International review of experimental pathology 34 cytokine induced pathology, part b inflammatory cytokines, receptors, and disease

Editorial Advisory Board Robert Kisilevsky Kingston, Ontario, Canada M Mihatsch Basel, Switerland Peter C Nowell Philadelphia, Pennsylvania Steen Olsen Aarhus, Denmark U Pfeifer Bonn, Germany Sibrand Poppema Edmonton, Alberta, Canada Stephen T Reeders New Haven, Connecticut Andrew H Wyllie Edinburgh, Scotland R M Zinkernagel Zürich, Switzerland International Review of EXPERIMENTAL φ PATHOLOGY Volume 34 CYTOKINE-INDUCED PATHOLOGY PART B: Inflammatory Cytokines, Receptors, and Disease Edited by G W Richter Department of Pathology University of Rochester Medical Center Rochester, New York Kim Solez Department of Pathology Faculty of Medicine University of Alberta Edmonton, Alberta Canada Guest Editor Bernhard Ryffel Institut für Toxikologie Eidgenössischen Technischen Hochschule Universität Zürich Schwerzenbach/Zürich Switzerland ACADEMIC PRESS, INC Harcourt Brace Jovanovich, Publishers San Diego New York Boston London Sydney Tokyo Toronto This book is printed on acid-free paper ® Copyright © 1993 by ACADEMIC PRESS, INC All Rights Reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher Academic Press, Inc 1250 Sixth Avenue, San Diego, California 92101-4311 United Kingdom Edition published by Academic Press Limited 24-28 Oval Road, London NW1 7DX Library of Congress Catalog Number: 62-21145 International Standard Book Number: 0-12-364935-8 PRINTED IN THE UNITED STATES OF AMERICA 93 94 95 96 97 98 QW Contributors Numbers in parentheses indicate the pages on which the authors' contributions begin Kathy Barrett, Sunley Research Institute, London, England (105) M Patricia Beckmann, Immunex Corporation, Seattle, Washington 98101 (123) C Paul Chow, Department of Safety Evaluation, Genentech, Inc., South San Francisco, California 94080 (43) William C Fanslow, Immunex Corporation, Seattle, Washington 98101 (123) Adriano Fontana, Section of Clinical Immunology, Department of Neurosurgery, University Hospital, CH-8044 Zürich, Switzerland ( 183) Michael Fountoulakis, Pharmaceutical Research, New Technologies, Hoffmann-La Roche Ltd., CH-4002 Basel, Switzerland (137) Brian Foxwell, Sunley Research Institute, London, England (105) Karl Frei, Section of Clinical Immunology, Department of Neurosurgery, University Hospital, CH-8044 Zürich, Switzerland (183) Gianni Garotta, Pharmaceutical Research, New Technologies, HoffmanLa Roche Ltd., Ch-4002 Basel, Switzerland (137) Reiner Gentz, Pharmaceutical Research, New Technologies, HoffmanLa Roche Ltd., Ch-4002 Basel, Switzerland (137) Georges E Grau, Department of Pathology, WHO-IRTC, University of Ge­ neva, CH-1211 Geneva 4, Switzerland (159) James D Green, Department of Safety Evaluation, Genentech, Inc., South San Francisco, California 94080 (43,73) Cindy A Jacobs, Immunex Corporation, Seattle, Washington 98101 (123) Thomas C.Jones, Clinical Research, Sandoz Pharma Ltd., CH-4002 Basel, Switzerland (209) Steven L Kunkel, Department of Pathology, University of Michigan Medi­ cal School, Ann Arbor, Michigan 48109 (7) xi xii Contributors Paul-Henri Lambert, Department of Pathology, WHO-IRTC, University of Geneva, CH-1211 Geneva 4, Switzerland (159) Gerhard Leitz, Corporate Medicine, Boehringer Ingelheim, Ingelheim, Germany (193) David H Lynch, Immunex Corporation, Seattle, Washington 98101 (123) Charles R Maliszewski, Immunex Corporation, Seattle, Washington 98101 (123) M J Mihatsch, Institut fur Pathologie, Universität Basel, CH-4003 Basel, Switzerland (149) Ken Mohler, Immunex Corporation, Seattle, Washington 98101 (123) Laurence Ozmen, Pharmaceutical Research, New Technologies, HoffmanLa Roche Ltd., CH-4002 Basel, Switzerland (137) Hans-Walter Pfister, Department of Neurology, University of Munich, Munich, Germany (183) Daniela Piani, Section of Clinical Immunology, Department of Neurosurgery, University Hospital, CH-8044 Zỹrich, Switzerland (183) Pierre-Franỗois Piguet, Department de Pathologie, Université de Gen­ ève, CH-1211 Genève 