The Pharmacology of Lymphocytes

Glossary of Common Immunological Terms.- 1.- 1 The Evolution, Ontogeny, and Physiologic Function of Lymphocytes.- A. What is a Lymphocyte?.- B. Phylogenetic Origin of Lymphocytes.- C. Ontogenetic Origin of Lymphocytes.- D. Generation of the B Cell Repertoire.- E. Generation of the T Cell Repertoire.- F. Genetically Controlled Nonresponsiveness.- G. Lymphocyte Function.- References.- 2 De Novo Expression of Receptors on T Cells.- A. T Cell Activation and De Novo Expression of Receptors.- B. Therapeutic Implications.- I. Immunosuppressive Therapy with M7/20 IL-2 Receptor-Specific Antibody.- II. The Effect of ART 18 IL-2 Receptor-Specific Antibody Treatment in Rat Cardiac Allografts.- III. Art 18 mAb Therapy Spares Suppressor T Cells.- References.- 3 Membrane Events During Lymphocyte Activation.- A. Introduction.- B. Phosphatidylinositol Turnover.- I. B Cells.- II. T Cells.- C. Protein Kinase C Translocation.- I. T Cells.- II. B Cells.- D. Electrophysiologic Studies.- I. K+ Channels.- II. Ca2+ Channels.- III. Na+ Channels.- E. Fluorescent Probe and Radioisotope Studies.- I. Membrane Potential.- II. Intracellular Free Ca2+ Levels.- III. Cytoplasmic Alkalinization.- IV. Regulatory Volume Responses.- References.- 4 Intracellular Events During Lymphocyte Activation.- A. Introduction.- B. Cytoskeletal Changes.- C. Lipid Changes.- I. Phosphatidylinositol Metabolism.- II. Phosphatidylcholine Metabolism.- III. Arachidonic Acid Metabolism.- IV. Summary of Lipid Changes.- D. Transport Changes.- I. Ions.- II. Nutrients.- E. Changes in Cyclic Nucleotides and Protein Phosphorylation.- I. Cyclic AMP.- II. Cyclic GMP.- III. Protein Phosphorylation.- F. Conclusions.- References.- 2.- 5Generation and Measurement of Antibodies.- A. Introduction.- I. B Cell Development Leading to Antibody Production.- II. Antibodies as Diagnostic Tools.- B. Induction of Antibody Formation.- I. In Vitro Antibody Formation.- II. In Vivo Antibody Formation.- C. Measurement of Immunoglobulin Secretion at the Cellular Level.- 1. Cell Suspensions from Lymphoid Organs of Mice.- 2. Cell Suspensions of Human Origin.- I. Antibody-Secreting Cell Assays.- D. Measurement of Circulating Immunoglobulins.- I. Precipitation-Based Assays.- II. Agglutination-Based Assays.- III. Ligand-Binding Assays.- References.- 6 Monoclonal Antibodies to Lymphocyte Surface Molecules as Probes for Lymphocyte Functions.- A. Introduction.- B. Methods for Monoclonal Antibody Generation.- I. Immunization Strategies.- II. Fusion.- III. Screening.- IV. Cloning.- C. Functional Molecules.- I. T Cell Lineage Restricted.- II. Growth Factor Receptors.- III. Receptors for Components of Complement.- IV. Leukocyte Adhesion Molecules LFA-1 and LFA-3.- D. Recognition Molecules.- I. T4 and T8: Class II and Class I Recognition Molecules.- II. Cell Receptor for Antigen.- E. Summary.- References.- 7 Interleukin 1 Production from Various Cells and Measurement of its Multiple Biologic Activities.- A. Introduction.- B. Production of IL-1 In Vitro.- I. IL-1 Induction from Peripheral Blood Monocytes.- II. Cell Sources of IL-1.- C. Production of IL-1 In Vivo.- I. Detection of IL-1 in the Circulation.- II. Detection of IL-1 in Synovial Fluid.- III. Detection of IL-1 in Urine.- IV. Detection of IL-1 in Peritoneal Fluid.- D. Assays for IL-1.- I. Lymphocyte Activation Assays.- II. Induction of Acute Phase Responses.- III. Assays for IL-1 Employing its Catabolic and Inflammatory Properties.- References.- 8 Production and Measurement of Interleukin 2 and Interleukin 3.