use of the Nude (Thymus- Deficient) Mouse in Biomedical Research, provided such guidelines. Since then many immunodeficient rodents have been identified, and the study of these models has increased our understanding of the development and function of the immune system. Concurrently, there has been a broadened awareness of the increased susceptibility of immunodeficient rodents to var- ious infectious agents. New construction materials, shipping containers, and animal-care equipment have helped to protect these animals from disease- producing agents. Many immunodeficient strains are now commercially available in the pathogen-free state and are maintained under rigid quality- assurance programs to guarantee their microbial and genetic status. Each of ~ r--~^~ a,__ these innovations, however, places greater pressure on the users of these models to plan in advance for their selection, transportation, housing, and maintenance. . . V11

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viii PREFACE The information contained in this volume is intended to assist investigators in selecting appropriate models for immunologic research. Current knowledge about the maintenance and breeding of these models is also included. The Committee on Immunologically Compromised Rodents has designed this book to be used in conjunction with several National Research Council publications, particularly the Guide for the Care and Use of Laboratory Animals, which was prepared by the Institute of Laboratory Animal Resources (ILAR) and published in 1985 by the U.S. Department of Health and Human ~ . cervices. The committee extends its appreciation to the contributors of this volume and to the staff of ILAR, especially Dr. Dorothy Greenhouse and Judith Grumstrup-Scott. Their dedication to and support of the committee have made the publication of this document possible. Fred W. Quimby, Chairman Committee on Immunologically Compromised Rodents

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Contents 1 INTRODUCTION ............ Immune System Function 2 ........... 1 Effect of Environmental Factors on Immune Function 11 General Considerations for Maintaining Immunodeficent Rodents 14 Mutations 15 Gene Markers and Chromosome Maps 16 Nomenclature and Sources of Immunodeficient Rodents 17 General Reading 34 2 HEREDITARY IMMUNODEFICIENCIES Mice with Single Mutations 36 Mice with Multiple Mutations 90 Inbred Strains of Mice 94 Outbred Mice 122 Rat Mutants 123 Inbred Strains of Rats 130 Guinea Pig Mutants 134 Hamster Mutants 138 1X ........... 36

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x CONTENTS INDUCED IMMUNODEFICIENCIES Chemical Inducers 140 Infectious Agents 143 Nutrition 144 Ionizing and Ultraviolet Radiation 144 Biological Inducers 145 Thymectomy 146 4 MAINTENANCE OF RODENTS REQUIRING ISOLATION ........................ General Considerations 148 Special Facilities and Equipment 149 Specialized Husbandry 151 Control of Infection 153 5 MATING SYSTEMS FOR MUTANTS Inbreeding 155 Propagation Without Inbreeding 159 .................... 140 .......... 148 .................. 155 6 GENETIC MECHANISMS GOVERNING RESISTANCE OR SUSCEPTIBILITY TO INFECTIOUS DISEASES 161 REFERENCES APPENDIX: HEMATOPOIETIC CELL-SURFACE ANTIGENS MENTIONED IN THE TEXT ......... GLOSSARY INDEX .......... 165 .. .. 213 217 233