4, Switzerland (159,173 ) Daniel G Remick, Department of Pathology, University of Michigan Med­ ical School, Ann Arbor, Michigan 48109 (7) Frank Rosenkaimer, Corporate Medicine, Boehringer Ingelheim, Ingel­ heim, Germany (193) An tal Rot, Sandoz Forschungsinstitut, A-1235 Vienna, Austria (27) Bernhard Ryffel, Institut für Toxikologie, Eidgenössischen Technischen Hochschule, Universität Zürich, CH-8603 Schwerzenbach/Zürich, Switzerland ( 3,69,149 ) Gerhard G Steinmann, Clinical Research, Boehringer Ingelheim, D-7950 Biberach, Germany (193) Angelika C Stern, Clinical Research, Sandoz Pharma Ltd., CH-4002 Basel, Switzerland (209) Timothy G Terrell, Department of Safety Evaluation, Genentech, Inc., South San Francisco, California 94080 (43,73) Pierre Vassalli, Department of Pathology, WHO-IRTC, University of Ge­ neva, CH-1211 Geneva 4, Switzerland (159) Contributors xiii Alfred Walz, Theodor Kocher Institut, Universität Bern, CH-3001 Bern 9, Switzerland (27) Peter K Working, Department of Pharmacology and Toxicology, Lipo­ some Technologies, Inc., Menlo Park, California 94025 (43) Roland Zwahlen, Institut für Tierpathologie, Universität Bern, CH-3001 Bern 9, Switzerland (27) Preface Cytokines and growth factors play an important regulatory role in the cross talk of different cell systems Cytokines are regulatory peptides that are produced by many different cell types in the body, and often have pleiotropic regulatory effects on hemopoietic, lymphoid, and inflammatory cells Recent developments in molecular biology have allowed the cloning and production of a variety of recombinant growth factors With the availability of pure recombinant proteins, neutralizing antibody, and the rapid devel­ opment of biological models, it became possible to define the physiological roles of many of these growth factors Furthermore, the clinical use of hemopoietic growth factors such as erythropoietin, granulocyte, and granulocyte—monocyte colony stimulating factors has recently been intro­ duced in different disease conditions Although these growth factors and cytokines are normally produced by the body, the exogenous and systemic administration of high doses of these growth factors may cause pathology For these volumes, I have asked experts in pathology to present experi­ mental findings obtained from the most recently studied cytokines and growth factors I am very pleased that most of the contributions include novel and, to a large extent, unpublished experimental findings, which might help us to understand the physiological and pathological changes associated with these peptides I appreciate very much the efforts of many scientists from around the world who have contributed to this volume, and I am convinced that it represents a unique review on cytokine pathology These volumes are essentially based on a workshop held in Basel, Switzerland (August, 1991), which was organized together with my col­ leagues T Hayes, M J Mihatsch, and G Zbinden The realization of the workshop was only made possible by generous financial support from the Sandoz Pharma Corporation in Basel Bernhard Ryffel xv Introduction Bernhard Ryffel Institut für Toxikologie Eidgenössischen Technischen Hochschule Universität Zürich CH-8603 Schwerzenbach/Zürich, Switzerland Tissue injury or exposure of an organism to pathogenic stimuli triggers a number of host cellular defense mechanisms, leading to inflammation Lo­ cally released mediators from endothelial cells, macrophages, mast cells, and connective tissue cells mediate the early inflammatory reaction These early mediators include bradykinin and histamine (which are potent vasodilators), complement components, prostaglandins, kinins, platelet-activating factor, and a number of granulocyte-derived proteases Only recently has the role of the cytokines in the recruitment of cells at the site of inflammation, in activation of immunoeffector cells, including the phagocytic system, and in tissue repair been recognized (see Table I) In this work the biological effects of interferon-γ, tumor necrosis