- A. Introduction.- B. Interleukin 2 (IL-2).- I. The T Cell Growth Factor, IL-2.- II. Production.- III. Measurement.- IV. Standardization.- V. Measurement of IL-2 mRNA by Northern Blot Analysis.- VI. Measurement of IL-2 mRNA by Microdot Hybridization.- C. Interleukin 3 (IL-3).- I. The Multilineage-Specific Hematopoietic Growth Factor, IL-3.- II. Production.- III. Measurement.- D. Human IL-3-Like Factors.- E. Conclusions.- References.- 9 Production and Measurement of Interferons.- A. An Overview of the Interferon System.- I. Introduction.- II. Discovery of Interferons.- III. Heterogeneity of Interferons.- IV. Multiple Biologic Effects of Interferons.- B. Interferon Induction/Production.- I. Induction.- II. Induction/Production by Cells In Vitro.- III. Production In Vivo.- IV. Mass Production and Purification.- C. Interferon Assays.- I. Biologic Assays.- II. Nonbiologic (Immunologic) Assays.- D. Interferon in the Clinic and its Future.- References.- 10 Factors Regulating IgE Synthesis.- A. IgE Regulation.- I. Development of an IgE Response.- II. Evidence for a Specific IgE Isotype Regulation.- III. Models of IgE Regulation.- IV. Methods for Measuring IgE-Specific Immunoregulation.- B. Production and Measurement of IgE-Regulating Factors.- I. Suppressive Factor of Allergy (SFA).- II. Human IgE-Binding Factors (IgE-BF).- III. IgE Class-Specific Suppressive Factors of T Cell Origin (IgE-TsF).- IV. IgE-Binding Factors (IgE-BF).- V. Glycosylation-Enhancing and -Inhibiting Factors (GEF and GIF).- C. Future Developments.- References.- 11 Generation, Biology, and Assay of Efferent Lymphokines.- A. Introduction.- B. Migration-Inhibitory Factor (MIF).- I. Original Observations and Biologic Characteristics.- II. Cellular Source.- III. Molecular Characteristics.- IV. Measurement.- C. Macrophage-Activating Factor (MAF).- I. Original Observations and Biologic Characteristics.- II. Molecular Characteristics.- III. Several MAFs and Steps in Macrophage Activation.- IV. Measurement.- D. Tumor Necrosis Factor (TNF-?).- I. Original Observations.- II. Biologic Characteristics.- III. Molecular Characteristics.- IV. TNF Receptors.- V. Identity of TNF-? with Cachectin.- VI. Measurement.- E. Lymphotoxin (TNF-?).- I. Original Observations.- II. Biologic Characteristics.- III. Producer Cells.- IV. Molecular Characteristics.- V. Synergism with Other Cytokines and Effects on Lymphocytes.- VI. Anticarcinogenic Activity.- VII. Measurement.- F. Osteoclast-Activating Factor (OAF).- I. Biologic Characteristics.- II. Molecular Characteristics.- III. Measurement.- G. Soluble Immune Response Suppressor (SIRS).- I. Biologic Characteristics.- II. Molecular Characteristics.- III. Measurement.- H. Chemotactic Cytokines.- I. Biologic Characteristics.- II. The Search for Molecular Characterization.- III. Measurement.- J. Concluding Remarks.- References.- 12 Lymphocyte Purification, Growth, Cloning and Functional Assays.- A. Introduction.- I. Tissue Culture.- II. Freezing and Thawing of Cells.- B. T Cell Growth and Cloning.- I. Introduction.- II. In Vivo Generation of Antigen-Primed T Cells.- III. Feeder Cells.- IV. Antigen In Vitro.- V. Sources of Interleukin 2.- VI. Antigen-Independent Growth and Cloning.- VII. Antigen-Dependent T Cell Lines.- VIII. Cloning from Antigen-Dependent T Cell Lines.- IX. Use of Transformed Cell Lines.- X. T Cell Hybridisation.- XI. Viral Transformation.- XII. Summary.- C. B Cell Growth and Cloning.- I. Introduction.- II. Spontaneously Transformed Cells.- III. Epstein-Barr Virus Transformation of Human B Cells.