This volume of Current Topics in Microbiology and Immunology was planned in parallel with an EM BO workshop on cell-cell Interactions in Leukocyte Homing and Differentiation held at the Basel Institute for Immunology in November 1992, and many of the workshop speakers have contributed to it. Cell adhesion is one of the most dynamic fields of biological research and presented in this book is the current knowledge on the structure and function of the major families of cell adhesion molecules-the integrins, the selectins, the immunoglobulin superfamily, and CD44. Complex interactions between the members of these families mediate diverse adhesion functions, including leukocyte-leukocyte interactions, lymphocyte homing, inflammation, and lymphocyte-stromal cell interaction during hematopoiesis. A great deal of emphasis is placed on the regulatory elements that control the expression and function of adhesion molecules. Cytokines not only induce the expression of certain adhesion molecules, but may also modify their functional status. For instance, the integrins exist in either an inactive nonfunctional form or an active functional form, and a number of intracellular or extracellular stimuli modify integrin function. This is particularly important during leukocyte binding to endothelium and transendothelial migration, which proceeds through a cascade of adhesion events. Although cell adhesion molecules play an important role in many processes, this book concentrates on their role within the immune system. A number of chapters discuss the migration of lymphocytes between hematopoietic organs such as the thymus, lymph nodes, Peyer's patches, and spleen.

By their powers of reason scientists will be able to extract from nature the answers to their questions. From: Critique of Pure Reason, 1781 Immanuel Kant (1724-1804), German Philosopher History is a composite of stories. The history of the biological disciplines has been written by all those who opened the gates of new knowledge by generating ideas and the experiments to support them. Previous authors have attempted various approaches to the history of virology, as is reflected in the numerous books and book-series issuing from the publishing houses. This volume is an attempt at a compre hensive yet compact survey of virology, which has meant penetrating the rigid limits of the separate disciplines of biology in which virologists have worked. Writing this history of experimental virology was really a search for the origins and for vital signposts to portray the wide scope of the knowledge attained thus far. This was done in com plete awareness of the fact that every presentation depends heavily upon the perspective of the observer, and of necessity communi cates only a part of the whole. The present scientific story hopes to recount the most important knowledge achieved during this past century - the first century of the exciting developments in virology."

In the 1960s, it was reported that interferons have antitumour activity in different experimental models. Since that time, numerous studies have been performed to elucidate the various mechanisms of action that have been proposed. However, there is much controversy in the literature and promising preclinical findings failed to translate into substantial clinical progress. The present book gives a critical overview of current knowledge of how interferons act in solid tumours. For this purpose, after two chapters of general aspects of interferon action and interaction, selected solid tumours which are commonly considered difficult to treat in advanced stages are discussed with respect to both preclinical data and clinical experience.

The research field of somatosensory processing in mammals has experienced revolutionary changes in recent years. Accumulation of basic and clinical data has greatly accelerated, and new phenomena have emerged. With the aid of new, refined methods, molecular and cellular changes have been described, underlying the signal transduction-transmission between the internal/external environment and the central nervous system have been described. The discovery of the interaction between the nervous and the immune system has, for example changed our view on the development of inflammatory diseases, while the cloning of genes encoding different trophic factors has boosted studies revealing profound changes in the regeneration of neurons, and induction of changes in phenotype. The study of the pre-and postsynaptic modulation of transmitter release, and the examination of the combined effects of amino acid and peptide transmitters has become recently possible by using cultured cell lines and in vitro techniques. Although it is in embryonic state, computational properties of single DRG cells under normal and pathological conditions are being investigated. Results soon or later will have a great impact on pain research and consequently ultimately in clinical pain management. This brief introduction indicates how our knowledge of the somatosensory system has increased dramatically recently. However, many investigators cultivate only a very specific field in the growing area of somatosensory research and find it difficult to integrate a more universal knowledge of their work.

