The Interferon System (2^nd Ed., 2nd ed. 1981. Softcover reprint of the original 2nd ed. 1981)

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.

I. Introduction.- A. An Historical Perspective.- 1. The Phenomenon of Viral Interference.- 2. Discovery of Interferon.- 3. Interference Mediated by Other Mechanisms.- B. An Overview of the Interferon System.- 1. Interferon Inducers.- 2. Induction Mechanisms.- 3. Genetic Information for Interferon Production.- 4. Interferon Messenger RNA.- 5. Interferon Production.- 6. Interferons.- 7. Interferon Binding.- 8. Genetic Information for Interferon Actions.- 9. Cellular Alterations Induced by Interferons.- a) Antiviral States.- b) Priming and Blocking.- c) Enhanced Susceptibility to Toxicity of Double-Stranded RNA.- d) Effects on Cell Surfaces.- e) Effects on Cell Multiplication.- f) Immunomodulations.- C. The Interferon System in vivo.- 1. Interferons as Prophylactic and Therapeutic Agents in Animals.- 2. Interferons in the Clinic.- II. Interferon Assays.- A. General Considerations.- B. Dose-Response Relationships.- C. Assay Methods.- 1. Plaque-Reduction Assays.- 2. Yield-Reduction Assays.- a) Reduction of Infectious Virus Yields.- b) Reduction of Haemagglutinin Yields.- c) Reduction of Haemadsorption.- d) Reduction of Neuraminidase Yields.- 3. Cytopathic Effect (CPE)-Inhibition Assays.- a) CPE-Reading Method.- b) Dye-Uptake Method.- 4. Radiochemical Assays.- 5. Other Antiviral Assays.- a) Reverse Transcriptase Inhibition Assay.- b) Immunofluorescence Assay.- c) EB Virus-Expression Assay.- d) Cytochemical Assays.- e) Agar Diffusion Assays.- f) pH Indicator Assay.- 6. Non-Antiviral Assays.- D. Factors Influencing Interferon Assays.- 1. Non-Interferon Contaminants.- 2. Period of Interferon Exposure.- 3. Challenge Multiplicity.- 4. Assay Duration.- 5. Concentration vs. Volume.- 6. Aging Effect.- E. Choice of an Assay System.- 1. Assay Method of Choice.- 2. Cells of Choice.- 3. Virus of Choice.- F. Reference Interferons and Standard Interferons.- III. Interferon Inducers.- A. Animal Viral Inducers.- 1. Adenoviruses.- 2. Myxo-Paramyxo Inducers.- 3. Rhabdoviruses.- 4. “Arbovirus” Inducers.- 5. Diplorna Viruses.- 6. Lymphocytic Choriomeningitis Virus.- B. Non-Viral Inducers of Interferons.- 1. “Foreign” Nucleic Acids.- 2. Fungal Extracts.- 3. Bacteria and Bacterial Products.- 4. Other Microorganisms Inducing Interferons.- a) Chlamydia.- b) Rickettsiae.- c) Mycoplasmas.- d) Protozoa.- 5. Mitogens and Immune Recognition Induction.- a) Mitogens.- b) Immune Recognition Induction.- c) Induction by Tumor Cells.- 6. Synthetic Inducers.- a) Anionic Polymers.- 1. Polycarboxylates, Sulfates and Phosphates.- 2. Polynucleotides.- b) Low Molecular Weight Inducers.- 1. Tilorone.- 2. Cationic Dyes.- 3. Propanediamine.- 4. BL-20803.- 5. MA-56.- 6. AET.- 7. U-25, 166.- C. Inferferon (?) Inducers.- D. Uninduced (Spontaneous) Interferons.- IV. Induction Mechanisms.- A. The Interferon Induction-Production Curve.- 1. The Induction Phase.- a) True Induction?.- b) Preformed Interferons?.- 2. The Interaction of Inducer and Cell.- 3. Induction Lag Periods.- a) The in vitro Lag.- b) Induction Lag in vivo.- c) Time of Appearance of Lymphocyte Interferons — Types I and II.- B. Mechanism of Induction by Viruses.- 1. Search for Double-Stranded RNA.- 2. Viral Events Effecting Induction.- C. Alternative Induction Mechanism Hypotheses.- 1. The Double-Stranded RNA Hypothesis.- 2. The Repressor-Depletion Hypothesis.- 3. The Basal-Level-Interferon Hypothesis.- V. The Genetics of Interferon Production.- A. Hybrid-Cell Analyses of Interferon Production.- 1. Production Regulation in Hybrid-Cells.- 2. Chromosomal Assignments for Interferon Production in Hybrid-Cell Lines.- B. Chromosomal Assignments for Interferon Production in Aneuploid Cells.- C. Epigenetic Complications of Assessing Genetic Contributions to Interferon Production.- 1. Age Effects on Interferon Production.- a) In vivo Age and Interferon Potential.- b) Interferon Production and in vitro Aging.- 2. Variations in Interferon Production by Human Diploid Cell Cultures.