Interferons and Their Applications

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.

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 (I...