This book is dedicated to the memory of Walter Brendel, late Professor of Experimental Surgery and Chairman of the Institute for Surgical Research at the University of Munich, Germany. For 20 years Walter Brendel organized the renowned Round Table Symposium on Applied Immunology, first in Kitzbiihel and later in Axams, Austria. On the occasion of the 20th symposium in January 1989 he gathered together a number of scientists who have been leaders in the field of transplantation immunology and clinical transplantation for the past two decades. All of them had participated at previous meetings, some on a regular basis. Many of the new discoveries in applied immunology and transplantation medicine were first presented and vividly dis cussed at the Round Table Symposia. The annual Kitzbiihel! Axams meetings became well-known and invitations much sought after, not only for this reason but also because of the uniquely intimate atmosphere that promoted the free exchange of research findings and theoretical cut and thrust.

Rapid progress in molecular biology, genetic engineering, and basic research in immunology has opened up new possibilities for application to diagnostic procedures and to clinical research. In a short period a new era of diagnosis dawned, covering nearly all fields of microbiology, immunology, and food technology. In consequence of this rapid development, scientists of many disciplines are involved studying infections of humans, animals, and plants or working in technical microbiology. The application of the newest findings of basic research to diagnostic work and to clinical research covers nearly all fields of microbiology and immunology. Moreover, it underlines the close relationship between diagnosis, therapy, and epidemiology. An outstanding example of these connections is given by the recent development of hepatitis B vaccine. The discovery and identification of a non cultivable agent by physicochemical and immunological methods were the heralds of a new era in the prevention of infectious diseases. This book provides an up-to-date, comprehensive review of developments and future aspects in various fields. I am convinced that the authors have succeeded in furnishing a large variety of new ideas and possibilities. K.-O. HABERMEHL Contents Time Realities in the Evaluation of Vaccines for Safety and Efficacy The Evaluation of Vaccines M. R. HILLEMAN . . . . ."

Once again the Current Topics in Microbiology and Immunology series presents a volume with up-to-date review articles on oncogenes. The well-known authority and editor of previous volumes in the series, Dr. Vogt, has accepted five contributions which critically evaluate recent research in the field.

In June 1986 a symposium was held in Giessen on Modern Trends in Virology. It was initiated by the Deutsche Forschungsgemeinschaft, which had supported virus research for the past 18 years in the Sonderforschungsbereich 47 at the University of Giessen. The purpose of the meeting was to serve as a forum for the members of the Sonderforschungsbereich to discuss scientific topics of mutual interest with about 200 virologists that had come from various parts of Europe, the United States, and Japan. It was not by chance that the symposium took place shortly after the 60th birthday of Rudolf Rott, who had founded the Sonderforschungsbereich in 1968 and has been its speaker ever since. Without his vision and his never resting energy Giessen would not have gained the position in the field of virology that it has today. This Festschrift, which contains the contributions presented at the plenary sessions of the symposium, is therefore dedicated to Rudolf Rott. HEINZ BAuER HANS-DIETER KLENK CHRISTOPH SCHOLTISSEK Table of Contents A Genetic Approach to Determining Glycoprotein Topology: The Influenza B Virus NB Glycoprotein has an Extracellular NHz-Terminal Domain Containing two N-linked Carbohydrate Chains R. A. LAMB and M. A. WILLIAMS . . . . . . . . . . . . . . . . . . . . . . . . . 1 Paramyxovirus Metabolisms Associated with the Cytoskeletal Framework Y. NAGAI, T. ToYODA, and M. HAMAGUCHI . . . . . . . . . . . . . . . . . . . 15 Correlation of High Evolutionary Rate of Influenza A Viruses in Man with High Mutation Rate Measured in Tissue Culture: A Hypothesis P. PALESE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

