Immune Deficiency and Cancer Epstein - Barr Virus and Lymphoproliferative Malignancies
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1 Immune Deficiency and Cancer Epstein - Barr Virus and Lymphoproliferative Malignancies
2 Immune Deficiency and Cancer Epstein-Barr Virus and Lymphoproliferative Malignancies Edited by David T. Purtilo University of Nebraska Medical Center Omaha, Nebraska Plenum Medical Book Company New York and London
3 Main entry under title: Library of Congress Cataloging in Publication Data Immune deficiency and cancer. Includes bibliographical references and index. 1. Lymphoproliferative disorders-etiology. 2. Epstein-Barr virus. 3. 1m munological deficiency syndromes-complications and sequelae. 4. Viral carcinogenesis. 5. Cancer-Immunological aspects. I. Purtilo, David Too II. Title. (DNLM: 1. Epstein-Barr virus-pathogenicity-con gresses. 2. Lymphoproliferative disorders-etiology-congresses. WH 700 S9895i 1982) RC646.2.I ' ISBN-13: e-isbn-13: : / Plenum Publishing Corporation Softcover reprint ofthe hardcover 1st edition Spring Street, New York, N.Y Plenum Medical Book Company is an imprint of Plenum Publishing Corporation All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical. photocopying, microfilming, recording, or otherwise, without written permission from the Publisher
4 This book is dedicated to the memory of Colin, Keith, and James, and to a healthy life for Billy, Nathan, and Kenny.
5 PREFACE The discoveries of Burkitt, Epstein, and Henle have laid the foundation for continuing generation of information regarding the mechanisms of induction of diseases by Epstein-Barr virus. The discovery of the virus two decades ago resulted from clinical and basic science collaborative studies on Burkitt lymphoma. Subsequently, nasopharyngeal carcinoma and infectious mononucleosis have been linked etiologically with the virus. During the first decade of research following the discovery of the virus, the mechanisms for the induction of BL, NPC, and IM were sought. At that time one prevailing view was that individual oncogenic strains of EBV were responsible for the different disorders. Paralleling the development of immunology in the 1970's was the accrual of knowledge about immunological events occurring during IM. These studies suggest that immune defense mechanisms determine the outcome of this viral infection rather than different viral strains. During the early 1970's, Starzl and Penn and Gatti and Good had noted an increased frequency of malignancy in renal allograft recipients and children with primary immune deficiency disorders, respectively. These observations provoked investigators to restudy the role of immune surveillance against malignancy. At that time immune surveillance was thought to occur against tumor-specific antigens; thereby neoplasms were eliminated. Breakdown of immune surveillance was reasoned to be responsible for the development of a wide variety of malignancies. However, after arduous research on experimental models and patients, it appears that the surveillance is relevant chiefly to virally induced malignancies in immune deficient individuals. Noteworthy, is the restricted appearance of only a few histologic types of malignancy in immune deficient patients. In the child with inherited immune deficiency, the predominant malignancy is malignant lymphoma of the B cell type. In children with primary immune deficiency, more than half of the cases of malignancy are malignant lymphomas. Similarly, malignancies in renal allograft patients are predominantly virally linked B cell lymphomas. Cutaneous squamous cell carcinomas, Kaposi's sarcoma, and uterine vii
6 viii PREFACE cervical carcinoma which are prevalent could be caused by ubiquitous viruses. In 1975 we described the X-linked recessive progressive combined variable immunodeficiency disorder (Duncan's disease) which is manifested as fatal infectious mononucleosis, aplastic anemia, agammaglobulinemia, or malignant lymphoma. X-linked lymphoproliferative syndrome (XLP) has served as a model for studying viralinduced diseases governed by immune responses. In a group of 100 patients with XLP approximately two-thirds have developed fatal infectious mononucleosis, 35% malignant B cell lymphoma, 19% a- or hypo-gammaglobulinemia, and 17% aplastic anemia. EBV genome has been identified in all of the surgical biopsy and autopsy tissues studied. Collaborative studies have revealed immune defects in individuals prior to infection by EBV which become accentuated f~llowing infection by the virus. The editor had reasoned that immune deficiency in transplant patients and other individuals with primary immune deficiency may allow EBV to evoke various clinical disorders. In 1981, he and George Klein asked colleagues throughout Europe and North America to contribute to a volume of Cancer Research. In the November issue the investigators documented that EBV-induced fatal lymphoproliferative diseases occurred in immune deficient allograft recipients and children with primary immune deficiency disorders. They also noted that often the malignant lymphomas were polyclonal B cell proliferative disorders simulating malignant lymphoma. In 1979 George Klein had hypothesized that polyclonal B cell proliferation in African children at risk for Burkitt lymphoma could convert to monoclonal malignancy vis-a-vis an 8;14 reciprocal