Therapeutic immunosuppression has very broad applications in clinical medicine, ranging from prevention and treatment of organ and bone marrow transplant rejection, management of various autoimmune disorders (e.g., rheumatoid arthritis), skin disease, and asthma. Whereas traditionally only a small repertoire of immunosuppressive agents was available for clinical use, recent discoveries have significantly increased the number of approved agents, resulting in numerous trials to further evaluate their potential. In addition, products of the biotechnology industry - monoclonal antibodies, cytokines, cytokine antagonists, and other products of genetic engineering that target key molecular pathways in disease pathogenesis - have either already made, or are on the verge of making an important impact on treatment. There is also considerable interest in the potential of cell-based therapies (particularly hematopoietic stem and dendritic cell therapy) of allo- and autoimmunity. Important recent advances in the immunotherapy of allergic diseases are also covered in this book. Gene therapy offers considerable promise for suppressing pathogenic processes in either transplantation or autoimmune disorders. The possibility of combining these important new advances to maximize benefit to the patient, and to minimize possible untoward effects (which are also given extensive coverage in this book), is one of the most exciting challenges of contemporary medicine. This volume is intended both for practising physicians and surgeons and for biomedical scientists at the graduate/postdoctoral levels, and is designed to provide the theory behind these various approaches to immunosuppression, and to provide state-of-the-art reviews of current developments in each area. Each chapter is contributed by one or more experts in the field. There was a need to bring this information together in a single volume, as much of the key recent developments have been dispersed throughout the biomedical literature, largely in specialized journals. Since, as in the past, important developments in immunosuppressive therapy in one branch of medicine (i.e. transplantation) are likely to benefit another (e.g., dermatology, rheumatology, gastroenterology), cross-disciplinary coverage of the mechanistic basis of the various therapeutic strategies in a single volume is likely to convey the potential of advances in therapy in the most coherent manner possible.

New Harvest includes contributions from specialists in medical, philosophical, psychological, religious, and legal fields. These essays are not simply a collection, but were developed from a single conception of the four ethical concerns of trans plan tation described in the first chapter. The indi vid ual chapters are all parts of a structure unified by the search for ethical foundations basic to the four concerns. Transplantation is surrounded by a great deal of under standable emotional sensitivi ty. The authors trust that words like "procurement," "harvest," and possibly other expressions found in this book will not offend. We use the current lan but do so with objectivity and respect for those who guage, are personally involved in transplantation. We have made room for, and indeed have invited, different and sometimes conflicting points of view on the complicated ethical ques tions raised by transplant operations. We can not assume that there is one right answer to these questions, at least at our present level of scientific knowledge and ethical wisdom. We do not presume to have identified and analyzed all the ethical questions raised with equal thoroughness. There are four ways in which the scope of the book is limited. Identifying these limitations also helps designate what it is in its own right. First, some questions have been given more attention than others.

As dogmas in stem cell research are losing their impact and recent findings regarding the use and cultivation of stem cells and tissue transplantation have opened up new therapeutic avenues, this Ernst Schering Research Foundation Workshop was initiated to highlight current and future approaches in this field. The only stem cells that have been used clinically for a long time is the hematopoietic stem cell as a source for bone marrow transplantation. Recent findings now indicate that hematopoietic stem cells, under certain conditions, are able to differentiate into endothelial, neural or muscle cells, providing exciting new therapeutic possibilities. They represent a future source for tissue engineering replacing defective cells or tissues and allowing diseased organs to regain their functions. Both reconstitution techniques are paving the way for the development of new therapeutic strategies, giving hope of being able to cure and not only treat patients.

