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Interferon has been and continues to be one of the more fas­ cinating substances produced by apparently all animals in response to particular stimuli. It has led to major revisions in concepts of cellular immunity and theories on the recovery of multicellular systems from viral infection. Since its discovery, interferon has held the interest of the molecular biologist, and definitive answers as to its clinical value are close at hand. The following treatise is an attempt by the authors to pre­ sent a complete picture of the many aspects of interferon. Having recently had the privilege of visiting the laboratories of the au­ thors and several others of our Soviet colleagues working in the interferon field, I was most impressed with the amount of research being done in this area. Since a great deal of this work is published in the Russian language, there is unfortunately a time lag until it can be received and translated. We are therefore most grateful to Drs. Solov'ev and Bektemirov for having produced this impres­ sive work which offers the opportunity to review the entire field and, very importantly, some of the work being done by our Soviet counterparts, and also to Plenum Publishing Corporation for pro­ viding the English translation. Work on the mechanism of interferon induction, the relative role of the cellular constituents, and work in cell-free systems and the molecular mechanism of the antiviral action of interferon continues to excite scientists in the field.

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Im ersten Teil des Buches werden Entwicklung, Aufbau und Systematik der Interferone sowie ihre Stellung innerhalb des Zytokin-Netzwerkes dargestellt. Weiterhin werden durch Interferone stimulierbare zytoplasmatische und nukleäre Veränderungen beschrieben. Der zweite Teil beschäftigt sich mit der klinischen Anwendung von Interferonen. Bei den wichtigsten malignen und benignen Krankheitsbildern werden die bisherigen Ergebnisse der Interferongabe dargestellt - auch in Kombination mit anderen systemischen und lokalen Behandlungsmaßnahmen - und mit herkömmlichen Behandlungsmethoden verglichen. Ziel des vorliegenden Buches ist es, möglichst umfassend und klar über Aufbau und Systematik des Interferonsystems sowie über seine bisherige klinische Bedeutung zu informieren.

Interferons were among the first cytokines to be studied clinically in recombinant form in the 1980s, beginning a new era of pharmacotherapy in internal medicine. Interferons were soon employed in the treatment of tumors and it was shown that those hematopoietic neoplasias which had been difficult to treat with chemotherapy responded well to interferon treatment. In the present volume, renowned international authors update the importance of interferons in various fields of internal medicine, dermatology, and urology. The book also contains a general introduction into the classification, structure, and mode of action of interferons. Further chapters discuss the range of side effects of these substances and point out possible focuses of further clinical interferon research.

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Interferon was first discovered in 1957. Over the last five years it has become almost a household word. Many believe it to be a drug with already proven efficacy against cancer and viral infection. The media has distorted any cool scientific view of the data available. We have learned much about the complexity of the interferon system. We know some of the switches involved in interferon gene expression and its secretion by virally and immune stimulated cells. We also know that it binds to a cell surface receptor, mediating its complex effects on target cells by a series of second messengers. The advent of the new techniques of modern molecular biology, such as monoclonal antibodies and gene cloning, has had tremendous impact on the rate of acquisition of knowledge. Such techniques have provided us with almost unlimited quantities of highly purified interferon for clinical trial in patients with a spectrum of infectious and malignant diseases. The information we have gathered raises many more questions. Why should there be several families of interferon genes? What is their true physiolo­ gical role? How are they interrelated functionally? Interferon is clearly a cellular hormone providing a means of communication between cells. ~fhether it has clinical value in the management of patients with diseased cells remains to be seen. This book sum­ marises our current knowledge of interferons as possible an- cancer agents. It is clear interferon is no penicillin for cancer.

This book is an update of Interferon, published in 1969 by Dr. Jan Vilcek. The field of interferon research has since expanded from its former narrow treatment of interferon strictly as an antiviral substance, such that The Interferon System now encompasses cellular modulations ranging from immune alterations to cell proliferative restrictions to antitumor activities. The steadily increasing number of these non-antiviral functions of interferons emphasizes the need for a comprehensive - and critical - review of the entire literature of interferon studies. The text, with its supporting bibliography, provides complete coverage of interferon research. A newcomer to the area should find here all the informa­ tion necessary to understand why interferon, which has been studied for more than twenty years and which originally stirred excitement over its clinical pros­ pects, is still inspiring speculation about this potential. For those already fa­ miliar with the seemingly perpetual clinical promise of interferon, this volume should serve as a valuable reference source, the largest bibliography on the subject ever to appear under one cover. Clearly, this book should be considered only as an introduction to the topic and as a reference source; most questions about the interferon system are still unanswered - even unasked. Hopefully this summation and critical evalua­ tion of work done to date will stimulate and facilitate further progress.

