Interferons and Their Applications

1 Interferons and Their Applications: Past, Present, and Future.- A. Introduction.- B. Interferon Research: The Beginnings.- C. The Current Windfall in Interferon Research.- D. Clinical Applications.- I. Viral Infections.- II. Cancer.- E. Looking Ahead.- I. Tasks for the Laboratory.- II. Challenges for Clinical Investigators.- F. Future Prospects.- G. Possible Socioethical Problems.- H. Conclusion.- References.- 2 Assay of Interferons. With 1 Figure.- A. Introduction.- B. Bioassays.- I. Cytopathic Effect Inhibition Assay.- 1. Subjective Endpoints.- 2. Objective CPE Inhibition Assays.- II. Plaque Reduction Assays.- III. Virus Yield Reduction Assays.- 1. Reduction in Infectious Virus Yield.- 2. Hemagglutinin Yield Reduction.- 3. Inhibition of Retrovirus Reverse Transcriptase.- 4. Neuraminidase Yield Reduction.- 5. Inhibition of Viral RNA Synthesis.- IV. Other Assays.- 1. Hemadsorption Inhibition Assay.- 2. Immunofluorescent Cell-Counting Assay.- 3. Reduction of DNA Synthesis.- 4. Other Assays of Limited Use.- V. A Reference Bioassay.- C. Data Analysis, Unitage, and Standardization.- I. Dose-Response Curves.- 1. Construction of Graphical Representations.- 2. Factors Affecting Slope and Assay Results.- II. Determination of Variability of Assay Results.- III. Standards.- 1. Calibration of Assay.- 2. Use of Laboratory and International Standards.- D. Interferon Standards.- I. Derivation.- II. Quality.- III. Stability and Its Prediction.- IV. Use and Limitations of Standards.- V. Sources of Standards.- E. Radioimmunoassays.- F. Summary.- References.- 3 Evolution of Interferon Genes. With 11 Figures.- A. Introduction.- B. Coding Region Nucleotide Sequence.- C 3? Noncoding Region Nucleotide Sequence.- D. Structural Evolution of the 3? Noncoding Region.- E. Coding Region Amino Acid Sequence.- F. Concluding Remarks.- References.- 4 Comparative Analysis of Interferon Structural Genes With 2 Figures.- A. Introduction.- B. Molecular Cloning of Some Human IFN-? cDNA and Chromosomal Genes.- C. Molecular Cloning of a Human IFN-? cDNA and Its Chromosomal Gene.- D. Comparative Structure of Some IFN-? and -? mRNAs and Proteins Deduced from cDNA Clones.- I. The Coding Regions.- II. The Signal Peptides.- III. The Noncoding Regions.- E. Comparative Structure of Some IFN-? and -?1 Chromosomal Genes.- F. Other Human IFN-? and -? Genes.- G. Chromosomal Localization.- H. IFN Structural Genes in Other Species.- J. Conclusions.- References.- 5 Comparative Structures of Mammalian Interferons With 9 Figures.- A. Introduction.- B. Purification and Characterization of Native Interferons.- I. Human Interferons-?.- 1. Purification.- 2. Characterization.- II. Human Interferon-?.- 1. Purification.- 2. Characterization.- III. Human Interferon-?.- IV. Mouse Interferons.- V. Comparison of Amino Acid Sequences of Human and Mouse Interferons.- C. Purification and Characterization of rDNA-Derived Interferons.- I. Human Interferons-?.- II. Human Interferons-?.- III. Human Interferons-?.- D. Protein Structure and Interferon Activity.- I. Disulfide Bonds.- II. Physical Studies.- 1. rDNA-Derived Interferons.- 2. Interferon Fragments.- III. Effect of Sequence Changes on Activity.- 1. NH2 Terminal Variations.- 2. COOH Terminal Variations.- 3. cDNA-Encoded Analogs.- IV. Carbohydrate Content.- 1. Native Human Interferons-?.- 2. Native Human Interferons-?.- 3. Native Human Interferons-?.- 4. Native Mouse Interferons.- E. Structure Prediction.- References.- 6 Regulatory Control of Interferon Synthesis and Action With 6 Figures.