Clinical Immunobiology Edited by VOLUME 2 FRITZ H. BACH, M.D. IMMUNOBIOLOGY RESEARCH CENTER DEPARTMENTS OF MEDICAL GENETICS AND SURGERY UNIVERSITY OF WISCONSIN MEDICAL SCHOOL MADISON, WISCONSIN ROBERT A. GOOD, Ph.D., M.D. MEMORIAL SLOAN-KETTERING CANCER CENTER NEW YORK, NEW YORK ACADEMIC PRESS New York and London 1974 A Subsidiary of Harcourt Brace Jovanovich, Publishers COPYRIGHT © 1974, 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. Ill Fifth Avenue, New York, New York 10003 United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London NW1 LIBRARY OF CONGRESS CATALOG CARD NUMBER: 72-77356 PRINTED IN THE UNITED STATES OF AMERICA List of Contributors Numbers in parentheses indicate the pages on which the authors' contributions begin. FRITZ, H. BACH, Immunobiology Research Center, Departments of Medi- cal Genetics and Surgery, University of Wisconsin Medical School, Madison, Wisconsin (63) MORTIMER M. BORTIN, May and Sigmund Winter Research Laboratory, Mount Sinai Medical Center, and the Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin (287) I. FLORENTIN, Institut de Cancérologie et d'Immunogénétique, Hôpital Paul-Brousse, Villejuif, France (33) H. HUGH FUDENBERG, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, California (153) E. GARCIA-GIRALT, Institut de Cancérologie et dlmmunogénetique, Hôpital Paul-Brousse, Villejuif, France (33) ROBERT A. GOOD, Memorial Sloan-Kettering Cancer Center, New York, New York (63) C. GRISCELLI, Immunology and Hematology Unit, Children's Medical Clinic, Hôpital des Enfants Malades, Paris, France (177) O. HALLE-PANNENKO, Institut de Cancérologie et dlmmunogénetique, Hôpital Paul-Brousse, Villejuif, France (33) xi xii LIST OF CONTRIBUTORS INGEGERD HELLSTRÖM, Departments of Pathology and Microbiology, Uni- versity of Washington School of Medicine, Seattle, Washington (233) KARL ERIK HELLSTRÖM, Departments of Pathology and Microbiology, Uni- versity of Washington School of Medicine, Seattle, Washington ( 233 ) N. KIGER, Institut de Cancérologie et d'Immunogénétique, Hôpital Paul- Brousse, Villejuif, France ( 33 ) H. SHERWOOD LAWRENCE, Infectious Diseases and Immunology Division, Department of Medicine, New York University School of Medicine, New York, New York (115) ALAN S. LEVIN, Department of Dermatology, University of California, San Francisco, School of Medicine, San Francisco, California, and Kaiser-Permanente Hospital, San Francisco, California (153) G. MATHE, Institut de Cancérologie et d'Immunogénétique, Hôpital Paul- Brousse, Villejuif, France ( 33 ) HERBERT F. OETTGEN, Memorial Sloan-Kettering Cancer Center, New York, New York (205) RICHMOND T. PREHN, The Institute for Cancer Research, Fox Chase Cen- ter for Cancer and Medical Sciences, Philadelphia, Pennsylvania (191) JON R. SCHMIDTKE, Department of Surgery, University of Minnesota Health Sciences Center, Minneapolis, Minnesota (265) L. SCHWARZENBERG, Institut de Cancérologie et d'Immunogénétique, Hôpital Paul-Brousse, Villejuif, France (33) RICHARD L. SIMMONS, Department of Surgery, University of Minnesota Health Sciences Center, Minneapolis, Minnesota ( 265 ) LYNN E. SPITLER, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, California, and Cancer Research Institute, Department of Medicine, University of Cali- fornia, San Francisco, San Francisco, California (153) E. DONNALL THOMAS, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, and the United States Public Health Service Hospital, Seattle, Washington ( 1 ) Preface We present the second volume of the serial publication Clinical Immunobiology, which has been designed to help the physician and student keep abreast of advances in the burgeoning field of clinical immunobiology. In the initial volume we made an effort to give some background of the fundamental lore of this rapidly develop- ing discipline. We now launch our considerations of the advances in clinical immunobiology by presenting through the writings of several leaders in the field progress being made to apply bone marrow transplan- tation to the treatment of such devastating diseases as aplastic anemia, aregenerative pancytopenia, leukemia, uniformly fatal severe combined immunodeficiency diseases, and Wiskott-Aldrich syndrome. The suc- cesses we report here represent, we are certain, only the toddling first steps in a new era of medical therapy. We will look to cellular engineer- ing in the form of bone marrow and thymus transplantation, and ulti- mately to macromolecular pharmacology, to correct inborn errors of metabolism, the effects of exposure to excessive amounts of radiation or cytotoxic chemicals, and hematopoietic failure based on malfunction of the complex process of normal