Curren t Topics in Microbiology 222 and Immunology Editors R.W. Compans, Atlanta/Georgia M. Cooper, Birmingham/Alabama· J.H. Hogle, Boston/Massachusetts· H. Koprowski, Philadelphia/Pennsylvania . F. Me1chers, Basel M. Oldstone, La Jolla/California· S. Olsnes, Oslo M. Potter, Bethesda/Maryland· H. Saedler, Cologne P.K. Vogt, La Jolla/California· H. Wagner, Munich Springer Berlin Heidelberg New York Barcelona Budapest Hong Kong London Milan Paris Santa Clara Singapore Tokyo Reproductive Immunology Edited by L.B. Olding With 17 Figures and 10 Tables , Springer Professor LARS B. OLDING, M.D., Ph.D. Department of Immunology, Microbiology, Pathology and Infectious Diseases Karolinska Institute Division of Pathology, F42 Huddinge University Hospital S-141 86 Huddinge Sweden Cover illustration: "The human fetus in the uterus". Pencil-drawing by Leonardo Da Vinci around 1510. Royal Library, Windsor Castle. Cover design: Design & Production GmbH, Heidelberg ISSN 0070-217X ISBN-13: 978-3.Q42-64475-7 e-ISBN-13: 978-3.Q42-606144 DOl: IO.lOO7/978-3.Q42-606144 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1997 Library of Congress Catalog Card Number 15-12910 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting other relevant literature. Typesetting: Scientific Publishing Services (P) Ltd, Madras SPIN: 10485040 27/3020/SPS - 5 4 3 2 I 0 - Printed on acid-free paper Foreword Discrimination of self from nonself is the major function of the immune system and understanding the mechanism(s) involved a main employer of immunologists. Hence, the age-old puzzle of why a fetus that contains a panel of major histocompatibility (MHC) antigens derived from its mother and its father is not rejected (spontaneously aborted) by lymphocytes from its mother who should theoretically recognize foreign MHC molecules from the father has remained of great interest. This dilemma has enticed immunologists and developmental biologists for many years. This volume was created to present the information currently on hand in this subject to the scientific public. The guest editor, Professor Lars Olding, has a long and distinguished history of contributions in this field, having been one of the main propo nents of the argument that lymphocytes from the fetus play an active role in this process by suppressing lymphocytes from the mother from proliferating and thereby acting as killer cells. His work has defined the phenomenon and identified suppressor molecules (factors) involved in the process. In a different but related chapter, Margareta Unander extends such observations to the clinical study of women with repeated "habitual" mIS carriages. But, in addition, there is the topography associated with maternal-fetal lymphoid cell interactions. Knowledge of the structural basis of the human placenta, and the immunobiology of the decidua and of trophoblasts are important issues for sol ving the puzzle. Information in these areas is supplied by several experts who have contributions in this line of research including Drs. Faulk, Clark, and Redline. To round out this volume, other contributors (Drs. Adinolfi, Chaouat, Menu, Papadogiannakis, Goldman, and Goldblum) discuss trafficking of leukocytes, other issues of T-cell reactivity in the fetus, newborn or mother, and antigen presentation in specialized cells at the maternal-fetal in terface. The lessons to be learned from study of the immunobiology of maternal-fetal interactions are not only important for the area VI Foreword of normal birth and spontaneous miscarriages, but have the po tential to provide both understanding and development of pharmacological approaches to enhance successful transplanta tion and gene therapy. La Jolla, California MICHAEL B.A. OLDSTONE Preface Reproductive immunology encompasses virtually all facets of modern immunobiology; accordingly, a complete review would be encyclopedic. Therefore, this volume includes only selected topics in recent research, older investigations of relevance, and topics which have been to some extent ignored by the inter national community of scientists in the field. Recent progress in immunogenetics that sheds light on the major histocompatibility complex (MHC) antigens on tropho blasts, particularly the unique HLA-G antigen on invading "frontier" trophoblasts, is reviewed by Drs. Ober and van der Ven. They also elucidate the old and controversial question of whether parental sharing of one or more HLA antigen compro mises gestation, a subject that has been studied in a secluded religious sect. Modern aspects of the human placental structure associated with strictly defined immune cells are then reviewed by