th This volume contains selected lectures presented at the 12 International Conference on Advances in Prostaglandin, Leukotriene and Other Bioactive Lipid Research: Basic Science and Clinical Applications which was held in Istanbul, Turkey, on August 25-29, 2002. This meeting brought together basic and clinical scientists for the purpose of discussing advances in bioactive lipid research with.special attention to cancer, cardiovascular diseases, gastrointestinal diseases and respiratory diseases. Topics covered included: the role of leukotrienes and lipoxins in of inflammation, the cytochrome P450 pathway, the genetics and genomics bioactive lipids, lipid peroxidation, apoptosis, angiogenesis, isoprostanes, receptors and inhibitors, cyclooxygenase and lipoxygenase pathways and inhibitors, prostaglandin synthases and receptor signaling, phospholipases and inhibitors. Sessions included plenary lectures with expertise in particular areas, oral presentation on selected topics and general poster sessions. J.M. Drazen (Boston, USA) discussed anti-leukotriene treatment in asthma patients while C. Brink (paris, France) presented the recent advances in leukotriene receptors. The recent advances in cytochrome p450 pathway described in the session organized by J.C. McGiff (Valhalla, NY, USA). T. Shimizu (Tokyo, Japan) and M. Balazy (Valhalla, NY, USA) gave an update on phospholipases and arachidonic acid peroxydation. The editors are greatful to the Organizing, Programme and Advisory Committees for their valuable contributions. We greatfully acknowledge the generous financial support provided by PharmaciaIPfizer, Fako Pharmaceuticals Inc. and Novartis Pharmaceuticals Inc. ofthe contributors to this volume, in particular We are also greatful to all to those who delivered their manuscripts by or before the requested deadline.

Proceedings of the NATO Advanced Study Institute on Immunotoxicology held at Acadia University, Wolfville, Nova Scotia, Canada, 14-23 July 1982

Almost 30 years ago RITOSSA described a new puffing pattern in salivary gland chromosomes of Drosophila following heat shock. This was the first description of a heat shock response. For years, development in this field remained modest and it took another decade before the relevant gene products-the heat shock proteins (hsp's)-were made visible by TISSIERES and co-workers. Subsequently, progress advanced more rapidly and we can now state that studies on the heat shock response have contributed much to our understanding of various principles in molecular and cellular biology such as control of gene expression and regulation of protein translocation. More recently, the study of hsp's has converged with immunology. There are several reasons for this: The chaperone function of certain hsp's makes them particularly apt for central functions of immunity, including antigen presentation and immunoglobulin synthesis. Furthermore, an effective immune response is often caused or followed by stress situations as they arise during trauma, inflammation, transformation, infection, or autoimmune disease. Due to their abundance during stress, hsp's can provide prominent antigens in many of these situations. This volume contains 11 chapters written by well-known experts dealing with various facets of the fascinating liaison between hsp's and immunity. The particular relation of hsp's to the immune system may be best illustrated by their intimate association with the major histocompatibility gene complex. Still, as discussed by GONTHER, the relevance of this fact to our understanding of hsp functions in immunity remaif)s speculative.

Radiation induces a variety of chemical processes in biological tissues. This volume is a synthesis of up-to-the-minute reviews on such photochemical and photobiological sensitized reactions with particular relevance to photomedicine. The first part gives a description of experimental techniques for the study of the primary processes after radiation absorption by biological systems. It is followed by chapters on singlet oxygen and photomedicine, considering both phototherapy and photochemotherapy. These sections also discuss the next generation of potential photosensitizing drugs.

The amazing world of the mononuclear phagocytes keeps expanding at a truly awesome pace. As a result, maintaining currency with the latest developments and controversies that pertain to this cell type is increasingly difficult. The aspects covered in this volume have been selected to provide an overview of subject areas that either have recently become much better understood or hold the promise of new levels of understanding as they are developed in the future. The scope of topics ranges from how these cells develop, through the means that are used to regulate them, to the roles that they have in different tissues and in a variety of infectious diseases.

Recent experimental and clinical progress in the evaluation of cytokines in treatment concepts for cancer patients is the central theme of this book in the ESO Monographs series. The discussion revolves on the experimental basis as well as current clinical experience with the use of human recombinant cytokines. It gives the state of the art and, as such, puts into perspective potential areas of growth and future research.

Through numerous discussions with colleagues it became apparent that the time was right to begin a series of workshop-like meetings on myeloid tumorigenesis. Myeloid tumors are the nonlymphocytic tumors of the hematopoietic system which include tumors of the neutrophilic, monocytic, erythrocytic, basophilic (mast cell) and megakaryocytic lineages. Pioneering studies in myeloid tumorigenesis were initially made in chickens with the discovery of retroviruses that induce various kinds of myeloid tumors acutely (myelocytomatosis, myeloblastosis, and erythroblastosis). These avian retroviruses were subsequently shown to contain the oncogenes v-myb, v-~, v-~, v-erbA, or v-erbB. There have been dramatic advances in studying the pathogenesis of hematopoietic tumors in genetically defined mammalian systems. Many of the well developed model systems in inbred mice, have focused on T- and B-1ymphoma development. Although myeloid tumors have been found in mice, they have not been studied as intensively as lymphoid tumors. Possibly this is because myeloid tumors are less common than lymphoid tumors. Recently, there has been renewed interest in murine myeloid tumor systems. This focus has resulted from 1) the discovery of inbred strains of mice (e. g. BXH-2, AKXD- 23, SJL/J) that are highly susceptible to spontaneous or induced myeloid tumorigenesis; 2) establishment of transplantable murine myeloid tumors (e.

