Table Of ContentB.G. Solheim S. Ferrone
E. Moller (Eds.)
The HLA System
in Clinical
Transplantation
Basic Concepts and Importance
With 48 Figures and 31 Tables
Springer- Verlag
Berlin Heidelberg New York
London Paris Tokyo
HongKong Barcelona
Budapest
Professor Bjarte G. Solheim
Department Group for Laboratory Medicine
University of Oslo
Rikshospitalet
0027 Oslo, Norway
Professor Dr. Soldano Ferrone
New York Medical College
Department of Microbiology
and Immunology
Valhalla, NY 10595, USA
Professor Dr. Erna Moller
Department for Clinical Immunology
Huddinge sjukhus
141 86 H uddinge, Sweden
ISBN-13: 978-3-642-77508-6 e-ISBN-13: 978-3-642-77506-2
DOl: 10.1007/978-3-642-77506-2
Library of Congress Cataloging-in-Publication Data
The HLA system in clinical transplantation: basic concepts and importance / B. G. Solheim, S. Fer
rone, E. Moller (eds.). p. cm. Includes bibliographical references and index.
1. Major histocompatibility complex. 2. HLA histocompatibility antigens. 3. Transplantation im
munology. I. Solheim, Bjarte B. II. Ferrone, Soldano, 1940-. III. Moller, Erna. [DNLM: 1. HLA
Antigens - Immunology. 2. Major Histocompatibility Complex. 3. Uansplantation Immunology.
WO 680 H676953] QRI84.315.H5 1993 617.9'5-dc20 DNLMIDLC for Library of Congress
92-48813 CIP
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. Duplica
tion 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 Copy
right Law.
© Springer-Verlag Berlin Heidelberg 1993
Sollcover reprint of the hardcover Is t edition 1993
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 informa
tion by consulting the relevant literature.
Typesetting: K + V Fotosatz GmbH, Beerfelden
23/3145-5 4 3 2 1 0 - Printed on acid-free paper
Preface
With this book we· want to address young graduate students, clini
cians involved in transplantation, and technicians in transplantation
immunology laboratories. The volume should give a comprehensive
but basic, up to date introduction to the structure, function, and
clinical importance of the HLA system. We believe that there is a need
for such a survey, and think that the present level of our knowledge
is an optimal occasion for publication. A significant number of ques
tions have now been resolved, and our knowledge has reached a level
of sophistication that provides the basis for additional questions and
answers.
Although the emphasis of this book is on the role of HLA anti
gens in clinical transplantation, their involvement in other clinical
contexts is also discussed. The main focus is on the human MHC an
tigenic system, but MHC systems in other species are described as
they contribute to our understanding of the structural and functional
characteristics of HLA antigens. Some important issues related to
laboratory techniques are also covered.
The contributors have a close affiliation to the field of transplan
tation immunology. A majority have even been playing important
roles in unraveling the HLA system and its functions. We believe this
has contributed significantly to the quality and clinical and practical
relevance of the book. As editors, we drew up the principal guidelines
and took care that the chapters can be read as separate entities,
although this invariably results in some overlapping.
In the Introduction the tremendous development of the field is
unraveled through the personal experiences of Nobel laureate Jean
Dausset and Felix T. Rapaport, while Jan Klein and Christian SchOn
bach in their chapter give a picture of the fascinating origin of MHC
diversity.
The part Genetics, Chemistry and Expression is opened by chap
ters by John Trowsdale and Isabel Hanson and by Jose Antonio
LOpez de Castro, which complement each other in introducing the
reader to the genetics and chemistry of the MHC genes and mole
cules. Jacques J. Neefjes and Hidde L. Ploegh present the dynamic
VI Preface
concept of the assembly and intracellular transport of MHC
molecules. Bernhard Mach and Walter Reith discuss the molecular
mechanisms implicated in the fine control of MHC class II gene ex
pression. In the final chapter of this part, Elizabeth Simpson dis
cusses minor transplantation antigens and draws attention to new in
sights into the structure of MHC molecules and the importance of
endogenous peptides and self-superantigens.