The last decade has seen an explosion in our understanding of how bacterial pathogens trick, cajole, usurp and parasitize their various hosts. This renaissance is due to the convergence of molecular and cellular techniques with the power of microbial genetics. The purpose of this volume is to introduce recent advances in understanding selected systems chosen from both plant and animal hosts of bacterial pathogens. This somewhat nonobvious choice of topics was spurred by the recent findings, detailed by several conributors to this volume, of common systems used to secrete virulence factors from pathogens of both plants and animals. These serendipitous findings underscored the importance of basic research approaches to parallel problems in biology. More importantly, they brought together investigators who may not have otherwise become conversant with each other's experimental systems. I, for one, find the kinds of synergism reflected in a volume of this sort to be one of the most pleasant aspects of science and hope that the reader, whether a newcomer to the field or an expert, can find a new slant to old problems in the reviews contained h, E: lre. It was, however, necessary to limit volume length, and this has forced the exclusion of a number of fascinating bacterial pathosystems.

This book is the published proceedings of the Sixth International Symposium on Trace Element Metabolism in Man and Animals. The Symposium was held at the Asilomar Conference Center in Pacific Grove, California, U.S.A. from May 31 through June 5, 1987. The decision to hold TEMA-6 at Asilomar was made at TEMA-5 in 1985. The International Guidance Committee decided to hold the meeting in California in part to recognize the significant cont i butions made to the field of trace element metabolism by Professor Lucille S. Hurley. As such, she was the obvious choice as chair of the local organ izing committee. One of the principal goals of Professor Hurley was that TEMA-6 serve as a forum for discussing the use and application of newer methodologies, such as molecular biology, computer modelling and stable isotopes, in studies of trace element metabolism. Based on the comments which the local organizing committee has received, this goal was achieved. The Symposium was attended by 275 scientists from 32 countries covering 6 continents. Twenty-five speakers were chosen for our plenary sessions."

Together with the two previous volumes of the Handbook of Experimental Pharmacology on histamine and antihistamines the present publication yields a picture of a still rapidly developing field of research. New techniques and new experimental approaches have brought us new knowledge and deeper insight into the biomedical significance of histamine, even if many questions remain to be answered about the functional and medical implications of this old biogenic amine. The present volume covers the progress in histamine research during the past two decades. A significant chapter concerns techniques for histamine determination. As the result of a consensus meeting in Munich in December 1988, a panel of eminent specialists arrived at common recommendations as to the usefulness of the available histamine assays for the most common experimental biomedical conditions. The heterogeneity of mast cells, with great differences in their reactivity to various stimuli, has become apparent, not only among species but also among the tissues of a species. New informa tion is presented about the mechanism of exocytosis. The old questions about the role of histamine in the mechanism of gastric secretion and in cardio vascular and respiratory functions have been studied with new techniques, and the role of HI and H2 receptors discussed. New observations have been made on the occurrence and possible functions of histaminergic neurons and histamine receptors in CNS where a new type of receptor, the H, seems to 3 be widely represented."

"Recent studies have discovered new known and characterized cytokines, allowing for advancement in miniaturization of micro-analytical methods as well as the extensive development of bio-informatics and nanotechnology. These advancements have allowed researchers to reduces sample sizes making for more accurate determinations then previously possible. In Cytokine Protocols: Second Edition, expert researchers in the field detail many of the methods which are now commonly used to study cytokines. These methods and techniques for studying cytokines include historical importance and the importance of researchers using bioassay, quantification, and characterization of cytokine related RNAs, posttranscriptional modifications of RNA, either naturally or artificially, and observations at the protein level. Written in the highly successful Methods in Molecular Biology (TM) series format, the chapters include the kind of detailed description and implementation advice that is crucial for getting optimal results in the laboratory. Authoritative and practical, Cytokine Protocols: Second Edition seeks to aid scientists in furthering the crucially important advancement of cytokine research."