A compendium of optimized methods to measure type I interferon efficacy as an antiproliferative or an antiviral agent. These cutting-edge techniques range from the simple to the highly complex and serve to illuminate the signaling cascades and the activation of enzymatic pathways prompted by interferon. The protocols follow the successful Methods in Molecular Medicine™ series format, each offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls. State-of-the-art and highly practical, Interferon Methods and Protocols offers researchers powerful tools not only to ascertain the functions of IFN-stimulatory gene products, but also to identify additional molecular pathways that will clarify our understanding of the many biological events influenced by IFNs.

Today, the basic mood of researchers and clinical investigators, both at the center and on the periphery of interferon studies, is optimistic regarding the future of interferons as therapeutic substances. Many also feel these polypeptides will prove invaluable probes in unraveling certain fundamental biochemical processes which control the life cycle and developmental pattern of many human cells. In contrast, only a year or two ago, this optimism had given way to an attitude almost of disenchantment as public and scientific expectations were raised steeply, then rapidly waned, as it turns out, prematurely. Both the mUltiple actions of interferons (a virtual cascade of biochemical reactions may be induced, as documented herein) and the high visibility of interferon research provided by the millions of dollars invested both by national health agencies and by multinational pharmaceutical companies, contributed to an upsweep in public attention to drug development probably unprecedented in this century. Virtually every oncologist, it would seem, was plagued by requests for the experimental agent, although they already had therapies of more proven value. As recently as 1980, even though interferon had achieved success against certain cancers and certain viral diseases, the variability in clinical results was seemingly ever present and little evidence emerged to suggest interferons could cure advanced diseases. Why then the resurgence of an optimistic mood? There are almost always many elements which contribute to happiness, and this is certainly true of the broad frontier of interferon and its place in biochemical research and treatment.

Die Therapie der Multiplen Sklerose stellt sich zunehmend differenzierter dar. Unterschiedliche Wirkstoffe sind entwickelt und klinisch untersucht, nicht alle halten der Prüfung stand. Die Behandlung mit Beta-Interferon ist jedoch inzwischen etabliert; die Entwicklung der Krankheit wird verzögert, die Lebensqualität der Patienten erhöht. Die 3. Auflage des Buches, von zwei Autoren neu bearbeitet, ordnet jüngste Ergebnisse klinischer und vorklinischer Studien in den bestehenden Kontext ein. Neue Befunde zur Entstehung sowie geänderte Empfehlungen zur Therapie der schubförmigen und der sekundär progredienten MS sind dargestellt. Vorgelegte Forschungsergebnisse werden kritisch gewürdigt, bislang nicht veröffentlichte Daten zugänglich gemacht. Experimentelle Behandlungsansätze sind ebenso besprochen wie der Einsatz von Interferonen gegen Virus- oder Krebserkrankungen. Marginalien leiten durch die Themenschwerpunkte.

The type I interferon (IFN) signaling pathway is well recognized as a pathway activated by viral infections. It is activated by a variety of microbial pattern recognition receptors including the Toll-like receptors, NOD-like receptors and several cytosolic receptors. Activation of the type I IFN pathway leads to the production of both antiviral factors and products that influence immune cell function. More recently it has been shown that bacteria are also capable of activating this pathway. Bacterial Activation of Type I Interferons reviews both the current understanding of how different bacterial species are able to activate this pathway as well as the influence type I IFNs have on the outcome to infection. Several different bacterial species are covered, spanning Gram positive and Gram negative, intracellular, extracellular, and different host infection sites. An introduction to the pathogenesis of each organism is provided, and the signaling molecules involved in the activation of the type I IFN pathway and the role it plays in animal infection models are also covered.

The type I interferon (IFN) signaling pathway is well recognized as a pathway activated by viral infections. It is activated by a variety of microbial pattern recognition receptors including the Toll-like receptors, NOD-like receptors and several cytosolic receptors. Activation of the type I IFN pathway leads to the production of both antiviral factors and products that influence immune cell function. More recently it has been shown that bacteria are also capable of activating this pathway. Bacterial Activation of Type I Interferons reviews both the current understanding of how different bacterial species are able to activate this pathway as well as the influence type I IFNs have on the outcome to infection. Several different bacterial species are covered, spanning Gram positive and Gram negative, intracellular, extracellular, and different host infection sites. An introduction to the pathogenesis of each organism is provided, and the signaling molecules involved in the activation of the type I IFN pathway and the role it plays in animal infection models are also covered.

The type I interferon (IFN) signaling pathway is well recognized as a pathway activated by viral infections. It is activated by a variety of microbial pattern recognition receptors including the Toll-like receptors, NOD-like receptors and several cytosolic receptors. Activation of the type I IFN pathway leads to the production of both antiviral factors and products that influence immune cell function. More recently it has been shown that bacteria are also capable of activating this pathway. Bacterial Activation of Type I Interferons reviews both the current understanding of how different bacterial species are able to activate this pathway as well as the influence type I IFNs have on the outcome to infection. Several different bacterial species are covered, spanning Gram positive and Gram negative, intracellular, extracellular, and different host infection sites. An introduction to the pathogenesis of each organism is provided, and the signaling molecules involved in the activation of the type I IFN pathway and the role it plays in animal infection models are also covered.