General surgery consists ofa main corpus of propaedeutic elements and clinical problems, which has been modified over the years by the separate development of numerous sub-specialistic branches. Although a common basis on the physiopathology of surgical trauma and post operative complications persists, as a result of general knowledge of surgical diseases, there is no doubt that in the spheres of doctrine and application, both research and clinical medicine have distinguished themselves autonomously in many surgical fields (orthopedics, neurosurgery, cardiovascular surgery, thoracic surgery, urology, etc.). It is therefore difficult to define the present configuration ofgeneral surgery, but without question abdominal surgery occupies a position of pre-eminent importance within the general framework. We are dealing, in fact, with pathological pictures which occur in a section ofthe body ofvast proportions, in which structures, organs, and morphologically complex spaces are arranged to carry out important functions. They are, therefore, subject to considerably complex pathological alterations, such as to establish an interesting field of diagnostic discussion and an exciting training-ground for surgical activity. It can be affirmed that the diagnosis and cures ofabdominal surgical diseases constitute a test ofthe surgeon's experience. Diagnosis is often entrusted to a differential process, the results ofwhich may be confirmed today by complementary diagnostics. This, however, must be guided by predominating clinical considerations, the exaggerated use of diagnostic techniques, detached from clinical examination, being the cause of very serious errors, which can mislead decision making and human contact, which is the basis ofcorrect medical practice.

It has been 15 years since the first report on the isolation of anti-Gal from human serum and the demonstration that this antibody is the most prevalent antibody in humans (Galili et al. , ]. Exp. Med. 160: 1519, 1984). Subsequent interdisciplinary studies in immunology, carbohydrate biochemistry, molecular biology, and evo- lution demonstrated the highly restricted specificity of anti-Gal for the carbohy- drate epitope Gal al-3Galpl-4GIcNAc-R, (termed here the a-gal epitope), the unprecedented evolutionary pattern of distribution of a-gal and anti-Gal in mam- mals, and explained the evolution of this antigen and antibody by analysis of the a 1 ,3galactosyltransferase gene, the gene that encodes the enzyme that synthesizes the a-gal epitope. These studies have suggested that a major selection process that occurred in the course of evolution of ancestral Old World primates resulted in the inactivation of the a1 ,3galactosyltransferase gene and the subsequent appearance of anti-Gal in these primates. Other studies in immunoparasitology have demon- strated the possible physiologic significance of anti-Gal in protection against cer- tain parasitic infections. Major scientific attention was focused on a-gal and anti-Gal with the real- ization in the early nineties that the interaction between this antigen and antibody is the major obstacle to xenotransplantation. The success of immunosuppressive drugs, in the last two decades of the 20th century, in preventing allograft rejection, has raised hopes for cure in many patients in need of organ transplant. Because of limited supply of allografts, only 20% of patients receive the needed organ.

The field of transplantation has grown exponentially over the last few decades, and leaders in the field may argue that we have seen only the tip of the iceberg. Perhaps in no other discipline is there a need for multidisciplinary dialogue, debate, and approaches to patient care. In preparing this book, we have attempted to introduce readers to a few of the key clinical and ethical issues confronting the field of transplantation today. In so doing, we recognize that the face of transplantation may change dramatically in the years to come. Nevertheless, the issues raised throughout this book will serve as a useful introduction to important clinical issues and as a catalyst for clinicians and researchers to expand the horizons of transplantation. Health professionals involved in evaluating and treating transplant patients must be knowledgeable of the indications for transplantation and patient outcomes and the process of evaluation and management. Chapters 1 and 2, focusing on solid organ transplantation and blood/marrow transplantation, provide this important contextual information. The next two chapters address what is often considered the most significant issue facing the field of transplantation - organ donation. While the number of patients needing transplantation has risen dramatically in recent years, the rate of organ donation has remained relatively stable. Chapter 3 highlights the many ethical issues surrounding the more general concept of organ donation, while Chapter 4 focuses specifically on the burgeoning interest in living organ donation.

In Drugs and the Liver: High Risk patients and Transplantation, leading physicians, hepatologists, pharmacologists, pathologists and transplant surgeons discuss the most recent advances in the field of liver disease and their treatment. Attention is focused on epidemiology, the diagnosis of disease (clinical chemistry, histopathology, medical imaging analysis), prognosis, prediction, and clinical management. Pathogenesis of diseases such as liver cirrhosis following viral disease or alcohol abuse are discussed at length, and special attention is dedicated to high risk patients (children, fulminant hepatitis). The other major topics include terminal liver failure, for which transplantation is now routine. The latter is discussed in depth, starting from the organ donor management, organ evaluation and preservation, new surgical techniques, post-transplant patient follow-up including side effects of immunosuppression, and reports of the latest drugs used to prevent rejection.