hematological development and maintenance. In these articles it is clearly brought forward that studies of marrow transplantation in man have provided new and exciting leads to the understanding of fundamental biological principles. For example, these studies have generated vital efforts toward the wider application of our new understanding of the histocompatibility determinants in man. This will surely need to be expanded and developed in future issues because studies in this direction not only make possible better matching for marrow transplants heretofore thought to be impossible, but yield evidence of fundamental relationships between the histocompatibility xiii xiv PREFACE determinants and the capacity to maintain our individuality in a hostile world through the ability to recognize and eliminate from the body that which is not self. Further, fundamental new information about leu- kemia seems to be contained in the evidence that, after successful marrow transplantation for this disease, the transplanted marrow may catch the leukemia. In the chapters by Lawrence, and Spitler, Levin, and Fudenberg, the rapidly expanding use of transfer factor to treat human disease is pre- sented against its appropriate background of fundamental studies. With this approach, some of the most recalcitrant and devastating of man's dis- eases are now being treated with a methodology that apparently engages the immunological system—or refurbishes a flagging or depressed cellular immunity. The results in some instances have been so extraordinary and the diseases apparently manipulated favorably so awful that the objections to the theoretical validity of the transfer factor approach often stated by critics (for example, the editors) must be satisfied while progress in this fantastic form of macromolecular pharmacology is re- corded. Because of its theoretical importance in the contexts of these contributions, a brief scientific report by Griscelli is presented—even though at the outset the editors promised no detailed scientific research papers in a series designed to present scientific advances to the practioner and student in a digested form. In the work of Griscelli and his colleagues (that is, incidentally, supported by simultaneous discoveries by Ballow and others in Minneapolis), the possibility of reconciling the influence of transfer factor and the immunologie dogma may emerge; it looks as though transfer factor may not be acting as specifically as was origi- nally thought. It is certainly much less difficult to harmonize a nonspecific influence of this relatively small molecule with the demands of molecular biology, than it is to postulate highly specific influence requiring the transfer of information. Perhaps inclusion of this bit of relatively raw research data is not such a bad idea, and from time to time the editors may use this approach as future controversies need to be resolved or an important advance documented before the dust has settled. Because immunobiology is making a vigorous effort to analyze cancer and even to address the issue of prevention and treatment of cancer, as was indicated in George Klein's chapter in Volume 1, a major section of Volume 2—five chapters—is devoted to these struggles. Strong, very cogent criticisms of the theory of immunosurveillance against cancer as stated originally by Ehrlich, reiterated by Thomas in relation to transplantation immunity in 1958, and extensively promulgated by Burnet, Good, and others, presents a needed balance as the Hellströms, Schmidtke and Simmons, and Oettgen, and Bortin present different, PREFACE XV and apparently useful, ways not only for looking at, but for manipulating imunity to cancer. Prehn's concept that a little immunity may be essen- tial to stimulate some malignant cells represents a fresh new view for which considerable support has been accumulated by the author and his associates. There seems little doubt that the general concept of immuno- surveillance may have to be set aside or modified to fit those challenges. In the chapter by the Hellströms, the importance of factors capable of suppressing the cellular immunity that regularly develops in experi- mental and clinical malignancies is described and defined. Antigen-anti- body complexes appear to be among inhibiting factors which suggest a number of approaches to the abrogation of such an influence. Oettgen's chapter balances the Hellström view with evidence that states clearly the complexity of approaching cancer from the immunologie view. He emphasizes the fact that antibodies of appropriate class and nature may have usefulness as we approach cancer therapy and management with immunological tools. Indeed, evidence