- D. Genetics of Interferon Production in vivo.- 1. Mendelian Analyses of Interferon Production.- 2. Non-Specific Factors Influencing in vivo Genetic Evaluations of Interferon Production.- a) Temperature.- b) Hormones.- c) Other Factors Modulating Interferon Production.- VI. Interferon Production.- A. Interferon Production at the Cellular and Molecular Level.- 1. Interferon Messenger RNA.- a) Indirect Evidence for Interferon Messenger RNA.- b) Extraction of Interferon Messenger RNA and Its Translation in Heterologous Cells.- c) Translation of Interferon Messenger RNA in Xenopus Oöcytes.- d) Translation of Interferon Messenger RNA in Cell-Free Protein- Synthesizing Systems.- e) Translation of Interferon Messenger RNA in Bacteria?.- 2. Superinduction or Superproductions?.- a) Interferon Enhancement by Metabolie Inhibitors.- b) Mechanisms of Superproduction.- 3. Regulatory Mechanisms on Interferon Production: The Refractory State in vitro (Hyporesponsiveness and Blocking).- 4. Posttranslational Processing of Interferons.- a) Interferon Precursor?.- b) Glycosylation of Interferon Proteins.- c) Secretion of Interferons.- B. Interferon Production at the Organism Level.- 1. Interferon Production in vivo.- a) Production of Interferon in Viral Infections.- b) Non-Viral Interferon Inducers in vivo.- c) Cell-Sources of Interferon.- 2. Hyporesponsiveness in vivo: Tolerance to Repeated Inductions.- a) Cross-Tolerance to Different Inducers.- b) Serum Hyporeactive Factor.- C. Mass Production of Interferons.- 1. Mouse Interferon.- 2. Human Leukocyte Interferon.- 3. Human Fibroblast Interferon.- 4. Human Lymphoblastoid Cell Interferon.- 5. Alternatives to Large-Scale Production.- 6. Which Human Interferon Should be Produced?.- VII. Interferons: Their Purification and Characterization.- A. Defining Interferons.- 1. Induction of Antiviral Activities.- 2. “Species Specifity” of Interferons.- 3. Acid-Stability of Interferons.- 4. Physicochemical Properties Generally Applicable to All Interferons: The Protein Nature of Interferons.- 5. Antigenicities of Interferons.- 6. Induction of Non-Antiviral Activities.- 7. A Summary Definition of Interferons.- B. Purification of Interferons.- 1. Purification of Mouse Interferons.- 2. Purification of Human Leukocyte (and Lymphoblastoid) Interferons.- 3. Purification of Human Fibroblast Interferon.- C. Characterization of Interferons.- 1. Heterogeneities of Interferons.- a) Molecular Weights of Interferons.- b) Stabiiities of Interferons.- c) Ligand Affinities of Interferons.- d) Biological Heterogeneities of Interferons.- e) Origins of Heterogeneities of Interferons.- f) Significance of Interferon Heterogeneities.- 2. Non-Antiviral Activities of Interferons.- VIII. The Genetics of Interferon Action.- A. Hybrid-Cell Analyses of Interferon Action.- B. Chromosomal Assignments for Interferon Actions in Aneuploid Cells.- 1. Antiviral Action of Human Interferon in Aneuploid Cells: Chromosome 21 Dosage Effect.- 2. Relationship of Non-Antiviral Actions of Human Interferons to Chromosome 21.- 3. Regulatory Chromosomes for Interferon Actions.- C. Role of Chromosome 21 in Interferon Actions: Interferon Binding.- 1. Interactions of Interferons With Cells: Initiation of Interferon Actions.- a) Indirect Studies on Interferon Binding.- b) Direct Studies on Interferon Binding.- 2. Chromosome 21 and Interferon Binding.- D. Epigenetic Complications to Assessing Genetic Contributions to Interferon Actions.- 1. Age Effects on Interferon Action.- 2. Cell Density Effect.- 3. Variations in Interferon Sensitivities of Diploid Cells.- 4. Other Factors Modulating Interferon Actions.- a) Antagonists.- b) Factors Influencing Early Interferon-Cell Interactions.- c) Miscellaneous Factors.- IX. Mechanisms of Antiviral Acfions of Interferons.- A. General Considerations of Antiviral Actions of Interferons.- 1. Conversion to the Antiviral State.- a) Kinetics of Development of Antiviral Activity.- b) Metabolie Requirements for Development of Virus Resistance.- c) Duration of the Antiviral State.- 2. Character of Interferon-Induced Virus Resistance.