An up-to-date overview of blood and marrow transplantations, the book discusses in detail Indication to transplantation and pre-transplant considerations. An outlook on the latest developments and their future aspects is included, while problems and pre- and post-transplant complications are fully explored.

Currently, individuals interested in seeking an in-depth discussion of transplantation immunology must seek individual articles published in several journals, or extrapolate information from various non-transplant immunology textbooks. The purpose of this text is to provide the reader with a single source of information for the basic science of immunobiology of organ transplantation. It is unique that it focuses on immunobiology from the basic research side, with an emphasis on the cellular and molecular levels. The readers will be physicians, scientists, and graduate students interested and engaged in the study of immunology as it relates to allo- and xenotransplantation. This book is designed to be the reference standard for the immunobiology of transplantation.

In recent years cell-based technologies have gained significant scientific attention, and have become a matter of intense public debate as well. Namely, (i) tissue engineering, the construction of tissues and whole organs using molecularly-designed resorbable biomaterials to create new tissue de novo with or without transplanting cells; (ii) the potential use of human embryonic stem cells for transplantation and regenerative medicine (with similar potential for adult-derived stem cells); (iii) and gene therapy, in relation with cell transplantation, have taken their places as the most discussed biomedical issues of the day. New findings in biomimetic materials, cell signalling pathways, extracellular matrix receptors and ligands, growth factors, and the human genome project are motivating the developments in these challenging research areas. This book includes manuscripts on tissue engineering, stem cells and gene therapies authored by world-renowned scientists of the field. The first section of the volume consists of four chapters giving perspectives for the current status and potential future of tissue engineering and stem cell technologies. The second section of the volume includes five chapters based on experimental and clinical data. In this section, the role of stem cells in liver tissue engineering, cell-based therapies in diabetes mellitus, and chronic degenerative diseases of the central nervous system, and adult-derived stem cell therapies are discussed. The two chapters of the third section focus on the biomarkers for tissue-engineered products, namely for tissue-engineered skin. The eight chapters of the fourth section discuss novel biomaterials developed for neural-, vascular-, aortic-, bone-, cartilage- and endocrine pancreas-tissue engineering applications. The last section of the book includes chapters on practical gene targeting applications, controlled release in gene therapy and tissue engineering, antibodies in cancer, acute-phase genes and phage-displayed peptide libraries. Proceedings of BIOMED 2002 The 9th International Symposium on Biomedical Science and Technology, held September 19-22, 2002, in Antalya, Turkey.

Integrated Biomaterials Science provides an intriguing insight into the world of biomaterials. It explores the materials and technology which have brought advances in new biomaterials, highlighting the way in which modern biology and medicine are synergistically linked to other key scientific disciplines-physics, chemistry, and engineering. In doing so, Integrated Biomaterials Science contains chapters on tissue engineering and gene therapy, standards and parameters of biomaterials, applications and interactions within the industrial world, as well as potential aspects of patent regulations. Integrated Biomaterials Science serves as a comprehensive guide to understanding this dynamic field, yet is designed so that chapters may be read and understood independently, depending on the needs of the reader. Integrated Biomaterials Science is attractive to a broad audience interested in a deeper understanding of this evolving field, and serves as a key resource for researchers and students of biomaterials courses, providing all with an opportunity to probe further.