factor, interleukin-8, transforming growth factor/3, and leukemia inhibitory factor are described in experimental animals It is obvious that the biological activity of this group of cytokines is not limited to inflammatory processes, because inflammation, immune response, and to some extent hematopoiesis are tightly linked Thus, the segregation of cytokines into functional groups is arbitrary and may only indicate the main biological activity of the molecule Thus, the pleiotropic cytokines IL-1 and IL-6 play an important role in inflammatory reactions I INTERFERON-γ Interferon-γ (IFN-γ; also known as immune interferon) is mainly produced by activated T lymphocytes and possibly by natural killer cells Other mem­ bers of the interferon family include fibroblast-derived interferon-a and leukocyte-derived interferon/3 Cloned human IFN-γ encodes a mature protein of 143 amino acids Active IFN-γ is a homodimeric molecule with a molecular mass of 45 kDa Murine IFN-γ has only 45% homology to the human molecule at the protein level The difference in structure is large enough that there is no cross-reactivity of the biological effects of human and mouse IFN-γ In contrast, the homology International Review of Experimental Pathology, Volume J4B Copyright © 1993 by Academic Press, Inc All rights of reproduction in any form reserved Bernhard Ryffel Table I Molecular Characteristics of Human Inflammatory Cytokines Cytokine Molecular mass (kDa) lnterferon-γ 45 (dimer) 45 T lymphocytes TNF-a 45 (trimer) 80 Macophages TNF-ß 60 (trimer) 75 T lymphocytes 80 Lymphocytes, macrophages IL-8 Homology with mouse protein (%) Source Activity Virus, macrophages, granulocytes, lymphocytes Lymphocytes, epithelium Endothelium, tumor cells Chemotaxis Receptor p80 p55/p75 p55/p75 p90 of mouse and rat IFN-γ is high, and thus the two molecules are interchangea­ ble for the two species All interferons have antiviral activity; interferon-γ has, in addition, regula­ tory functions for macrophages (macrophage activation), T and B lympho­ cytes, and granulocytes Among interferons, interferon-y is the most effective inducer of de novo synthesis of major histocompatibility (MHC) class II antigens in macrophages in addition to stimulation of class I antigens Interferon-γ synergizes with lipopolysaccharide (LPS)-induced production of IL-1, IL-6, and tumor necrosis factor-a (TNF-α) in macrophages Besides the macrophage activation, interferon-γ has effects on T and B lymphocytes In T lymphocytes interferon-γ possibly acts as an autocrine or paracrine growth factor Interferon-γ receptors are widely distributed in tissues and have been recently cloned The homology of the human and murine receptor proteins are low and no cross-reactivity occurs with the ligands The biological effect in vivo, especially in infectious diseases and malignancies, has been evalu­ ated and exploited in specific clinical situations II TUMOR NECROSIS FACTOR An investigation of the antitumor effect of the LPS component of endotoxin derived from gram-negative bacteria led to the discovery of the TNF mole­ cule, which has direct tumoricidal activity against a range of tumor cells in vitro Activated macrophages are the main cellular source of TNF-α A second type of TNF molecule, isolated from activated T lymphocytes, is called lymphotoxin, or TNF-/3 Both TNF molecules have been molecularly Section I Introduction defined and consist of three identical monomeric subunits, 17 kDa each for TNF-α and 20 kDA each for TNF-ß The homology between TNF-α and -ß is only 36% at the amino acid level From an evolutionary point of view, the two molecules are probably derived from a common ancestral gene The mouse homologues of TNF-o: and -ß are also only distantly related The homology between mouse and human TNF-a, however, is about 80% at the amino acid level and TNF-/3 shows approxi­ mately 75% overall homology for the two species Based on these consider­ ations, a partial cross-reactivity of human TNF-α and -ß for biological activity on murine cells is predictable Both TNF molecules bind to widely