- A. Regulatory Control of IFN Synthesis.- I. Introduction.- II. Human IFN Genes.- 1. A Multigene Family.- 2. Location of IFN Genes.- III. Regulation of IFN Synthesis.- 1. Superinduction.- 2. Cellular RNA Metabolism During Induction.- IV. Virus-Resistant Cell Mutants.- B. Regulatory Control of IFN Action.- I. Introduction.- II. Genetic Factors Controlling Sensitivity to ifN.- 1. Human Chromosome 21.- 2. Mouse Genes for Sensitivity to ifN.- III. Other Factors Influencing IFN Action.- 1. Antiviral Activity.- 2. Nonantiviral Activities.- IV. Clinical Considerations.- 1. IFN Therapy.- 2. Combination Therapy.- 3. “Misregulation” of IFN Action.- References.- 7 Application of Recombinant DNA Technology to Expression of Human Interferon Genes.- A. Introduction.- B. General Comments on the Experimental Strategies for Cloning IFNs.- I. Specific Comments on Cloning IFN-?.- II. Specific Comments on Cloning IFN-?.- III. Cloning IFN-7.- C. Comments on Strategies for IFN Production in rDNA Hosts.- D. Examples of Findings Directly Derived from Cloning Experiments.- I. Multigene Families.- II. Chromosomal Clustering of IFN-? and IFN-?.- III. Absence of Introns in IFN-? and IFN-?1.- IV. Species and Tissue Specificity of IFNs.- References.- 8 The Molecular Mediators of Interferon Action With 2 Figures.- A. Introduction.- B. The Inhibition of Protein Synthesis by Double-Stranded RNA.- C. 2?,5?-01igo(A).- I. 2?,5?-01igo(A) Polymerase.- II. 2?,5?-01igo(A)-Activated Endonuclease (RNAse L).- III. Degradation of 2?,5?-01igo(A).- D. Degradation of Viral RNA in Infected Cells.- I. The Localized Activation of 2?,5?-01igo(A) Polymerase-RNAse L.- II. The Requirement for Double-Stranded RNA.- E. Other Antiviral Mechanisms.- I. Protein Kinase Activated by Double-Stranded RNA.- II. Other Metabolic Changes in Interferon-Treated Cells.- F. Conclusions.- References.- 9 The Cellular Effects of Interferon.- A. Introduction.- B. Cell Growth Inhibition by IFN.- I. Assay Systems.- 1. Viable Cell Counts.- 2. Colony Formation.- 3. Measurement of Macromolecular Synthesis.- II. Variables in Analysis of Growth Inhibition by IFN.- 1. Cell Type.- 2. Type of IFN.- 3. Conditions of IFN Treatment.- 4. Reversibility of IFN Effect.- III. Proof That Cell Growth Inhibitor Is IFN.- 1. Physical/Chemical Proof.- 2. Neutralization by Antiserum.- 3. Purification.- 4. Cell Mutants Resistent to IFN.- C. Effects of IFN on Cell Cycle.- D. Other Cellular Effects of IFN.- I. Morphology.- II. Mobility.- III. Physiologic Cell Responses to IFN.- IV. Phagocytosis.- V. Interaction with Chemicals or Factors Affecting Growth.- VI. Anticellular Effects of 2?,5?-01igonucleotide.- VIL Effect on Synthesis of Specific Proteins.- VIII. Cell Membrane-Associated Changes.- IX. IFN Effects on Cyclic Nucleotides.- X. IFN Effects on Prostaglandin Synthesis.- XL IFN Effects on Steroidogenesis.- G. Effects of IFN on Cellular Differentiation.- I. Fibroblast-Adipocyte Conversion.- II. Myoblast-Myotube Conversion.- III. Erythroid Differentiation.- 1. Friend Leukemia Cells.- 2. Myeloid Leukemia Cells.- H. Conclusions and Epilogue.- References.- 10 Interferon Induction by Viruses. With 8 Figures.- A. Introduction and Perspective.- B. A Quantitative Approach to Interferon Induction by Viruses: Defining the Interferon-Inducing Particle.- C. Dose (Multiplicity)-Response (Interferon Yield) Curves for Interferon Induction/Production.- I. Type r?l Curves.- II. Type r=l Curves.- D. dsRNA as the Interferon Inducer Moiety of Viruses: One Molecule as the Threshold for Induction.- E. One Molecule of dsRNA as the Interferon Inducer Moiety of Different Viruses.