In the part Biological Function oj MHC Molecules, Nobel
laureate Baruj Benacerraf's discussion of the biological function of
HLA molecules is followed by Dow-Rhoon Koh and Tak W. Mak's
chapter on the role of MHC molecules in thymic development and
selection of T-cell repertoires. A picture of the molecular mechanisms
of HLA associated autoImmunity is drawn by Hugh O. McDevitt and
associates. Peter E. Lipsky introduces the reader to the sign~ trans
ducing capacity of MHC class I molecules, while Michael Edidin dis
cusses interactions between MHC molecules and other cell surface
molecules. Finally, Michael Feldman and Lea Eisenbach present ex
tensive evidence supporting the thesis that MHC antigens control
growth and metastatic properties of tumor cells.
The section Allorecognition oj HLA Molecules focuses on aspects
of tissue typing and allorecognition. Ben A. Bradley and associates
present T-cell recognition and typing methods, while Julia Bodmer
and collaborators discuss current methods for serological identifica
tion of HLA antigens by alloantisera and monoclonal antibodies,
and methods which are likely to be applied in the future utilizing
recombinant DNA technology. Alan Ting analyzes the relevance of
HLA antibodies, non-HLA antibodies, and serologic cross-match
methods in organ transplantation. Finally, Erna Moller and Suchitra
Sumitran Karuppan discuss the alloimmune cellular and humoral
response in the transplant patient.
The part HLA Matching is opened by Torbj0rn Leivestad and as
sociates with a discussion and demonstration of the relevance of
HLA matching in clinical organ transplantation. Transplantation
tolerance and the nonreactivity to noninherited maternal HLA an
tigens is presented by Frans H. J. Claas and collaborators, while Per
Fauchald and associates discuss approaches to avoid humoral im
munization and to condition immunized patients for transplantation.
Jean Franc;ois Bach and Jean-Paul Viard start the part on Im
munosuppression with a survey of immunosuppressive therapy. Her
man Waldmann focuses on selective depletion of alloreactive cells in
transplantations, while Inger Lundkvist and colleagues discuss the
possibilities, implications, and potential serious complications from
the application of monoclonal antibodies for modification of alloim
munity. Finally, Soldano Ferrone and associates present intriguing
data on an idiotypic network in HLA immunization with the develop
ment of antiidiotypic antibodies following blood transfusions and a
Preface VII
possible beneficial role of antiidiotypic antibodies on the outcome of
renal allografts.
The problem of organ Rejection is presented in a two chapter sec
tion. Risto Renkonen and collaborators summarize cellular and mo
lecular mechanisms and the role of viral infections, and David
Hughes discusses fine needle aspiration biopsy in the rejection diag
nosis of human renal allografts.
Bone Marrow Transplantation is an increasingly important issue
within clinical transplantation. Olle Ringden discusses procedures
and results when related donors are used, while Patrick C. Beatty
focuses on the possibilities and limitations introduced by the use of
unrelated donors. Finally, Gunnar Kvalheim summarizes the status of
bone marrow purging.
The current feasibility of xenografting is analyzed by Jo Buyske
and Hugh Auchincloss.
Finally, Malignancy After Transplantation, which represents a
serious and not infrequent complication, is extensively reviewed by
Israel Penn.
With respect to nomenclature, we want to draw the attention to
two important contributions by Jan Klein and collaborators in 1990.
The first presents a nomenclature for the major histocompatibility
complex of different species, while the second proposes a revised
nomenclature of mouse H-2 genes. The two papers are reproduced in
an addendum to this book.
We would like to thank all the contributors for their cooperation
and interest in preparing their chapters, and are grateful to the
publisher for help during the various phases of preparation of this
volume.