Pre- and post-operative care of transplant patients is an aspect of Critical Care Medicine in which most ICU physicians and nurses have received little or no formal training and are left to cope with this complex population with only incomplete 'on-the-job experience' as a guide. In response to this clinical knowledge gap, ICU Care of Abdominal Organ Transplant Patients provides a concise bedside resource fo intensivists, surgeons, and nurses caring for abdominal organ transplant patients before and after surgery. In a concise, practical style, the authors offer concrete solutions to questions and situations confronted by ICU clinicians. Chapters address general principles of immunosuppression, infectious complications, management, and nursing considerations, plus indications, approach to anesthesia, transplant procedure, and post-operative care for liver, kidney, pancreas, islet cell, and small bowel and multivisceral transplantation.

In all varieties of organ transplants, early results have dramatically improved over the past two decades and failures due to acute rejection are becoming rarer. Efficient immunosuppressive regimens have been developed with the objective of very good results at 1, 3 and 5 years. Successful transplants, however, are significantly less frequent at 10 and 20 years, and many patients require retransplantation. Many factors are involved in late graft loss and it is now well recognized that, in addition to chronic rejection, a number of non-immunologic factors play a prominent role. In the case of renal transplantation, a reduced mass loss (transplantation of a single kidney, sometimes from an aged donor, ischemic injury and alteration of some nephrons in the case of early acute rejection) will result in slowly progressing chronic renal failure, even in the absence of any supplementary attack of an immunological nature. The new treatments must be analyzed in the light of their capacity to reduce these late failures. Several preventive measures can also limit both immunologic and non-immunologic factors of late transplant deterioration.

In the past few years the transplantation of organs in man has received publicity unprecedented in medical history. The first heart grafts were covered by press, radio, and television on a scal equiva lent to the news of the outbreak of a major war. Unwarranted and extravagant optimism has been followed by bitter criticism. This has undermined public confidence in the medical profession and seriously impeded progress in an important endeavour aimed at reducing human suffering. This unfortunate situation has arisen from widespread ignorance amongst the public and the medical profession of the background, present achievements, and future potential of organ grafting. Short statements by experts, frequently misquoted or cut short by television interviewers, and misinformed derogatory pronouncements by prejudiced medically qualified men, with no knowledge of the field, have produced a sorry state of confusion. It is the purpose of this book to attempt to clarify organ transplantation. The principles of organ transplantation are common to all organs but I will confine most of the discussion to transplantation of four vital organs, namely the kidney, liver, heart, and lung. ROY CALNE Cambridge January 1970 CONTENTS Preface IX List of Illustrations Xlll Acknowledgements XVll I. THE IDEA I II. THE SURGERY 7 III. REJECTION 15 IV. PREVENTION OF REJECTION 23 v. TISSUEMATCHING 39 VI. ORGAN PRESERVATION 47 VII. SUITABLE DONORS 53 VIII. ORGAN TRANSPLANTS 57 IX. ETHICS AND THE LAW 81 X."

This is a time ofexcitement and progress in the field ofxenotransplantation. The work described in this book traces the development of the science of cross-spe cies transplantation, summarizes the current state ofour knowledge, and focuses on approaches directed toward future clinical application. The important question is not whether xenotransplantation will succeed, but rather how and under what circumstances xenografts will provide predictable enough results to warrant clinical application. The fact that the best results to date in clinical xenografting were achieved over three decades ago should not be a matter of discouragement, but rather a stimulus to apply new approaches to this area of work. The shortage of human organs for transplantation is cited frequently as the driving force behind the increased interest in xenotransplantation. This shortage is an undeniable fact, but there are additional potential advantages of xenotrans plantation, such as the ability to schedule replacement surgery on an elective basis and the modification of animals, organs, and tissues to improve acceptabil ity in the human host. The advances in the basic science ofxenotransplantation outlined in this book give hope that the immunologic barriers to xenotransplantation will be overcome and that transplanted organs and tissues will succeed consistently in humans. However, if our experience with human allografts provides an analogy, we may anticipate that clinical progress in xenografts will be plagued by failures and rewarded by successes, often without a complete understanding of the mechan isms involved."