- I. Vesicular Stomatitis Virus.- IL Sindbis Virus.- III. Reovirus.- IV. Mengo Virus.- V. Newcastle Disease Virus.- VI. Sendai Virus.- F. Summary.- References.- 11 Interferon Induction by Nucleic Acids: Structure-Activity Relationships With 4 Figures.- A. General Considerations.- B. Nucleic Acid Strandedness and Its Consequences for Interferon Induction.- I. Double-Strandedness is an Absolute Prerequisite for the Interferon-Inducing Ability of Polynucleotides.- II. To Act as an Interferon Inducer, the Double-Helical Complex Should be Sufficiently Thermostable.- III. The Polynucleotide Should not be Degraded by Nucleases Before it Reaches Its Destination.- C. The Effectiveness of a Nucleic Acid Complex as an Interferon Inducer Depends on the Molecular Size of the Complex and/or Its Constituent Homopolymer Strands.- D. Interferon Induction by Synthetic Polynucleotides Depends on the Structure of the Nucleotide Building Block.- I. Interferon Induction by Synthetic Polynucleotides is Critically Dependent on the Nature of the Ribose-Phosphate Backbone.- II. Interferon Induction by Synthetic Polynucleotides is Critically Dependent on the Nature of the Heterocyclic Bases in the Interior of the Double Helix.- E. Role of Polynucleotide Conformation in the Interferon Induction Process.- F. The Spectrum of Biologic Activity of Exogenous Nucleic Acids.- References.- 12 Production and Characterization of Human Leukocyte Interferon With 2 Figures.- A. Introduction.- B. Production.- I. Leukocyte Preparation.- II. Propagation of Inducing Virus.- III. Preparation of Agamma Serum and Media.- IV. Interferon Induction in Leukocyte Cultures.- C. Purification.- I. Cantell Method.- II. High Pressure Liquid Chromatography.- III. Antibody Affinity Chromatography.- D. Characterization.- E. Discussion.- References.- 13 Lymphoblastoid Interferon: Production and Characterization.- A. Introduction.- B. Spontaneous Formation of Interferon by Lymphoblastoid Cells.- C. Interferon Formed by Lymphoblastoid Cells After Induction.- D. Interferons Made by Namalwa Cells.- I. Factors Influencing Production.- 1. Production Conditions.- 2. Medium and Serum.- 3. Inducers.- 4. Enhancers.- 5. Other Factors.- II. Kinetics of Production.- III. Large Scale Production.- IV. Clinical Use.- 1. Safety Aspects.- 2. Clinical Trials.- V. Characterization.- 1. Heterogeneity and Carbohydrate Content.- 2. Antigenic Characteristics.- 3. Monoclonal Antibodies to Components of Namalwa and Leukocyte Interferons.- 4. Specific Activity of Pure Namalwa Interferon.- 5. Other Properties.- References.- 14 Fibroblast Interferons: Production and Characterization..- A. Introduction.- B. Production.- I. Human.- 1. Superinduction.- 2. Large Scale Production Using Diploid Cells.- 3. Cell Substrates for Human Interferon Production.- 4. Production of Fibroblast Interferons in Microbial Cells.- II. Mouse.- 1. Virus-Induced Systems.- 2. Large Scale Production Systems.- 3. Superinduction.- 4. Cloning of Mouse Interferon.- C. Characterization of Fibroblast Interferons.- I. Molecular Weight Studies.- 1. Human Fibroblast Interferon.- 2. Mouse Interferons.- II. Stability.- III. Heterogeneity of Interferons.- 1. Human Fibroblast Interferon.- 2. Mouse Interferons.- IV. Glycosylation of Interferons.- 1. Human Fibroblast Interferon.- 2. Mouse Interferons.- V. Purification Studies.- VI. Amino Acid Composition and Sequence.- 1. Human Fibroblast Interferon.- 2. Mouse Interferons.- VII. Conclusions.- References.- 15 Immune Interferon. With 9 Figures.- A. Position of Human Immune Interferon in the Lymphokine System.