The 8th volume in the Proteases in Biology and Disease series focuses on the role of proteases in virus function and their potential as anti-viral targets. Viral infections are still difficult to threat and some remained life-threatening diseases in spite of antiviral drug research over decades. Proteases are still regarded as an Achilles heel of the pathogens and, thus, protease inhibitors may help to handle the known and the emerging viral threads. The book discusses viral proteases of the most important pathogenic viruses, responsible for severe diseases: AIDS, SARS, Hepatitis, Cytomegalovirus, T-cell lymphotropic virus, Picornavirus. This book focuses specifically on the viral proteases, crucial prerequisites for viral entry into cells and viral replication. Viral proteases represent an important pharmaceutical target. The current stage of protease inhibitor development and therapy are summarised and discussed by experts in the field. This volume represents a timely and valuable continuation of the Proteases in Biology and Disease series. The reader will learn the potential for proteases as targets for effective anti-virals. This book will be a valuable source of information on viral proteases and provoke further research in this important field."

Recent years have seen unprecedented outbreaks of avian influenza A viruses. In particular, highly pathogenic H5N1 viruses have not only resulted in widespread outbreaks in domestic poultry, but have been transmitted to humans, resulting in numerous fatalities. The rapid expansion in their geographic distribution and the possibility that these viruses could acquire the ability to spread from person to person raises the risk that such a virus could cause a global pandemic with high morbidity and mortality. An effective influenza vaccine represents the best approach to prevent and control such an emerging pandemic. However, current influenza vaccines are directed at existing seasonal influenza viruses, which have little or no antigenic relationship to the highly pathogenic H5N1 strains. Concerns about pandemic preparedness have greatly stimulated research activities to develop eff- tive vaccines for pandemic influenza viruses, and to overcome the limitations inh- ent in current approaches to vaccine production and distribution. These limitations include the use of embryonated chicken eggs as the substrate for vaccine prod- tion, which is time-consuming and could involve potential biohazards in growth of new virus strains. Other limitations include the requirement that the current inac- vated influenza vaccines be administered using needles and syringes, requiring trained personnel, which could be a bottleneck when attempting to vaccinate large populations in mass campaigns. In addition, the current inactivated vaccines that are delivered by injection elicit limited protective immunity in the upper respiratory tract where the infection process is initiated.

Retroviruses arguably belong to the most fascinating of all viruses because of their unusual and highly efficient mode of replication involving reverse transcription and integration of the viral genome and a complex system of transcriptional and post transcriptional regulatory mechanisms. The importance of ret roviruses as human and animal pathogens has also enhanced scientific and medical interest in this diverse group of viruses and has spurred an intensive search for novel and improved antiviral agents. More recently, analysis of retroviral replication and in particular understanding the formation and composition of the virus particle has received additional attention because of the promise of retroviral vectors as vehicles for human somatic gene therapy. Many recent advances have been made in our understanding of the molecular mechanisms governing as sembly and release of infectious retrovirus particles. This book attempts to summarize these recent developments and to provide an overview of our current knowledge on retrovirus particle formation. The individual chapters of the book deal with specific steps in the pathway of retroviral morphogenesis and maturation, starting at the time when the components of the virus have been synthesized within the infected cell and ending once the infectious virion has been released from the cell. An introductory chapter provides a comparative description of the structure and morphology of various retroviruses."

Several aspects of clinical medicine are poised on the edge of a new era with the introduction of therapeutic antibodies. This revolution has been made possible by major advances in immune technology, which are now beginning to mature into clinical practice. This volume is aimed at all clinicians involved with this form of treatment, especially accident and emergency physicians, clinical immunologists, and pharmacologists. It covers both the basic technology, and also all the main clinical areas of application: septic shock, auto-immune disease, and cancer. The future of therapeutic antibodies is also discussed, including exciting new developments in "catalytic antibodies". This is the first occasion on which all these topics have been brought together in a single volume, thus making it an important reference source for physicians and researchers in this fast-moving area.