Parkinson's disease, a degenerative brain disorder, affects an estimated 0.25-0.50% of the population. Symptoms result from neuronal degeneration in the nigrostriatal dopaminergic pathway and include tremor, rigidity and gradual slow- ness of spontaneous movement. The cause of Parkinson's disease is only partially understood; both environmental factors and a genetic predisposition have been im- plicated in its etiopathogenesis. Neural transplantation is being used experimentally for providing an alternative biological source of dopamine both in animal studies and in experimental clinical trials. This book is the result of 15 years of research on the transplantation of dopaminergic neurons in the striatum of the weaver mouse, a neurological mutant characterized by genetically-determined degeneration of midbrain dopamine neurons. The weaver mouse constitutes the only available laboratory model with a chronic progressive disease that mimics Parkinsonism. The other two models currently used to investigate dopaminergic mechanisms rely on the use of the neurotoxins- hydroxydopamine and methylphenyltetrahydropyridine for the selective removal of dopaminergic neurons from an otherwise healthy organism. Structural and functional aspects of transplantation of mesencephalic dopamin- ergic grafts into the striatum of weaver mice are reviewed, including histochemical correlates of graft survival and integration, numerical aspects of donor neuron survival, ultrastructural findings on synaptogenesis, neurochemical indices of dopam- ine uptake function and receptor binding, gene expression of several structural and neurotransmitter-receptor related molecules, the levels of striatal amino acid receptors, and the behavioral effects of unilateral and bilateral neuronal transplantations.

Organ Shortage: The Solutions is the latest subject in the Continuing Education series, organized by Fondation Marcel Merieux and Universite Claude Bernard in Lyon. The annual subject is chosen to reflect the status of the topical issues of the year, as taught by leading international experts. The contribution of transplantation and clinical immunology to advanced medicine is considerable and promising. The annual volumes in this series keep the reader abreast of these developments. "

Non-myeloablative allogeneic stem cell transplantation (also known as mini-transplantation or reduced-intensity conditioning transplantation) is a major advance in the field of hematopoietic transplantation within the last 5 years. This approach uses non-cytotoxic or reduced-intensity cytotoxic therapy to prepare patients for allografting of hematopoietic stem cells and lymphocytes. It has the potential to deliver the potent anti-tumor immunotherapy and bone marrow replacement capacity of allogeneic stem cell transplantation to patients with reduced treatment-related morbidity and mortality. It may also enable allogeneic transplantation in patients who would be considered ineligible for conventional transplants because of co-morbidity or advanced age. However, this approach may necessitate more careful monitoring of post-transplant chimerism and malignant disease-status than is usual with conventional allografting. There is also controversy regarding the best preparative regimen and graft-versus-host disease prophylaxis to use.

MICHAEL F.A. WOODRUFF Emeritus Professor of Surgery, University of Edinburgh This book grew out of a very successful conference on Organ Transplantation held in Kuwait in December 1982. The material presented at the conference has been expanded and brought up to date, and the result is a well written and authoritative account of many aspects of organ transplantation by a distinguished team of contributors drawn from many countries. A unique feature of the book is the account it contains of the development of organ transplantation in the Middle East. Although, as yet, it has been virtually impossible in Islamic countries to take organs after death for use as transplants, it is beginning to look as if this situation may change. Meanwhile, using living volunteer donors and a small number of cadaveric organs sent from other countries, transplant teams in Kuwait and Turkey are obtaining results with kidney transplants which are as good, in terms of both transplant survival and patient survival, as those reported from acknowledged centres of excellence in the United States, Europe and other countries where organ transplantation has been established for many years.

This volume is based on a very successful meeting on organ transplantation that was held in Kuwait in 1990 under the auspices of the Middle East Society for Organ Transplantation. An international group of organ transplant experts attended this conference and their contributions and deliberations have been recent1y updated to produce this definitive and authoritative summary of current clinic al practice in organ transplantation. The initial chapters appropriately focus on the immunology of organ trans plantation with special emphasis on the initial events in the induction of alloreactivity, the mechanisms of rejection, and the potential for tolerance induction. A strong emphasis is placed on the diagnosis of rejection by cellular analysis. The section on immunosuppression deals with several new areas of clinical therapy. The section on renal transplantation is unique in several respects, the long-term results from various countries, including the Middle East, are summarized, the use of living unrelated donors and of ABO incom patible donors - all strategies to maximize organ availability - are presented."