- B. Production of HuIFN-?.- I. Inducers.- II. IFN-? System.- III. Large Scale Production of HuIFN-?.- C. Properties of IFN-?.- D. Purification of IFN-?.- E. Characterization of IFN-? Induced by Staphylococcal Enterotoxin A.- I. Transfer of the Antiviral Activity Between Leukocytes and Epithelial Cells.- II. Anticellular Properties of IFN-?.- III. Potentiation of IFN-? Action.- IV. Antigenic Classification of IFN-?.- V. Electrodynamic Characterization of IFN-?.- VI. Physicochemical Properties of IFN-?.- VII. Classification of IFN-? Subspecies.- VIII. Detection of Other Biologically Active Molecules in IFN-? Preparations.- IX. Mechanism of Induction of the Antiviral State by IFN-?.- F. The Prospect of Using IFN for Treatment of Viral and Neoplastic Diseases.- References.- 16 Comparative Biologic Activities of Human Interferons.- A. Introduction.- B. Native Interferons: Cell Source.- C. Biologic Activity.- I. Antiviral Properties.- II. Growth Inhibition.- III. Immunoregulatory Properties.- IV. Other Biologic Properties.- V. Absorption and Distribution.- D. Recombinant DNA-Derived Interferons.- E. Conclusions.- References.- 17 Manufacture and Safety of Interferons in Clinical Research.- A. Introduction.- B. Manufacture.- I. Introduction.- II. Purity.- III. Potency.- C. Safety.- I. Cell Substrates.- 1. Primary Human Leukocytes.- 2. Lymphoblastoid Cells.- 3. Fibroblast Cells.- 4. Bacteria (Recombinant DNA).- II. Final Product.- D. Summary.- References.- 18 Nonpolynucleotide Inducers of Interferon. With 4 Figures.- A. Introduction.- B. Chemical Structures.- C. Comparative Interferon, Antiviral, and Antitumor Activity.- D. Hyporeactivity.- E. Summary.- References.- 19 Agents Which Modulate the Activity of Interferon.- A. Introduction.- B. Antineoplastic Agents.- I. Antiviral Effects.- II. Antitumor Effects.- C. Antiviral Agents.- I. Acyclovir.- II. Isoprinosine.- III. Trifluorothymidine.- IV. Adenine Arabinoside.- D. Ganglioside-Binding Agents.- E. Hormones.- I. Glucocorticoids.- II. Estrogens.- F. Growth Factors.- G. Prostaglandins.- H. Vitamins.- I. Vitamin A.- II. Vitamin C.- J. Histamine Antagonists.- K. Differentiation-Promoting Agents: DMSO, TPA, Insulin.- L. Conclusion.- References.- 20 Effects of Interferon and Its Inducers on Leukocytes and Their Immunologic Functions..- A. Introduction.- B. Effects of Interferon and Its Inducers on Antibody Production.- C. Effects of Interferon on Cell Surface Antigen Expression on Lymphoid Cells.- I. Mouse Cells.- II. Human Cells.- D. Effects of Interferon on Mitogen- or Antigen-Induced Lymphocyte Proliferative and Cytotoxic Responses.- I. Mouse Lymphocytes.- II. Human Lymphocytes.- E. Effects of Interferon on Delayed-Type Hypersensitivity Responses.- F. Effects of Interferon and Its Inducers on Macrophage functions.- I. Phagocytic Activity of Mouse Macrophages.- II. Tumoricidal Activity of Mouse Macrophages.- III. Cytotoxic Activity of Human Monocytes and Macrophages Against.- Tumor and Virus-Infected Cells.- G. Effects of Interferon and Its Inducers on Natural Killer Cell Activity.- I. Discovery and Possible Roles of NK Cells.- II. Mouse NK Cell Activity.- III. Human NK Cell Activity.- H. Summary and Concluding Comments.- References.- 21 Clinical Use of Interferons: Localized Application in Viral Diseases With 3 Figures.- A. Introduction.- B. Respiratory Virus Infections.- I. Basic Anatomy and Physiology.- II. Intranasally Administered IFN.- 1. Early Trials.- 2. Recent Trials.- 3. Transport of Exogenous HuIFN Across the Human Nasal Mucosa.- III. Conclusions.