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.

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.

Any professional concerned with immunology will be interested in this book dedicated to the memory of Milan Hasek, former director of the Prague Institute of Experimental Biology and Genetics. Prof. Hasek was a congenial scientist and most amiable person - a personal friend of almost all leading immunologists around the world. He was displaced from his post of director in 1970, yet had a lasting impact upon his students and the group known as the Prague School of Immunogenetics. The topics covered in the contributions range from tolerance, immune network, and immunogenetics to the immunology of bacterial and viral infections. They are written by 27 of Prof. Hasek's former co-workers who emigrated to western countries around or after 1968 and became well-known and distinguished scientists in the field. The papers include their personal reflections of the Prague Institute, their impressions upon arriving abroad and their interesting experimental work since then. The book also provides a complete bibliography of their publications after leaving Czechoslovakia.

The fourth workshop on Mechanisms in B-Ce11 Neoplasia was held in Bethesda. Maryland. at the National Institutes of Health on March 24. 25 and 26. 1986. The meeting was attended by approximately 150 participants and 58 presentations were given. The purpose of these workshops and the yearly publications has been to provide a means for exchanging the rapidly developing information in this field and to bring maJor problems into focus. Edited trans- cripts of the 1983 and 1985 workshops were published by Editiones Roche Bas1e, Switzerland. Papers brought to the 1984 workshop were published in Current Topics in Microbiology and Immunology, Vol. 113. Numerous retrovira1 recombinant viral constructs are now in general use in a variety of test systems, both in vivo and in vitro. These are proving to have interesting bio10gica1-prQperties. ------- Kecent1y developed systems for inducing B cell tumors are described: 1) The development of spontaneous ~-ce11 tumors in transgenic mice carrying deregulated mlGBP genes and the Ig heavy chain promoter; 2) a method for inducing *p1asmacytomas in BAL~/c mice with short latent periods of ca 70 days by infecting pristane treated mice with retroviruses carrying various types of deregulated mlGBP genes; 3) induction of pre-B cell tumors with erbB containing recombinant retroviruses; 4) induction of B-ce11 and other tumors by infection of neonates with recombinant retroviruses. Several retrovira1 constructs containing mlGBP sequences do not induce B-ce11 tumors in pristane conditioned mice *.

During the past few decades we have witnessed an era of remarkable growth in the field of molecular biology. In 1950 very little was known of the chemical constitution of biological systems, the manner in which information was transmitted from one organism to another, or the extent to which the chemical basis of life is unified. The picture today is dramatically different. We have an almost bewildering variety of information detailing many different aspects oflife at the molecular level. These great advances have brought with them some breath-taking insights into the molecular mechanisms used by nature for replicating, distributing and modifying biological information. We have learned a great deal about the chemical and physical nature of the macro molecular nucleic acids and proteins, and the manner in which carbohydrates, lipids and smaller molecules work together to provide the molecular setting of living systems. It might be said that these few decades have replaced a near vacuum of informa tion with a very large surplus. It is in the context of this flood of information that this series of monographs on molecular biology has been organized. The idea is to bring together in one place, between the covers of one book, a concise assessment of the state of the subject in a well-defined field. This will enable the reader to get a sense of historical perspective what is known about the field today - and a description of the frontiers of research where our knowledge is increasing steadily."

F. B. Michel Asthmology is the neologism I suggested for ideas which were acceptable at the begin the title of a book published in 1981 on ning of the 20th century, and in particular bronchial asthma [4,5]. to Pasteur's concept of "one cause, one ill ness", many syndromes like high blood Among a certain number of scientific pressure or asthma are the result of the publications on this subject, it is one of the overlapping of hereditary factors and ac few suggestions that I have the weakness to quired factors. This is one reason why asth feel somewhat proud of. In fact, this word has had the career I hoped it would and, ma is not really an illness in the real sense judging by the frequency with which it is of the word but, a clinical and functional respiratory syndrome [1]. used in both written and spoken language, it did answer a need. I had no intention of The innate, the "terrain", transmitted by suggesting one more neologism but it heredity, can possibly concern two factors: seemed to me that the word asthmology The bronchial hyperreactivity factor (BHR), had an element of novelty and, above all, is often present in early childhood and its produced the necessary awareness of the reality is a result of the studies of large need to bring together, within a kind of groups of homo- and heterozygotic twins.