has accumulated that some of the cell-mediated immunities involved in resistance to cancer cells may utilize antibodies. Details of this advance will be set forward in a future volume. It is clear already that antibodies are not all bad in cancer, nor is cell-mediated immunity necessarily all good. As was set down in the first volume by Starzl and Putnam, and Klein, it is clear that widely disseminated epithelial malignancy inadvertently transplanted along with successful organ transplants can be eliminated from the body by immunological attack if only the host can look at the tumor as though the antigens added are "strong" rather than "weak" antigens. The final two chapters in this series concern themselves with the possibilities of this approach. Simmons shows that in some experi- mental tumor systems manipulation of the surface of the cancer cell by enzymatic means can provide this advantage and will permit, in these experimental circumstances, prevention and even treatment of es- tablished cancer. Bortin presents ingenious means by which allogeneic recognition and immune assault might be used in approaching residual cancer or leukemia. We anticipate that clinicians will find as much that is useful and exciting in the second compilation of this series as we have found in bringing together this cluster of advances in clinical immunobiology. It is becoming clear to us in responses to, and reflections on, Volumes 1 and 2, what some of the requirements of future volumes may be. Rapidly developing methodologies in this field require forthwith a volume defining the best and most useful immunobiologic methodologies presented in a manner that will be helpful to the physician and to his laboratory associates. This will come soon. The magnificent potential xvi PREFACE of cellular engineering, coupled as it is to advancing knowledge of immunogenetics, requires that the current state of the latter part be put forward succinctly and clearly so that it can be understood and used by doctors. Rapidly developing knowledge of immunobiological pertur- bations during infection, and especially the clinical immunobiology of viral, bacterial, and fungal diseases and their relationships to auto- immunity, needs exposition. Descriptions of new knowledge of the primary immunodeficiencies, and especially of the diseases associated with genetically based perturbations of the biologic amplification systems, like complement and phagocytosis, must be attended to. Even the cor- rection of some of these can be the basis for exciting reading. We feel certain that the series on advances in clinical immunobiology is fairly launched and we look forward to future volumes with enthusiasm. FRITZ H. BACH ROBERT A. GOOD Contents of Volume 1 Structure-Function Relations in the Lymphoid System Robert A. Good The Immunoglobulins Richard Hong Cellular Immunity H. Sherwood Lawrence Transplantation Immunology Thomas E. Starzl and Charles W. Putnam Immunological Tolerance A. C. Allison Inflammation Michael T. Lamm and Chandler A. Stetson, Jr. Fundamental Immunogenetics—Their Application to Histocompatibility Fritz H. Bach and Marilyn L. Bach Humoral Amplification Systems in Inflammation Lawrence G. Hunsicker, Bruce U. Wintroub, and K. Frank Austen Immunosuppression Eugene M. Lance Tumor Immunology George Klein Allergy L. M. Lichtenstein Immunological Deficiency Disease Fred S. Rosen Subject Index xvii 1 Bone Marrow Transplantation E. DONNALL THOMAS2 Department of Medicine, University of Washington School of Medicine, Seattle, Washington, and the United States Public Health Service Hospital, Seattle, Washington I. Introduction 2 II. Terminology 4 III. Technique 4 IV. Histocompatibility 5 V. Preparation of the Recipient 7 VI. Clinical Results 8 A. Syngeneic Grafts 8 B. Allogeneic Grafts between HL-A-Matched Donor and Recipient Pairs 9 C. Allogeneic Grafts between HL-A-Mismatched Donor and Recipient Pairs 11 VII. Special Consideration According to Underlying Disease 11 A. Leukemia 11 B. Aplastic Anemia 14 VIII. Support for the Patient without Marrow Function 16 A. Support by Red Blood Cell Transfusions 17 B. Support by Platelet Transfusions 17 C. Support by Granulocyte Transfusions 18 D. The Problem of Sensitization to Transplantation Antigens by Blood Transfusion 19 E. The Problem of GVH Disease from Immunocompetent Cells in Transfused Blood 19 F. Protection against Infection 20 1 Supported by Research Grants CA 10895, CA 10167 and AI 09419, Contract PH 43-67-1435 and Training Grant CA 05231 from the U.S. Public Health Service, and by Grant CI-52 from the American Cancer Society. 2 Recipient of Research Career Award 5 K6 AI 02425 from the U.S. Public Health Service. 1