distributed receptors in tissues De­ spite the marked difference in amino sequences, TNF-α and TNF-/3 bind to common cell surface receptors The human TNF receptor is composed of a 55- and a 75-kDa protein Both receptor proteins bind the TNF molecules independently and the possibility that the two receptor proteins mediate a different biological effect is presently under investigation The biological activities of TNF-α and -ß are quite similar and are charac­ terized by a broad spectrum of action, including activation of T and B lymphocytes, activation of macrophages and granulocytes, inhibition of hematopoiesis, a cytotoxic effect for tumor cells, and activation of endothelial cells Furthermore, these molecules cause cachexia after in vivo administra­ tion The tumoricidal properties of TNF molecules are presently being tested in cancer patients III INTERLEUKIN-8 IL-8 belongs to a large family of low-molecular-weight peptides with chemotactic activity for neutrophilic granulocytes (See Zwahlen et al, this volume, for a discussion of the molecular characteristics and biological properties of IL-8 ) In contrast to other activators of neutrophilic granulo­ cytes, such as GM-CSF, local injection of IL-8 causes an accumulation of granulocytes, but does not cause activation of these cells or tissue de­ struction References Aguet, M., Dembic, C, and Merlin, G ( 1988) Cell 55, 273 Beutler, B., Greenwald, D., and Hulmes, J D ( 1985) Nature {London) 316, 552 Gray, P W., and Goeddel, D V ( 1982) Nature {London) 298, 859 Gray, P W., and Goeddel, D V ( 1983) Proc Nat Acad Sci U.S.A 80, 5842 Gray, P W., Aggarwal, B B., Benton, C V., et al {1984) Nature {London) 312, 721 Hacklett, R J., Davis, L S., and Lipsky, P E ( 1988)./ Immunol 140, 2639Jones, E Y., Stuart, D I., and Walker, N P C ( 1989) Nature {London) 338, 225 218 Index rheumatoid, 39 tumor necrosis factor and, 165 Aspartate aminotransferase (AST) interferon-γ and, 80, 83, 85 recombinant human transforming growth factor-ßl and, 50, 60 AUC analysis, soluble cytokine receptors and, 126 Autoantibodies, soluble IFN-γ receptor and, 144 Autoimmune disease pulmonary fibrosis and, 173 tumor necrosis factor and, 163, 167—168 Autoimmunity, soluble IFN-γ receptor and, 138, 144-146 Autologous bone marrow, recombinant human GM-CSF and, 211-212, 215 B cells cytokine receptors and, 106, 109-112 soluble IFN-γ receptor and, 143-144 tumor necrosis factor and, 10, 161 B lymphocytes inflammation and, - interferon-γ and, 97 pulmonary fibrosis and, 178 soluble IFN-γ receptor and, 137 Bacteria interferons and, 197 recombinant human GM-CSF and, 209 tumor necrosis factor and, 8, 10, 12, 23, 160 Bacterial meningitis, immune-mediated injury in, 183-184, 190-191 neuronal cell death, 189-190 TGF-ß, 187-188 TNF-c*, 184-187 Bacterial sinusitis, recombinant human GM-CSF and, 214 Basement membrane interferon-γ and, 83 tumor necrosis factor and, 13 Basophils interleukin-8 (IL-8) and, 30, 39 recombinant human transforming growth factor-ßl and, 53 BCG infection bacterial meningitis and, 189 tumor necrosis factor and, 163-165, 167 Bilirubin, recombinant human transforming growth factor/31 and, 50, 52 Bleomycin pulmonary fibrosis and, 173, 176, 178 tumor necrosis factor and, 163-166, 168 Blood clearance, soluble cytokine receptors and, 127-131 Body temperature, interferon-γ and, 76—77, 83, 85, 96 Body weight interferon-γ and, 76, 77, 85 interferons and, 201 leukemia inhibitory factor and, 70 recombinant human transforming growth factor/31 and, 50 soluble cytokine receptors and, 127 Bone leukemia inhibitory factor and, 69—72 recombinant human transforming growth factor-j8l and, 53, 60, 63-64, 66 Bone marrow cytokine receptors and, 113 interferon-γ and, 77, 80, 83, 85-86, 97, 99 interferons and, 199 leukemia inhibitory factor and, 70-71 recombinant human GM-CSF and, 209, 212-215 tumor necrosis factor and, 9, 16, 164 Bovine serum albumin, interleukin-8 (IL-8) and, 30 C5A, interleukin-8 (IL-8) and, 28, 39 Cachetin, tumor necrosis factor and, 164 Cachexia leukemia inhibitory factor and, 70—72 tumor