When I entered the field of allergy in the early 1970s, the standard textbook was a few hundred pages, and the specialty was so compact that texts were often authored entirely by a single individual and were never larger than one volume. Compare this with Allergy Frontiers: Epigenetics, Allergens, and Risk Factors, the present s- volume text with well over 150 contributors from throughout the world. This book captures the explosive growth of our specialty since the single-author textbooks referred to above. The unprecedented format of this work lies in its meticulous attention to detail yet comprehensive scope. For example, great detail is seen in manuscripts dealing with topics such as "Exosomes, naturally occurring minimal antigen presenting units" and "Neuropeptide S receptor 1 (NPSR1), an asthma susceptibility gene." The scope is exemplified by the unique approach to disease entities normally dealt with in a single chapter in most texts. For example, anaphylaxis, a topic usually confined to one chapter in most textbooks, is given five chapters in Allergy Frontiers. This approach allows the text to employ multiple contributors for a single topic, giving the reader the advantage of being introduced to more than one vi- point regarding a single disease.

If tumor viruses did not exist in nature they might have been created by scientists interested in basic mechanisms of develop- ment, differentiation, and tumorigenesis. In contemporary euka- ryotic cell biology tumor viruses playa similar role to that which bacteriophages once had for the molecular biology of prokary- otes. Tumor viruses provide extremely useful probes for the above cellular processes since their life cycle is genetically pro- grammed and can be followed at DNA, RNA, and protein levels. The experimental systems reviewed in this volume utilize a wide variety of viruses. A comprehensive introduction to this field has recently been published in the volumes of Molecular Biology o/Tumor Viruses: DNA Tumor Viruses, 2nd edition, edited by J. Tooze; and Molecular Biology o/Thmor Viruses: RNA Tumor Viruses, 2nd edition, edited by R. Weiss, N. Teich, H. Varmus, and J. Coffm, by Cold Spring Harbor Laboratories in 1980 and 1982. Polyoma and SV40 viruses (see the chapter by A. Levine) and adenoviruses (see the chapter by W. Doerfler) are double- stranded DNA-containing viruses. Polyoma and SV40 are struc- turally related viruses which contain a genome of approximately 5 kilo basepairs, while the DNA of adenovirus is about 7 times more complex. These DNA tumor viruses are understood at a genetic and molecular level which is comparable to our know- ledge of A and T4 bacteriophages. Retroviruses, the subject of the remaining four chapters, con- tain a single-stranded RNA genome of 5-8 kilobases.

Due to the topology and structure of the lymph nodes, their role in the pathogenesis and development of diseases is a very special one. Each organ and even each organ-related region of the body has its own group of lymph nodes, specific topological reactions, such as in circumscribed inflammation or in the metastatic spread of malignant tumors. On the other hand, all the lymph nodes of an organism join in a uniform function effected by highly differentiated structures. Volume 84 of Current Topics in Pathology presents our current knowledge about the structure and reaction patterns of this "sec ondary" lymphoid organ. Despite our original intention to publish all the contributions in one book, it became necessary to divide them: Part 1 focuses on the involved nodal compartments, cell types, and functions, while Part 2 describes their reactions in inflammatory, neo plastic, and immune-deficient diseases. Even with the cooperation of more than 30 authors, the coverage cannot be exhaustive. The scope of both parts is limited to those reactions that can be described by direct and indirect morphological methods, including modern tech niques such as immune electron microscopy."

The rapid and continuous upsurge of interesting data in the subject of tumor immunology necessitates the publication of an annual series to furnish the updated materials to the students, researchers, and clinicians in this rapidly advancing field. Concepts and methodologies are ever changing. Also, current research in tumor immunology promises to offer breakthroughs in the future. Important is the need to communicate to the right people the exact role of immunodiagnostic methods and immunological intervention in cancer preven tion and treatment. The role of immunotherapy in combination with conven tional modalities of treatment needs to be understood in its proper perspective. Oncogene, interferon, lymphokines, monoclonal antibodies, natural killer cells, platelet-mediated cytotoxicity of antibody-coated target cells, suppressor cells, platelet-derived factors, plasma-blocking factors, control of suppressor cell func tion, abrogation of plasma-blocking factors, and so forth, are some of the areas that are continually advancing. Progress in these areas will have implication in cancer therapy. Further, it is already understood that if immunocompetence of the host can be maintained at a reasonably good level, there exists the potential to increase the therapeutic indexes of conventional modalities of treatment. This series will attempt to present updated information in all these areas based on con tributed and solicited articles."

Contents: Introduction and Overview Lymphopoietic Growth Factors: Pathophysiology of T-Cell Mediated Shock Induced by Bacterial Superantigens - Natural Killer Cells and Interleukin-2-Activated Killer Cells - TumourImmunogenicity Induced by Exogenous Interleukins - Cytokine Gene Therapy of Cancer - Analysis of T-Cell Receptor Variability in Tumour Infiltrating Lymphocytes - Clinical Studies with Interleukin-2: An Overview - Clinical Trials with Local Administration of Lymphopoietic Growth Factors - Clinical Trials with Interlaukin-2. The Rome Experience. Haematopoietic Growth Factors: Lymphohaematopoietic Growth Factor Use in Lung Cancer Patients - Clinical Trials with Haematopoietic Growth Factors and Peripheral Blood Stem Cells