In 1976 the International Committee on Taxonomy of Vi ruses (ICTV) created the family Iridoviridae to encompass several different vertebrate and invertebrate viruses that did not fit into any of the other established groups. The unifying features of this new family were (1) polyhedral symmetry; (2) large (approximately 170 kilobase pairs), lin ear, double-stranded DNA genomes; and (37) a cytoplas mic site of replication. The name "iridovirus" was derived from the observa tion that larvae infected with many of the insect viruses, as well as purified pellets of these viruses, glowed with a blue or green iridescence - presumably due to the Bragg effect of the viral crystals. However, none of the vertebrate "iridoviruses" displayed this particular characteristic. An attempt was made to substitute the more descriptive name of "icosahedral cytoplasmic deoxyribovirus," but not only was this term too unwieldy, it also did not conform to the latinized nomenclature the ICTV wished to adopt. So, for both historical and esthetic reasons, "Iridoviridae" was adopted as a family name, with Iridovirus as the genus represented by the type 1 iridescent insect virus, Tipula iri descent virus. At the 1982 ICTV Meeting, enough biochem ical data had accumulated to permit the establishment of the following five genera in the family Iridoviridae: English vernacular International Type species name name 1. Small iridescent Iridovirus Tipula iridescent virus insect virus (Type 1) 2. Large iridescent Chloriridovirus Mosquito iridescent insect virus virus (Type 2) 3."

The Brescia division of the Italian Association of Blood donors (AVIS Brescia) celebrated its 50th anniversary in 1985. The idea of organizing a Postgraduate Course on Viral Hepatitis on this occasion developed for ob vious reasons. Viral hepatitis is a major concern in blood transfusion and Brescia is located in the region of Lombardy characterized by a high HBsAg carrier rate in its population. Thus it seemed timely to convene a scientific forum in which the present state of knowledge on viral hepatitis would be summarized. This would allow us to review the tremendous progress achieved over the last 15 years, and also to focus on latest developments which pave the way for future investigation. The publication of the proceedings of this meeting was considered use ful, since it provides a tangible reminder of a comprehensive overview of the broad topic of viral hepatitis, its complications, and its connections with the practice of blood transfusion. The organizers were fortunate in obtaining the active participation of recognized experts in a variety of hepatological diSCiplines. Their contri butions summarized the more mature areas of knowledge in the field, in cluding clinical aspects, epidemiology and morphology, as well as newer developments in the forefront of hepatitis research, like new diagnostic techniques, oncogenesis, treatment, and vaccination."

Rapid progress continues to be made in understanding the molecular and cellular events that comprise B-Iymphocyte differentiation. This is due in part to the high level of inter est shown by many investigators from diverse disciplines, who find this subject suitable for addressing some of the fundamental issues of immunobiology. B-cell developmen tal models are being extensively used to investigate cell-cell interactions, molecular mediators of differentiation and proliferation, differential onset of gene programs, and gene rearrangement and expression, as well as the generation of the immune response itself. Not surprisingly, increased understanding of B-cell differentiation sometimes results from the application of new techniques that permit greater insight into the cells comprising the system and the genetic mechanisms by which these cells express their differentiative potential. However, experimental strategies based upon the novel application of established technologies have also led to the clarification of many issues, as well as to the discov ery of previously unrecognized problems. One problem, well recognized by those active in the field, is how to keep up with significant developments as they appear. The purpose of this book, part of a series devoted to analysing current issues in biology, is to help overcome this problem. No attempt at comprehensive cov erage of all of the issues has been made. Rather, a more thorough analysis of a few topics is presented."