Dr. Redline. Next, the decidua and its occupancy by bone-mar row-derived cells with strong immunological potency are thor oughly discussed by Drs. Arck and Clark. Immunomodulation of these cells is crucial for successful implantation of the blastocyst. The important problem of the ontogeny, differentiation, and maturation of fetal immunity is discussed at length by Dr. Adi nolfi in terms of both the natural and. acquired states. Drs Chaouat and Menu subsequently provide an overview of ma ternal T-cell reactivity, which is important for the recognition of fetal antigens, as shown in vitro and in animal experiments. The ability of the trophoblast to evade recognition, destruction, and rejection by maternal cytotoxic immune cells is the topic reviewed by Drs. Torrey, McIntyre, and Faulk. They propose that pro tection might be delivered by "blocking antibody" raised against an antigen common to both trophoblasts and lymphocytes. This observation, although controversial, has attracted great interest. The extent and possible importance of leakage of fetal leukocytes into the maternal circulation within the placenta - and perhaps in the opposite direction as well - is the controversial issue detailed in the chapter by Dr. Papadogiannakis. The importance of VIn Preface nonspecific suppressor-T-cell actlVlty in cord blood, pros taglandins, and alpha-fetoproteins in modulating maternal-fetal immune reactions is the subject of a chapter written by Drs. Olding, Papadogiannakis, Barbieri, and Murgita. New aspects of functional suppressor cells and of the genuine immunomodu latory potency of prostaglandins and alpha-fetoproteins are em phasized. Despite the mass of new information on reproductive im munobiology during the last three decades, few clinical applica tions have emerged. The difficulty in extrapolating results from experiments with animals or from in vitro investigations to the conditions of human pregnancy is obvious. Rarely can one study immunological events in vivo at the maternal-fetal interface in the human placenta, and laboratory animals differ too greatly in structure and function from humans for ready application of research outcomes. However, one clinical application is reviewed here by Dr. Unander: the treatment of women who have normal fertility but repeatedly undergo spontaneous (chronic or "habi tual") abortions, with leukocyte transfusions that produce the missing blocking antibodies. This kind of treatment is the subject of much controversy, but can apparently be successful. It is a well-known phenomenon that mothers continue to protect their babies after birth by means of antibodies transferred in breast milk. Less well known is that maternal immune cells in this milk might actually penetrate the barrier of the newborn's gut, as re viewed by Drs. Goldman and Goldblume in the chapter that concludes this volume. I am indebted to the authors for their great efforts in pre paring their reviews and to the publishers for their kind co operation and skill. Stockholm, April 1997 LARS B. OLDING List of Contents e. OBER and K. VAN DER VEN Immunogenetics of Reproduction: An Overview R.W. REDLINE The Structural Basis of Maternal-Fetal Immune Interactions in the Human Placenta 25 P.e. ARCK and D.A. CLARK Immunobiology of the Decidua. . . . . . . . . . . . . . . . . . . 45 M. ADINOLFI Ontogeny of Human Natural and Acquired Immunity 67 G. CHAOUAT and E. MENU Maternal T Cell Reactivity in Pregnancy? 103 D.S. TORRY, 1.A. McINTYRE, and W.P. FAULK Immunobiology of the Trophoblast: Mechanisms by Which Placental Tissues Evade Maternal Recognition and Rejection. . . . . . . . .. 127 N. PAPADOGIANNAKIS Traffic of Leukocytes Through the Maternofetal Placental Interface and Its Possible Consequences 141 L.B. OLDING, N. PAPADOGIANNAKIS, B. BARBIERI, and R.A. MURGITA Suppressive Cellular and Molecular Activities in Maternofetal Immune Interactions; Suppressor Cell Activity, Prostaglandins, and Alpha-Fetoproteins . . . . . . . . . . . . . . . . . . . . . . .. 159 A.M. UNANDER The Immunopathology of Recurrent Abortion. . . . . . .. 189 A.S. GOLDMAN and R.M. GOLDBLUM Transfer of Maternal Leukocytes to the Infant by Human Milk ............................. 205 Subject Index ............................... 215 List of Contributors (Their addresses can be found at the beginning of their respective chapters.) ADINOLFI, M. 67 MENU, E. 103 ARCK, P.e. 45 MURGITA, R.A. 159 BARBIERI, B. 159 OBER, e. 1 CHAOUAT, G. 103 OLDING, L.B. 159 CLARK, D.A. 45 PAPADOGIANNAKIS, N. 141,159 FAULK, W.P. 127 REDLINE, R.W. 25 GOLDBLUM, R.M. 205 TORRY, D.S. 127 GOLDMAN, A.S. 205 UNANDER, A.M. 189 McINTYRE, ] .A. 127 VAN DER VEN, K.