- IV. Abelson Virus Transformation of Murine B Cells.- V. B Cell Hybridisation.- VI. Growth and Cloning of Transformed Cells.- VII. Purification of Normal B Cells.- VIII. Summary.- D. Concluding Remarks.- References.- 13 Screening Strategies for Detecting Immunotherapeutic Agents.- A. Introduction.- B. General Principles of Immunotherapeutic Drug Development.- I. Target Diseases.- II. Cellular Targets for Immunotherapeutic Agents.- C. Screening Methodology.- I. Quantification of Lymphocytes.- II. Functional Assays.- D. Future Developments in Screening Methodology.- I. Biochemical Assays of Lymphocyte Activation.- II. Radioreceptor Assays.- III. Monoclonal Antibodies.- E. Clinical Trials of Immunotherapeutic Agents.- References.- 3.- 14 Selected Autacoids as Modulators of Lymphocyte Function.- A. Introduction.- B. Histamine.- C. Catecholamines.- D. Prostaglandins and Leukotrienes.- E. Concluding Remarks.- References.- 15 Lipid Mediators and Lymphocyte Function.- A. Introduction.- B. Essential Fatty Acids.- I. Role in Lymphocyte Activation.- II. Actions on Lymphocytes In Vitro.- III. Actions on Lymphocytes In Vivo.- C. Prostaglandin E.- I. Cell-Mediated Immunity.- II. Humoral Immunity.- D. Other Prostaglandins and Thromboxanes.- E. Lipoxygenase Metabolites.- I. Effects In Vitro.- II. Effects In Vivo.- F. Peroxides.- G. Platelet-Activating Factor.- References.- 16 Thymic Hormones and Lymphocyte Functions.- A. Introduction.- B. Chemistry of the Four Available Thymic Peptides.- I. Thymosin ?l.- II. Thymopoietin.- III. Thymulin.- IV. Thymic Humoral Factor.- C. Effect of Thymic Hormones on Lymphocyte Markers and Functions.- I. Marker Studies.- II. Effect on T Cell Functions.- III. Mode of Action at the Cellular Level.- D. Conclusions.- References.- 4.- 17 Glucocorticosteroids.- A. Introduction.- B. History.- C. Effects of Steroids on Lymphocyte Function In Vivo.- D. Effects of Steroids on Lymphocyte Function In Vitro.- I. Humoral Immunity.- II. Cellular Immunity.- E. Effects of Steroids on Monokines and Lymphokines In Vitro.- F. Mechanisms of Action.- G. Conclusion.- References.- 18Slow Acting Antirheumatics.- A. Introduction.- B. Characteristics of Therapy.- C. The Immunologic Basis of Rheumatoid Arthritis.- D. Disease-Modifying Antirheumatic Drugs.- E. Summary.- References.- 19 Cyclophosphamide.- A. Introduction.- B. Effects of Cyclophosphamide on Cells of the Immune System.- C. Immunomodulation by Cyclophosphamide.- I. Immunosuppression and Immunostimulation In Vivo.- II. Tolerance Induction and Termination.- III. In Vitro Activities.- D. Effects of Cyclophosphamide on Autoimmune Animal Models….- I. Adjuvant Arthritis Disease of Lewis Rats.- II. Murine Models for Systemic Lupus Erythematosus.- E. Clinical Aspects of Cyclophosphamide Therapy.- F. Summary.- References.- 20 Lobenzarit (CCA).- A. Introduction.- B. Chemistry.- C. Toxicology.- D. Pharmacokinetics.- E. Immunopharmacologic Studies.- I. Prevention of Autoimmune Disease and Immunomodulation in MRL-Mp-lpr/lpr (MRL/1) Mice.- II. Prevention of Autoimmune Disease and Immunomodulation in NZB/NZW F1 Hybrid Mice.- III. Therapeutic Effect on Adjuvant Arthritis in Rats.- IV. No Inhibitory Effect on Acute Inflammation.- V. Immunoregulatory Effects.- VI. Effects on Immunocompetent Cells.- F. Clinical Studies.- I. Multicenter Double-Blind Controlled Study.- II. Long-Term Study.- 21 Cyclosporins: Immunopharmacologic Properties of Natural Cyclosporins.- A. Introduction.- B. In Vitro Methods.- I. Proliferative Response of Lymphocytes to Mitogenic Stimulation.