M. B. A. OLDSTONE Viruses are generally studied either because they cause significant human, animal or plant disease or for their utility as materials to probe a basic phenomenon in biology, chemistry, genetics or molecular biology. Arenaviruses are unusually interesting in that they occupy both of these categories. Arenaviruses cause severe human diseases known primarily as the hemor rhagic fevers occurring in South and Latin America (Bolivia: Machupo virus and Argentina: Junin virus) and in Africa (Lassa virus). Because such viruses produce profound disability and may kill the persons they infect, they are a source of economic hardship in the countries where they are prevalent. Further, they provide new problems for health care personnel owing to the narrowing of the world as visitors from many countries increasingly travel to and from these endemic areas. In addition, lymphocytic choriomeningitis virus (LCMV) can infect humans worldwide, although the illness is most often less disabling than those elicited by other arenaviruses. Yet LCMV is likely of greater concern to non-arena-virologists and experimentalists using tissue culture or animals, i. e. , workers in molecular biology, cancer research, virology, immunobiology, etc. , because normal appearing cultured cells or tissues and animals used for research may be persistently infected with LCMV without manifesting clinical disease or cytopathology and transmit that infection to laboratory workers (reviewed OWSTONE and PETERS 1978). For example, HINMAN et al.

The present volume of "Current Topics in Microbiology and Immunology" is a series of papers on subjects that are relevant to the growing use of 'wild mice' in immunological, microbiological and genetical research. 'Wild mice' is a jargonistic term that is used chiefly in the laboratory to refer to the naturally living forms of house mice (Mus musculus) and also other species closely related to M. musculus. This group of species is designated by systematists as the genus Mus. Immunologists began 20 years ago to study the polymorphisms of 1mmunoglobulins and major histocompatibility complex antigens in wild mice. An extrordinary extension of the highly polymorphic array of phenotypes known in inbred mice was encountered. Breeding stocks of wild mice were brought into the laboratory. This included not only M. musculus but a)so many of the available species in the genus Mus-from Southeast Asia ~nd Europe. This availability led to other comparisons of 'wild' and inbred mice and the discovery of other new and interesting phenotypes and genotypes. It became apparent that inbred strains of mice provided only a limited window for viewing the genetic diversity of Mus musculus.

The publication of Bronchoalveolar Mast Cells and Asthma marks the emergence of The Bloomsbury Series in Clinical Science, an important and novel series that will highlight, review and record major areas of research, development and practice in the field of clinical science. A number of other monographs are now in an advanced state of preparation and their release will establish not only their individual significance but that of the series as a whole. My thanks are due to the Editorial Board who have provided the ideas and selected the authors and whose continuing enthu siasm is so vital to the success of the series. Michael Jackson of Springer-Verlag merits special thanks for initially realising the potential of such a series and then guiding us all through to the time of its launch. Marianne Williams has supported us all and has provided the important link between Editorial Board and pub lisher. The author of this first publication, Kevin Flint, was tragically killed during its preparation, and we hope that the book will serve as a tribute to the memory of Kevin for all who were lucky enough to know him. Barry Hudspith has been of enormous help in finalising the work and in shaping the form of the book."

To the entomologist all insects have six legs; the layman tends to use the term "insect" to include the eight-legged spiders and mites. All these creatures are correctly classified as arthropods. Many thousands of the hundreds of thousands of recognised species of arthropods are found in the human environment-domestic, occupational and rec reational. Those species which are obligate parasites of man, the human scabies mite and the head and body lice, produce familiar clinical syndromes. They remain important in medical practice and have been the subject of a great deal of recent research. This is beginning to throw much light on the immunological mechanisms which largely determine the reactions of the host. Dr. Alexander has provided a detailed survey of this work. The wasps, bees, ants and other Hymenoptera which may sting man in self-defence can cause painful, even fatal reactions. The recent work on this important subject has also been thoroughly reviewed. Every dermatologist of experience will admit that he sees many patients in whom he makes a diagnosis of "insect bites," if he has the confidence to do so, or of "papular urticaria" or "prurigo" when he lacks such confidence, mainly because he is at a loss to know which arthropod is likely to be implicated. In his survey of the enormous literature in the entomological, public health and dermatology journals Dr. Alexander has provided an invaluable guide in which the solutions to these clinical mysteries can be sought."