Oslo, Valhalla, and Huddinge, B. G. Solheim
October 1992 S. Ferrone
E. Moller
Contents
Introduction
The Life and Times
of the Human Major Histocompatibility Complex
J. Dausset and F. T. Rapaport ........................... 3
Origins of Mhc Diversity
J. Klein and C. SchOnbach 16
Genetics, Chemistry and Expression
MHC Genes
J. Trowsdale and L Hanson. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Class I and Class II HLA Proteins and Genes:
An Overview of Structure, Polymorphism, and Expression
J. A. L6pez de Castro .................................. 49
Assembly and Intracellular Transport of MHC Molecules
J. J. Neefjes and H. L. Ploegh ........................... 63
Regulation and Deregulation of HLA Class II Genes
B. Mach and W. Reith ................................. 82
Minor Transplantation Antigens
E. Simpson ........................................... 91
Biological Function of MHC Molecules
Biological Function of HLA Molecules
B. Benacerraj ......................................... 109
MHC Molecules in Thymic Development
and Selection of the T Cell Repertoire
D.R. Koh and T. W. Mak ............................... 119
The Molecular Mechanisms
of HLA Associated Autoimmunity
R. Tisch, L. Fugger, S.M. Singer, and H O. McDevitt...... 148
The Capacity of Class I MHC Molecules
to Function as Signal Transduction Elements
T. D. Geppert, H Gur, and P. E. Lipsky .................. 167
The Major Histocompatibility Complex and Cell Physiology
M Edidin ..........................................- .. 177
MHC Control of Growth
and Metastatic Properties of Tumor Cells
M Feldmann and L. Eisenbach ......................... 185
Allorecognition of HLA Molecules
HLA Molecules in Allorecognition:
T Cell Recognition and Typing Methods
E. Kaminski, A. Martin, and B. A. Bradley 201
B Cell Recognition and HLA Typing: Current Methods
and Future Possibilities. Role of Alloantibodies
and Monoclonal Antibodies as Reagents
J. G. Bodmer, S. G. E. Marsh, J. M Heyes, L. J. Kennedy,
J. H Moses, A. M Sadler, and S. Tonks .................. 214
HLA Antibodies, Non-HLA Antibodies,
and Crossmatch Methods
A. Ting .............................................. 232
Transplantation of the Alloimmunized Patient
E. Moller and S. Sumitran-Karuppan .................... 243
HLA-Matching
HLA Matching in Clinical Organ Transplantation
T. Leivestad, F. Vartdal, and E. Thorsby ................. 261
Contents XI
Transplantation Tolerance
and Noninherited Maternal HLA Antigens
F. H. 1. Claas, L. Zhang, and 1. 1. van Rood . . . . . . . . . . . . . .. 270
What To Do with the Immunized Patient.
How to Avoid Humoral Immunization
P. Fauchald, D. Albrechtsen, A. V. Reisaeter, A. Jakobsen,
and B. G. Solheim ..................................... 277
Immunosuppression
Immunosuppressive Therapy
1.-F. Bach and 1.-P. Viard ... . . . . . . . . . . . . . . . . . . . . . . . . . . .. 287
Selective Depletion of Alloreactive Cells in Transplantation
H. Waldmann ......................................... 300
Immunological Considerations
on the Use of Monoclonal Antibodies
for In Vitro and In Vivo Modification of Alloimmunity
L Lundkvist, D. Holmberg, and G. Thfveson ............. 306
Anti-idiotypic Antibodies in the HLA System
S. M. Mariani, E. A. Armandola, and S. Ferrone . . . . . . . . . .. 317
Rejection
Cellular and Molecular Mechanism of Rejection
and Role of Viral Infection
R. Renkonen, L Lautenschlager, and P. Hiiyry ............ 327
Fine-Needle Aspiration Biopsy in Rejection Diagnosis
D. Hughes ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 339
Bone Marrow 'ftansplantation
Bone Marrow Transplantation Using Related Donors
O. Ringden ........................................... 351
Marrow Transplantation from Unrelated Donors
P. G. Beatty ........................................... 366
XII Contents
Purging of Bone Marrow
G. Kvalheim .......................................... 373
Xenografting
Xenografting: Is It Feasible?
J. Buyske and H. Auchincloss Jr. 383
Malignancy after 'fiansplantation
Tumors in Transplanted Patients
1. Penn .............................................. 395
Addendum
Nomenclature for the Major Histocompatibility Complexes
of Different Species: A Proposal
J. Klein et al. ......................................... 407
Revised Nomenclature of Mouse H-2 Genes
J. Klein et al. ......................................... 412
Subject Index ......................................... 419