- B. Antiviral Mechanisms: Sites of Interferon Actions Against Viruses.- 1. Inhibition of Virus Attachment, Penetration and Uncoating.- 2. Inhibition of Virus Transcription.- 3. Inhibition of Virus Translation.- a) Inhibition of Virus Translation in Cells.- b) Inhibition of Virus Translation in Cell-Free Systems.- 4. Inhibition of Maturation and Release.- C. An Oversimplified Summation of Interferon-Induced Antiviral Actions.- X. Non-Antiviral Actions of Interferons.- A. The Breadth of Interferon Action: The Expanding Realm of Interferonology.- B. Inhibition of Non-Viral Agents.- C. Priming.- D. Blocking.- E. Cell-Multiplication-Inhibition.- 1. Evidence That Interferon Is the Active Component Inhibiting Cell- Multiplication.- 2. Cellular Systems Inhibited by Interferon.- 3. Metabolie Alterations in Interferon-Treated Cells.- 4. Restraints Imposed by Interferon.- F. Toxicity Enhancement.- G. Enhanced Synthetic Activities.- H. Surface Alterations In du ced by Interferons.- I. Enhanced Immunolysis.- J. Enhancement of Phagocytosis.- K. Macrophage “Activation”.- L. Delayed-Type Hypersensitivity-Inhibition.- M. Graft-vs-Host Reactions: Effects of Interferon on Transplantation.- N. Effects of Interferon on Antibody Production.- 1. In vivo Antibody Production.- 2. In vitro Antibody Production.- XI. Pharmacokinetics of Interferons.- A. Distribution of Interferon.- 1. Circulating Interferon Levels.- 2. Clearance From the Cerebrospinal Fluid: The Blood-Brain Barrier for Interferon.- 3. Transplacental Passage and Other Barriers to Distribution of Interferon.- B. Metabolism of Interferons.- 1. Renal Clearance.- 2. Catabolism of Interferon: Role of Carbohydrates.- C. Effective Interferon Levels.- XII. Antiviral Actions of Interferons in Animals.- A. Natural Recovery Processes From Viral Infections.- 1. Progression of Virus Infections.- a) Localized Infections.- b) Generalized Infections.- 2. Factors Modifying Pathogenesis: Interactions With Interferon Mechanism.- a) Restriction of Establishment of Infections.- b) Elimination of Established Infections.- B. Antiviral Studies With Interferons and Interferon Inducers in Animals.- 1. Localized Infections.- a) Effect of Exogenous Interferons.- b) Effects of Inducers of Endogenous Interferons.- 2. Generalized Infections.- a) Effects of Exogenous Interferons.- b) Combined Effects of Interferons and Other Agents.- c) Effects of Inducers of Endogenous Interferons.- 3. Unifying Speculation on Inducer Toxicities.- XIII. Antitumor Activities of Interferons in Animals.- A. Activities Against Virally-Induced Tumors.- 1. Antitumor Effects of Exogenous Interferons.- 2. Antitumor Effects of Inducers of Endogenous Interferons Against Virally-Induced Tumors.- 3. Combined Antitumor Efficacies of Interferon and Other Antitumor Agents.- B. Activities Against Transplantable Tumors.- 1. Antitumor Effects of Exogenous Interferons.- 2. Antitumor Effects of Inducers of Endogenous Interferons Against Transplantable Tumors.- C. Activities Against Chemically- and Radiation-Induced Tumors.- 1. Antitumor Effects of Exogenous Interferons.- 2. Antitumor Effect of Inducers of Endogenous Interferons Against Chemically- and Radiation-Induced Tumors.- D. Mechanisms of Antitumor Activities of Interferons.- 1. Virus-Induced Tumors.- 2. Transplantable Tumors.- XIV. Interferon in the Clinic.- A. Preliminary Testing of Interferons: Therpeutic-Index of Interferon?.- B. Antiviral Activities of Interferons in Man.- 1. Localized Infections.- a) Prophylaxis With Interferon.- b) Therapy of Localized Infections.- 2. Systemic Viral Infections.- a) Disseminated Herpesvirus: Varicella-Zoster.- b) Cytomegalovirus Infections.- c) Hepatitis B Virus Infections.- d) Interferon Therapy in Other Viral Diseases.- 3. Antiviral Effects of Interferon Inducers in Man.- a) Virus Interference in Man.- b) Poly rl-Poly rC in the Clinic.- c) Propanediamine and Its Vehicle.- C. Cancer Therapy With Interferon.- 1. Antitumor Activity of Interferon Inducers in Man.- 2. Effects of Interferon.- XV. Prelude to the Interferon System.- Acknowledgements.- References.- Appendix to the References.