Workshops on the mechanisms of B cell neoplasia have been organized alternatively in Bethesda and Basel since 1983. Prog ress in our understanding of the development and responses of B lymphocytes is presented and discussed with the aim and hope to understand what might go wrong when B lymphocytes are transformed into malignant cells. Such knowledge might lead to better diagnosis, prevention and even cure of these terri ble diseases. The presentations at the Bethesda workshops are published as papers in volumes of Current Topics in Microbiol ogy and Immunology, while the presentations and discussions in Basel were transcribed and published in Editions Roche. For the first time, a Basel workshop (held 4th-6th October 1998) that has been recorded and, in part, transcribed is being published as papers and discussions within Current Topics. This volume is the latest of a long series which documents the excitements of ground-breaking discoveries as well as the frustrations of our inability to fully understand the mechanisms leading to B cell neoplasia. The papers at the workshop are presented when possible in the sequence in which they were given. However, to facilitate the organization and reading of the book and to highlight gen eral topics and themes, the papers are organized into five sec tions: I B Cell and Plasma Cell Development II Chemokines and Chemokine Receptors III Chromosomal Translocations, DNA Rearrangements and Somatic Hypermutations IV Biology of Lymphomagenesis, B-CLL, Autoimmunity V Myeloma, Plasmacytomas and Related Subjects.

Immunotherapy began in 1774 when the Dorset farmer Benjamin Jesty inoculated his wife and two sons with the pus from the teat of a cow suffering from cow pox, using his wife's knitting needle as a vaccinating implement. It has made slow progress. Meanwhile the science of Immunology has burgeoned so much that if all immunologists read every page of the Journal of Immunology, let alone the other Immunology journals, then they would have no time left to write for it. I am pleased that some of them have found the time to write for this volume. In spite of the rapid expansion in immuno logical knowledge and the undreamt of complexity of the immune system that has been unravelled, immunologists have remained until recently erudite but therapeutically effete. Indeed anyone purporting to treat disease by immuno logical methods has been in danger of being labelled a quack or a crackpot. Happily things are changing. The nine chapters of this volume detail nine quite different approaches to manipulating the immune system for therapeutic benefit. All are experimental and they have been attended with greater or lesser degrees of success. In some cases their main effect has been to elucidate the complexity of the problem. On the other hand, there are people alive and well today as a result of these approaches who would otherwise have perished. Immunotherapy is here to stay and it can only get better."

Although long known as a parasite of medical and veterinary importance, interest in Toxoplasma gondii has increased with its emergence as a major cause of death in immunosuppressed individuals, and with recognition of its suitability as a model system for molecular and cellular investigations of apicomplexan parasites. The NATO workshop brought together 32 scientists working in different areas of toxoplasmosis research to gain an overview of progress in the field. Molecular studies have been carried out on genomic and extrachromosomal DNA. They reveal that Toxoplasma is very highly conserved, genetic mapping is underway and preliminary linkage analysis suggests recombination is rare; moreover all virulent strains share the same isoenzyme markers and are seen to be essentially clonal by RFLP analysis [Boothroyd, Darde, Wilson]. Despite considerable structural homology between Toxoplasma and related apicomplexan parasites there is little direct overlap in gene sequence data. Good progress has been made in cloning functional genes and in elucidation of PI anchors [Cesbron-Delauw, Johnson, Mercereau-Puijalon, Striepen]. The structure of molecules on the surface and within dense granules, rhoptries and micronemes has in some cases been determined and provides clues as to the targetting and function of these proteins.

Expression of an immune response is the net result of complex synergis tic and antagonistic activities performed by a variety of cell types. It includes macrophages, T and B populations which may interact in performance of a response, and suppressor cells interfering with it. Accordingly, a lack of res ponse may not necessarily indicate absence of immunocompetent cells, but rather nonexpression of competence. Thus, one should consider two possible situations, which are by no means mutually exclusive, to account for immuno logic unresponsiveness: (a) one or more of the cell populations composing the synergistic unit is absent or immature, and (b) an antagonistic unit which interferes with the response is dominating. In view of this, an approach to development of immune reactivity necessitates parallel surveys of development of cells with the potential to perform, as well as of cells which can suppress the response. Classification of the various cell types has been based so far on their phenotypic properties (e. g., membrane antigen markers, cell receptors, pro duction and secretion of immunoglobulins, etc. ). Genotypically, T and B cells may represent either separate, independent cell lines, or different stages of development within the same cell lineage."