Current Topics in Medical Mycology, is intended to summarize current research areas in medical mycology for medical my- cologists and other scientists who are working in microbiology and immunology. Topics to be included in each volume will serve as contemporary reviews, summaries of current advance- ments and future directions, and mechanisms to enhance the interdisciplinary use of medically important fungi in under- standing pathogenesis, epidemiology, mycotoxins, taxonomy, and other areas where basic, applied, and clinical sciences are used. Michael R. McGinnis v Contents Series Preface v Contributors ix Ultrastructural Correlates of Antimycotic Treatment MARCEL BORGERS 2 Soluble Polysaccharides of Cryptococcus neoformans ROBERT CHERNIAK 40 3 Tinea Imbricata RODERICK J. HAY 55 4 Adhesion and Association Mechanisms of Candida albicans MICHAEL J. KENNEDY 73 5 Peptide Transport in Candida albicans: Implications for the Development of Antifungal Agents FRED NAIDER and JEFFREY M. BECKER 170 6 Epidemiology of Coccidioidomycosis DEMOSTHENES PAPPAGIANIS 199 7 Immune Response to Paracoccidioides brasiliensis in Human and Animal Hosts ANGELA RESTREPO M. 239 vii Vlll Contents 8 Morphogenetic Transformation of Fungi MAXWELL G. SHEPHERD 278 9 Epidemiology of Nosocomial Fungal Infections DAVID J. WEBER and WILLIAM A. RUTALA 305 Melanins and Their Importance in 10 Pathogenic Fungi MICHAEL H. WHEELER and ALOIS A. BELL 338 11 Cytochrome P-450 of Fungi: Primary Target for Azole Antifungal Agents Yuzo YOSHIDA 388 Index 419 Contributors JEFFREY M. BECKER, Ph.D.

This volume deals with the structure and function of molecules that have, during the last decade, turned out to have a central role in immune responses. Trans plantation antigens were discovered and characterized by Gorer about 50 years ago, and the biological basis for the unequalled complexity of their variability between individuals within a species, in spite of extreme conservation between species, was the subject of intense research and discussion for many years. During the days of belief in "immune surveillance" against spontaneously developing tumors, it was suggested that histoincompatibility between members of one species would prevent cancer from being a contagious disease and thus a threat to the species. Immunologists involved in human transplantation had to learn and care about the complexity, especially after 1967, when it was found that HLA antigens were the products of the human MHC. Rejection of HLA-identical sib kidney grafts was so rare, even in those days, that cases of rejection were described in scientific papers."

Anergic reactions and anergic diseases are found in many fields of medicine. As wen as affecting the skin, allergic diseases occur in internal organs such as the lungs and the kidneys and in the vascular and nervous systems. Interdisciplinary understanding and cooperation thus seem necessary to get a better insight into allergic reactions in the different fields of medicine in order that we may give our patients the best diagnostic and therapeutic care. Allergic diseases are on the increase. Studies from Sweden show that 15% of the population there are atopic, and some people speculate that in Germany about 10%-15% of all adults suffer from one of the many different allergic conditions. We in our clinic also have the impression that the incidence of atopic reactions has increased in recent years. The figure of 15% would mean something like 200 000 people in Munich alone We all know that a wide variety of environmental factors can induce allergic reactions in the skin, the respiratory system, or internal organs. The most important anergens in our environment are pollen, molds, animal dander, housedust mite, food or food additives, various insects, industrial compounds and drugs. The direct costs of hospital and community medical care, other services, and drugs to help patients with asthma, hay fever, and skin allergies have in creased considerably in the last 10 years. The figures should make it clear to everybody that we are dealing with a health and environmental problem of great practical importance."

This volume contains the contributions to the workshop "The Semiotics of Cellular Communication in The Immune System" which took place at "11 Ciocco" in the hills north of Lucca, Italy, September ~-12, 1986. The workshop was the first meeting of what we hope will be a broad consideration of communication among lymphocytes, and focused on the new interdisciplinary branch of biological sciences, immunosemiotics. It is in the realm of the possible, if not the probable, that in the future a number of scientists larger than the thirty present at 11 Ciocco will find immunosemiotics to fill a need in scientific thinking and a gap between biology and the humanities. This might lead to growth and flourishing of the branch, and in this case the first conference and this first book could be blessed by the impalpable qual ity of becoming "historical", if in an admittedly 1 imited sense. Just in case this should happen the organizers/editors think it wise to set the record straight at this particular time, about the sequen~e of events and circumstances that crystallized the archeology of the "11 Liocco" gathering. They feel a sort of obligation to this endeavor: it has happened all too often that innocent historians have been left in utter confusion by the careless founders of new religions, schisms, revolutions, et cetera, who simply forget to jot down the facts before the whirlwind of time engulfs them in its fog.

Sepsis and infection are the major enemies of the intensive care patient in whom immunological defenses are severely impaired. This major problem is thefocus of attention in this book, based on the presentation of the First International Congress on the Immune Consequences of Trauma, Shock, and Sepsis, which is one of the first attempts to exchange ideas on the state-of-the-art in this area of immunology. Both basic and clinical research, including new centres of attention, are described. The growing role of immunology in medicine opens new avenues to the under- standing of trauma and sepsis and will allow the design of novel therapeutic approaches.