- C. Ocular Virus Infections.- I. Basic Anatomy and Physiology.- II. Intraocularly Adminstered IFN.- 1. Early Trials.- 2. Recent Trials.- III. Conclusions.- D. Miscellaneous Virus Infections.- E. Summary.- References.- 22 Clinical Use of Interferons: Systemic Administration in Viral Diseases.- A. Introduction.- B. Herpesviruses.- I. Herpes Simplex Viruses.- II.Cytomegalovirus.- III.Varicella Zoster Virus.- IV. Epstein-Barr Virus.- V. Summary of Herpesvirus Infections.- C. Hepatitis B Virus Infection.- D. Other Virus Infections.- E. Pharmacokinetics and Toxicology of Systemically Administered Interferon.- I. Pharmacokinetics.- II. Toxicology.- References.- 23 Clinical Use of Interferons: Central Nervous System Disorders With 5 Figures.- A. Introduction.- B. Pharmacology.- I. Pharmacokinetics.- II. Tolerance.- C. Clinical Use.- I. Viral Diseases of the Central Nervous System.- 1. Rabies.- 2. Herpesviruses.- 3. Arbovirus Encephalitis (Togaviruses).- 4. Slow Virus Diseases (Conventional Viruses).- 5. Slow Virus Diseases (Unconventional Viruses).- II. Dysimmune Neurologie Diseases.- 1. Multiple Sclerosis.- 2. Recurrent Dysimmune Polyneuropathy (Landry-Guillain-Barré Syndrome).- III. Degenerative Diseases of the Central Nervous System.- 1. Amyotrophic Lateral Sclerosis.- 2. Alzheimer’s Presenile Dementia.- IV. Neoplasms of the Central Nervous System.- D. Conclusions.- References.- 24 Clinical Investigation of Interferons: Status Summary and Prospects for the Future.- A. Introduction.- B. Leukocyte Interferon (IFN-?).- I. Malignant Lymphoma.- II. Acute Leukemias.- III. Multiple Myeloma.- IV. Breast Cancer.- V. Other Tumors.- C. Fibroblast Interferon (IFN-?).- D. Recombinant DNA-Derived Interferon.- E. General Comments About Studies to Date and Future directions.- F. Conclusion.- References.- 25 Utilization of Stabilized Forms of Polynucleotides With 9 Figures.- A. Introduction.- B. Thiolated Derivatives.- C. DEAE-Dextran.- D. Liposomes.- E. Stabilization with Polylysine.- F. PICLC in Monkeys.- G. Importance of Size of Components of PICLC.- H. Antiviral Studies in Monkeys.- J. Adjuvant Actions.- K. Studies in Humans.- L. Comparison of Interferon Inducers with Exogenous Interferon.- References.- 26 Therapeutic Applications of Double-Stranded RNAs With 3 Figures.- A. Introduction.- B. Spectrum of Actions Produced by dsRNA.- I. Effects on Humoral Immune Response.- II. Effects on Cell-Mediated Immune Response.- III. Effects on the Hematopoietic System.- IV. Mitogenic and Toxic Effects on Cells.- V. Pyrogenic Effect.- VI. Other Effects.- C. Poly(I) · poly(C): Antiviral and Antitumor Activities and Toxicity.- I. Animal Studies.- II. Human Studies.- D. Modulating the Spectrum of Activities Triggered by dsRNA.- E. Poly(I) · poly(C12U): An Interferon Inducer with Few Toxic Responses.- F. Conclusions.- References.- 27 Monoclonal Antibodies to Interferons.- A. Introduction: The Preparation and Use of Monoclonal Antibodies.- I. Comparison of Monoclonal and Conventional Antibodies.- II. Production of Monoclonal Antibodies.- B. Conventional Antibodies to Interferon.- C. NK2: A Monoclonal Antibody to Human Interferon-?.- I. Isolation.- II. Properties.- 1. Characterization.- 2. Specificity.- III. Uses.- 1. Purification of Interferon.- 2. Immunoradiometric Assay.- 3. Immunofluorescent Studies.- 4. Applications of NK2-Purified Interferon.- 5. Use of NK2 as a Research Reagent.- D. Other Monoclonal Antibodies to Human Interferon-?.- E. Monoclonal Antibodies to Human Interferon-? and -?.- F. Monoclonal Antibodies to Mouse Interferon.- References.