1.1 Classification of Togaviruses The family, Togaviridae, is composed of the alphaviruses, the flaviviruses, rubella (a rubivirus), and the pestiviruses (Fenner, 1976). Of these four genera, two (the alpha- and flaviviruses) are transmitted by blood-sucking arthropods, specif ically mosquitoes and ticks. Among the togaviruses, extensive studies of defective interfering (DI) particles have so far been carried out only with Sindbis virus (SV) and Semliki Forest virus (SFV), both members of the alphavirus genus. Since these viruses are so similar, in most cases it will be assumed that what is true of one is also true of the other. 1.2 Definition of Defective Interfering (DI) Particles Defective interfering viral particles, as defined by Huang (1973), have the follow ing properties: (1) they are deletion mutants and therefore lack large amounts of the genetic material present in the standard virus; (2) they contain the same viral structural proteins as standard virus; (3) they are unable to replicate alone; however, they are replicated in cells co-infected with standard virions; and (4) at the same time as they require standard virus to replicate, they inhibit the replication of standard virus and hence are interfering."

Throughout the centuries, inflammation has been considered as a disease in itself. This misconception arose from the inability to distinguish between inflammatory changes and the insults which induce them. The understanding of the distinction between the genesis of inflammation and the tissue reactions that follow is attributed to JOHN HUNTER, who, at the end of the 18th century, substantially contributed to the analysis of inflammation in objective terms. Today, however, we are still trying to find explanations for Celsus' Signs in terms of structural and functional changes occurring in the inflamed tissue. There are drugs which modulate these signs but, without a detailed knowledge of the basic physiopathological events, it is impossible to understand their mechanism of action. Notwithstanding, the effects of anti inflammatory drugs provided new knowledge of the relevance of the signs and symptoms to the sequence of biochemical and morphological changes occurring in inflammation. When we accepted the invitation to edit a Handbook on Inflammation and Anti Inflammatory Drugs, we were aware of the magnitude of the task. We knew the impossibility of covering the whole field in detail, especially taking into account the rapid accumulation of experimental knowledge which would, in all likelihood, overtake the process of publication."

Phenomena as diverse as tuberculin sensitivity, delayed sensitivity to soluble proteins other than tuberculin, contact allergy, homograft rejection, experimental autoallergies, and the response to many microorganisms, have been classified as members of the class of immune reactions known as delayed or cellular hypersensitivity. Similarities in time course, histology, and absence of detectable circulating immunoglobulins characterize these cell-mediated immune reactions in vivo. The state of delayed or cellular hypersensitivity can be transferred from one animal to another by means of sensitized living lymphoid cells (CHASE, 1945; LANDSTEINER and CHASE, 1942; MITCHISON, 1954). The responsible cell has been described by GOWANS (1965) as a small lymphocyte. Passive transfer has also been achieved in the human with extracts of sensitized cells (LAWRENCE, 1959). The in vivo characteristic of delayed hypersensitivity from which the class derives its name is the delayed skin reaction. When an antigen is injected intradermally into a previously immunized animal, the typical delayed reaction begins to appear after 4 hours, reaches a peak at 24 hours, and fades after 48 hours. It is grossly characterized by induration, erythyma, and occasionally necrosis. The histology of the delayed reaction has been studied by numerous investigators (COHEN et al. , 1967; GELL and HINDE, 1951; KOSUNEN, 1966; KOSUNEN et al. , 1963; MCCLUSKEY et al. , 1963; WAKSMAN, 1960; WAKSMAN, 1962). Initially dilatation of the capillaries with exudation of fluid and cells occurs.