- II. Generation of Soluble Factors Affecting the Immune Response.- III. Proliferative Response of Lymphocytes to Allogeneic Stimulation: Murine Mixed Lymphocyte Reaction.- IV. Induction of Cytotoxic T Cells in a One-Way Mixed Lymphocyte Reaction.- V. Primary Humoral Immune Response to Sheep Red Blood Cells.- VI. Secondary Humoral Immune Response Against a T Cell-Specific Antigen (DNP-KLH) In Vitro.- VII. Cytotoxic and Cytostatic Activity In Vitro with the P-815 Mastocytoma Cell Line.- C. In Vivo Methods.- I. Formation of Plaque-Forming Cells (Humoral Immune Response).- II. Delayed-Type Hypersensitivity Reaction in Mice.- III. Localized Graft-Versus-Host Reaction.- D. Autoimmune Disease Models.- I. Freund’s Adjuvant-Induced Arthritis.- II. Formation of Autoantibodies in Experimental Allergic Myasthenia Gravis.- E. Transplantation Models.- I. Skin Allograft Reaction in Mice.- II. Kidney Allograft Reaction in Rats.- III. Heterotopic Heart Transplantation in Rats.- F. Discussion.- References.- 22 Muramyl Dipeptides.- A. Introduction.- B. In Vivo Quantitative and Qualitative Changes in Specific Immune Responses Produced by MPDs.- I. Characteristics of Antibody Responses After MDP Treatment.- II. T Cell-Mediated Responses.- III. Immunosuppression.- C. In Vivo Changes in Cell Compartments of the Immune System Following MDP Administration.- D. Role of Lymphocyte Populations in Antibody Responses of Cell Cultures Stimulated with MDPs.- E. In Vitro Direct Responses of Lymphocytes to MDP in the Absence of Antigenic Stimulation.- I. Mitogenic Effect of MDPs.- II. Polyclonal Activation.- III. Influence of MDPs on Mitogenic Responses.- IV. Effect of MDP on Thymoma Cell Lines.- V. In Vitro NK Cell Induction.- F. In Vitro Indirect Responses of Lymphocytes to MDPs.- G. Conclusions.- References.- 23 Antipurines and Purine Metabolism.- A. General Introduction.- B. Antipurines: 6-Mercaptopurine and Azathioprine.- I. Historical Perspective/Background.- II. Metabolism.- III. Effects on Lymphocyte Subsets.- C. Adenosine Deaminase and Purine Nucleoside Phosphorylase Deficiencies.- D. Conclusions.- References.- 24 Isoprinosine and NPT 15392: Hypoxanthine-Containing Immunomodulators.- A. Isoprinosine.- I. Chemistry.- II. Pharmacokinetics and Bioavailability.- III. Pharmacology.- IV. Toxicology.- V. Pharmacodynamics.- VI. Clinical Efficacy and Safety.- B. NPT 15392.- I. Toxicology.- II. Immunopharmacology.- III. Clinical Experience.- References.- 25Bacterial and Fungal Products.- A. Bacterial Products as Mitogens and Immunomodulators.- I. Bacterial Peptidoglycans.- II. Endotoxic Lipopolysaccharide and Lipid A.- III. Outer Membrane Protein.- IV. Lipoteichoic Acids and Related Amphiphiles.- V. Others.- VI. Speculation.- B. Fungal Polysaccharides as Immunopotentiators Against Cancer.- I. Lentinan.- II. Krestin and Schizophyllan.- References.- 26 Nonsteroidal Anti-inflammatory Drugs: Effects on Lymphocyte Function.- A. Introduction.- B. Principal Effects of Nonsteroidal Anti-inflammatory Drugs.- C. Effects of Nonsteroidal Anti-inflammatory Drugs on Lymphocytes.- I. Clinical Observations.- II. T Cell Effects.- III. B Cell Effects.- D. Conclusion and Outlook.- References.- 27 Future Prospects for Drugs Design of Lymphocyte Modulators.- A. Introduction.- B. Potential Targets for Lymphocyte Modulators.- C. Lymphocyte Modulators.- I. Transplantation and Autoimmunity.- II. Chronic Inflammatory Processes.- III. Acute Hypersensitivity Reactions.- IV. Infections and Cancer.- D. Conclusions.- References.