translocation resulting in a 14q+ aberration. The Manolovs had described in 1971 this specific chromosomal alteration. This seminal study has provided an opportunity to investigate the role of immunoglobulin gene (heavy and light chains) and oncogene (c-myc and B-lym) rearrangements in the induction of Burkitt lymphomas. In this volume we update recent studies on EBV and the role of immune deficiency in the induction of lymphoproliferative diseases. On September 22-23, 1982 a symposium was held in Omaha, Nebraska. Many of the chapters contained herein were the outgrowth of the presentations and discussions at the meeting. I have asked several investigators to prepare manuscripts for inclusion in this book. The editor takes responsibility for the errors introduced in editing these manuscripts. The continuing elaboration of a very wide spectrum of diseases provoked by Epstein-Barr virus in individuals with various types of immunological disorders has been surprising to many. Epstein-Barr virus was becoming the forgotten virus in
7 PREFACE ix cancer research. Many had assumed that the road blocks to proving that EBV was oncogenic in Burkitt's lymphoma and nasopharyngeal carcinoma would not be overcome. Explosive growth knowledge in molecular virology, immunopathology, cytogenetics, and immunopharmacology has opened new vistas to mechanisms whereby this virus induces many diseases in human beings. We can now diagnose EBV infection accurately and quantitate immunological deficiencies. Improved diagnosis and the advent of new drugs to treat the patients and measures to prevent immune deficiency offer bright prospects for obviating EBV-induced diseases. The contributors are thanked for their creative product. This book goes beyond reportage by development of testable hypotheses. The research reported here from my laboratory was supported by contributions to the Lymphoproliferative Research Fund and PHHS grant number 30196, awarded by the National Cancer Institute, DHHS, the American Cancer Society RD161, and the Nebraska Department of Health LBS06. The expert photographic work of Mr. James Smith and Sergio Diaz is appreciated. Karen Spiegel, who typed the manuscript under the guidance of Ms. Leslie Schmidt, is acknowledged with gratitude. My wife, Ruth Purtilo, Ph.D., is thanked for her consultation and support in my investigation of patients with immune deficiency. David T. Purtilo, M.D. Professor and Chairman Department of Pathology and Laboratory Medicine, Professor of Pediatrics, and Professor in Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical Center Omaha, Nebraska
8 CONTENTS Immune Deficiency, Epstein-Barr Virus (EBV) and Lymphoproliferative Disorders... 1 D.T. Purtilo CLASSICAL EPSTEIN-BARR VIRUS ASSOCIATED DISORDERS Infectious Mononucleosis and Complications J. Linder and D.T. Purtilo Nasopharyngeal Carcinoma G.R.F. Krueger Burkitt '8 Lymphoma J. Linder and D.T. Purtilo INHERITED IMMUNE DEFICIENCY AND LYMPHOPROLIFERATIVE MALIGNANCIES Hematopathology of X-Linked Lymphoproliferative Syndrome D.T. Purtilo Responses to Epstein-Barr Virus in Immune Deficient Patients S. Harada, E. Tatsumi, H. Lipscomb, and D.T. Purtilo Immunodeficiency to Epstein-Barr Virus in Chediak-Higashi Syndrome F. Merino xi
9 xii CONTENTS MODEL SYSTEMS FOR EPSTEIN-BARR VIRUS-TARGET CELL INTERACTION Expression of Virus-Associated Functions in Cells Transformed In Vitro by Epstein-Barr Virus: Epstein-Barr Virus Cell Surface Antigen and Virus-Release From Transformed Cells B. Sugden In Vitro Modulation of Epstein-Barr Virus- Carrying Lymphoblastoid Cell Lines J. Roubal, E. Anisimova, and K. Prachova Epstein-Barr Virus in New Host Cells D.J. Volsky Biology of Epstein-Barr Virus H. Wolf Herpesvirus-Induced Lymphoproliferative Diseases in Non-Human Primates D.R. Johnson Relationship of Immune Deficiency and Oncogenic Viruses to Malignant B Cell Lymphomas: Mouse and Man P.K. Pattengale ACQUIRED IMMUNE DEFICIENCY AND LYMPHOPROLIFERATIVE DISORDERS Allograft Transplant Cancer Registry I. Penn Lymphoma in Cardiac Transplant Recipients Associated with Cyclosporin A, Prednisone, and Anti-Thymocyte Globulin (ATG) C.P. Bieber, R.L. Heberling, S.W. Jamieson, P.E. Oyer, M. Cleary, R. Warnke, A. Saemundsen, G. Klein, W. Henle, and E. Stinson Lymphoproliferative Diseases in Renal Allograft Recipients D.W. Hanto, G. Frizzera, K.J. Gajl-Peczalska, D.T. Purtilo, and R.L. Simmons Chronic Mononucleosis M. Tobi, and A. Morag
10 CONTENTS xiii The Syndrome of Acquired Immunodeficiency Among a Subset of Homosexual Men J.A. Sonnabend, S.S. Witkin, R.B. Purti10, and D.T. Purti10 Lymphopro1iferative Diseases and Kaposi's Sarcoma in Homosexual Males D. Abrams GENETIC FACTORS IN LYMPHOMAGENESIS Mendelian Predisposition to Lymphomagenesis H.T. Lynch, and G.S. Schuelke Chromosomal Defects and Their Role in Lymphomagenesis A.A. Sandberg PREVENTION OF EPSTEIN-BARR INDUCED DISEASES IN IMMUNODEFICIENT INDIVIDUALS Interferon Therapy in Herpes Virus Infections M. Fiala, and S. Chatterjee Epstein-Barr Virus and Marrow Transplantation Recipients H.J. Meuwissen, and D.T. Purti10 Immunoreconstitution by Bone Marrow Transplantation Decreases Lymphopro1iferative Malignancies in Wiskott-A1drich and Severe Combined Immune Deficiency Syndromes ' S.L. Neudorf, A.H. Fi1ipovich, and J.H. Kersey Contributors Index
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