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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.

Over the last half of century interferon (IFN), originally discovered as an antiviral protein, has developed from an inhibitor of viral replication to a major force in the antiviral response. Initially studied only by few virologists, IFN was generally considered as a poorly defined protein of limited importance. The development of molecular techniques lead to the identification of a family of IFN genes and has shown an unexpected complexity of type I IFN genes and their expression. Presently, some aspects of the of the pathogen mediated induction of IFN gene expression are understood at molecular level, while others are still at the stage of description. Both Toll like receptors and cytoplasmic RNA helicases were shown to recognize viral nucleic acids and the basis of a distinct recognition of viral nucleic acids from the cellular ones are emerging. Important insights on the virus recognition entity, leading to the expression of interferon and interferon induced genes, have been made in the recent year, which are challenging the accepted concept of the critical role of dsRNA in IFN induction. The availability of genetically modified mice that are lacking either essential components of the interferon inducing pathway, or interferon signaling pathway fully confirmed the original idea, made soon after its discovery, that interferon is the first cellular defense against viral infection.

Interferon alpha-2 is a genetically engineered, highly purified pharmaceutical agent that has undergone extensive phase I and phase II clinical study in more than 1000 patients. The material has biological activity by intravenous, intramus­ cular and subcutaneous routes. Clinical toxicity principally involves the 'influen­ za like' syndrome previously seen with native interferons. Other important toxi­ cities include anorexia, hepatitis, confusion and myelosuppression. Tolerable doses in multiple schedules and routes of administration have been determined. Phase II clinical trials with multiple routes and schedules of administration have been performed. Significant clinical activity has been found in non­ Hodgkin's lymphomas (both low grade and high grade), refractory and relapsing multiple myeloma, hairy cell leukemia, Kaposi's sarcoma, with suggestions of activity in Hodgkin's disease, renal cell carcinoma, and melanoma. The studies performed to date have for the most part involved small numbers of heavily pre-treated patients. Large-scale clinical trials in some of these disea­ ses are now warranted in populations of patients with as little bulk disease and prior treatment as is feasible for each tumour type. This is particularly the case in . Hodgkin's disease and subcategories of the non-Hodgkin's lymphomas. Alterna­ tely, interferon alpha-2 might be used to maintain remissions induced by other modalities (i. e. , in NHL, multiple myeloma, ovarian cancer). In some advanced disease settings, combinations of interferon alpha-2 with chemotherapeutic agents should now be investigated.

Interferon alpha-2 is a genetically engineered, highly purified pharmaceutical agent that has undergone extensive phase I and phase II clinical study in more than 1000 patients. The material has biological activity by intravenous, intramus­ cular and subcutaneous routes. Clinical toxicity principally involves the 'influen­ za like' syndrome previously seen with native interferons. Other important toxi­ cities include anorexia, hepatitis, confusion and myelosuppression. Tolerable doses in multiple schedules and routes of administration have been determined. Phase II clinical trials with multiple routes and schedules of administration have been performed. Significant clinical activity has been found in non­ Hodgkin's lymphomas (both low grade and high grade), refractory and relapsing multiple myeloma, hairy cell leukemia, Kaposi's sarcoma, with suggestions of activity in Hodgkin's disease, renal cell carcinoma, and melanoma. The studies performed to date have for the most part involved small numbers of heavily pre-treated patients. Large-scale clinical trials in some of these disea­ ses are now warranted in populations of patients with as little bulk disease and prior treatment as is feasible for each tumour type. This is particularly the case in . Hodgkin's disease and subcategories of the non-Hodgkin's lymphomas. Alterna­ tely, interferon alpha-2 might be used to maintain remissions induced by other modalities (i. e. , in NHL, multiple myeloma, ovarian cancer). In some advanced disease settings, combinations of interferon alpha-2 with chemotherapeutic agents should now be investigated.

Over the last half of century interferon (IFN), originally discovered as an antiviral protein, has developed from an inhibitor of viral replication to a major force in the antiviral response. Initially studied only by few virologists, IFN was generally considered as a poorly defined protein of limited importance. The development of molecular techniques lead to the identification of a family of IFN genes and has shown an unexpected complexity of type I IFN genes and their expression. Presently, some aspects of the of the pathogen mediated induction of IFN gene expression are understood at molecular level, while others are still at the stage of description. Both Toll like receptors and cytoplasmic RNA helicases were shown to recognize viral nucleic acids and the basis of a distinct recognition of viral nucleic acids from the cellular ones are emerging. Important insights on the virus recognition entity, leading to the expression of interferon and interferon induced genes, have been made in the recent year, which are challenging the accepted concept of the critical role of dsRNA in IFN induction. The availability of genetically modified mice that are lacking either essential components of the interferon inducing pathway, or interferon signaling pathway fully confirmed the original idea, made soon after its discovery, that interferon is the first cellular defense against viral infection.