Fresh insights into the pathogenic mechanisms by which hyperglycemia induces tissue and organ injurt are the basis for rapidly evolving promising therapies in diabetes. Especially promising as targets for intervention are products of oxidative stress, including kinins and growth factors. Improving results of renal replacement regimes now incorporating pancreatic islet transplants are able to delay and prevent end-organ damage in diabetic individuals. The evolving story of the taming of diabetes is of direct concern to nephrologists, endocrinologists, ophthalmologists, primary care physicians and medical students.

Malignancies are frequent complications in organ transplantation, mainly as the result of infection with certain viruses and of long-term immunosuppression. The epidemiology confirms that the increased incidence concerns certain cancers, especially HIV-related skin cancers and EBV-related lymphoproliferative malignancies. This book covers all currently available information on this important topic of the relationships between transplantation and malignancies: preexisting cancers, posttransplant cancers, their etiology and pathophysiology, their prevention and treatment. A significant part of the volume is devoted to prophylaxis, early detection and modern forms of therapy in posttransplant lymphomas. As a conclusion of all these new data, the theory of immunosurveillance deserves to be significantly modified.

With contributions by D. Albrechtsen, O.H. Bentdal, H. Bondevik, I.B. Brekke, P. Fauchald, J.G. Fjeld, A. Flatmark, A. Foss, A. Hartmann, H. Holdaas, R. Innes, A. Jakobsen, N.E. Klow, B. Lien, O. Oyen, P.F. Pfeffer, K. Rootwelt, G. Sodal and K. Vatne

This volume is the work product of an international group of authors who are experienced in the field of musculoskeletal allografts. The chapters are written by experts in many differing areas of allografting and represents the current knowledge in this rapidly changing dynamic field. The reconstructive community and their patients owe a significant debt of gratitude to Doctors Czitrom and Winkler for this volume. William F. Enneking, M. D. Preface What follows is the result of a timely project bringing together the newest ideas of top experts worldwide in a rapidly growing technology: Orthopaedic Allograft Surgery. The title of the book reflects a method rather than a speciality. It transgresses well established subspecialities of orthopaedic surgery such as joint replacement, oncology, spine, trauma and sports medicine. The technology encompasses knowledge of tissue banking, biology and biomechanics, both in a research and clinical sense. The common denominator for those interested is the need and ability to provide or use allogeneic tissues in orthopaedic applications. Inherent to a multiauthored text based on chapters written by authors from many parts of the world is a variety in format and style. While we tried to some extent reducing large discrepancies, there was no attempt made to eliminate dissimilar ities. We did not aim for a homogeneous textbook. Rather, we asked for originality, novelty, individuality in the presentation of data and concepts. Consequently, chapters vary in format from that seen in a scientific article to that of a descriptive essay."

Common Liver Diseases and Transplantation: An Algorithmic Approach to Work Up and Management provides a review of liver diseases and transplantation that is comprehensive enough to provide an intellectual basis for the data, yet simple enough to be read and assimilate into clinical practice rapidly. Common Liver Diseases and Transplantation by Dr. Robert S. Brown Jr is written with an intended flow and structure. The early chapters are summaries on topics such as early and late liver disease, workup and diagnosis, and pre- and post-transplant problems. The chapters that follow are liver disease-specific and cover the liver diseases physicians will encounter in their patients. The in-depth chapters provide disease-specific epidemiology and outcomes, as well as diagnostic tables and more detailed algorithms and management approaches. With two decades worth of teaching liver disease both formally as well as in rounds and informal "chalk talks" with residents and fellows, Dr. Robert S. Brown Jr presents a way to think about clinical liver problems with a simple algorithmic method. Common Liver Diseases and Transplantation: An Algorithmic Approach to Work Up and Management will serve as a useful resource for gastroenterologists, fellows, medical students, internists, and internal medicine residents.