necrosis factor and, 168 Calcium cytokine receptors and, 111-112 interleukin-8 (IL-8) and, 29-30 leukemia inhibitory factor and, 70 recombinant human transforming growth factor/31 and, 50 Cancer inflammation and, interferons and, 196, 198, 203-204 recombinant human GM-CSF and, 209-211, 215 Capillary leak syndrome, recombinant human GM-CSF and, 215 Carbohydrate, leukemia inhibitory factor and, 69 Index Carcinomas, interferons and, 196-197, 199-200 Cathespin G, interleukin-8 (IL-8) and, 29 CD4 pulmonary fibrosis and, 178 tumor necrosis factor and, 164, 168 CD8, pulmonary fibrosis and, 178 CD40, cytokine receptors and, 108-109 cDNA cytokine receptors and, 105-107 interferon-y and, 75 interferons and, 194 leukemia inhibitory factor and, 69 soluble cytokine receptors and, 124 soluble IFN-γ receptor and, 139 Central nervous sytem, bacterial meningitis and, 184, 189-190 Cerebral malaria, tumor necrosis factor and, 163-168 Cerebrospinal fluid, bacterial meningitis and, 184-186 Chemotaxis interleukin-8 (IL-8) and, 30, 39-40 recombinant human transforming growth factor/31 and, 44 soluble cytokine receptors and, 123 Chemotherapy, recombinant human GM-CSF and, 209-211, 215 Chinese hamster ovary (CHO) cells recombinant human transforming growth factor/31 and, 46, 60 soluble cytokine receptors and, 125, 129-131, 134 Cholestasis, recombinant human transforming growth factor/31 and, 52 Cholesterol interferon-γ and, 83, 85 recombinant human transforming growth factor/31 and, 50 Chromatography, soluble IFN-γ receptor and, 139 Chromosomes cytokine receptors and, 116 interferon-γ and, 74 interferons and, 194, 199 soluble IFN-γ receptor and, 139 Chronic granulomatous disease, interferons and, 200 Chronic myelogenous leukemia, interferons and, 196, 199 219 Circulatory shock, tumor necrosis factor and, 162 Clinical chemistry, interferon-γ and, 77, 85, 98 Clinical experiences with interferon family, 193-195, 206 efficacy, 198-200 pharmacology, 195-198 toxicity, 200-206 with recombinant human GM-CSF, 209-216 Clones cytokine receptors and, 105-108, 110-113, 115 inflammation and, 3-4 interferon-γ and, 75 leukemia inhibitory factor and, 69 soluble cytokine receptors and, 124 soluble IFN-γ receptor and, 139, 145 Coagulative necrosis, tumor necrosis factor and, 16 Collagen interferons and, 198 interleukin-8 (IL-8) and, 37 pulmonary fibrosis and, 174-175, 178 tumor necrosis factor and, 161, 163 Colony-stimulating factors, see also specific Colony-stimulating factors bacterial meningitis and, 184 Concanavalin A interleukin-8 (IL-8) and, 30 soluble IFN-y receptor and, 139 Connective tissue recombinant human transforming growth factor/31 and, 50 tumor necrosis factor and, 160 Connective tissue-activating peptide III, interleukin-8 and, 29 Cornea, interferons and, 196 Cortex, recombinant human transforming growth factor/31 and, 53 Cyclic AMP, cytokine receptors and, 108, 111, 115-116 Cytokine receptors, 105-106 hematopoietic factor receptor family, 109-114 immunoglobulin supergene family, 114-115 interferon-γ, 115—116 interleukin-2, 115-116 soluble, 123-125, 130, 134-135 blood clearance, 126-133 220 Index fusion protein, 131-133 ILI, 126-128 IL-4, 127-129, 131-133 pharmacokinetics, 125-126 tissue distribution, 127-130 TNF, 129-133 tumor necrosis factor receptor family, 106-109 nerve growth factor, 108 Cytokines, pulmonary fibrosis and, 173-179 Cytoplasm cytokine receptors and, 106, 109, 112-113 leukemia inhibitory factor and, 71 recombinant human transforming growth factor/31 and, 52-53 tumor necrosis factor and, 13 Cytotoxic T lymphocytes interferon-γ and, 74 soluble IFN-γ receptor and, 145 Cytotoxicity bacterial meningitis and, 189 cytokine receptors and, 108 interferons and, 197 recombinant human GM-CSF and, 209-210 recombinant human transforming growth factor-/3l and, 65 soluble IFN-γ receptor and, 138 Delayed-type hypersensitivity, tumor necrosis factor and, 168 Depression, interferons and, 201 Dermal toxicity, recombinant human transforming growth factor/31 and, 46-49 Dexamethasone, bacterial meningitis and, 187 Differentiation, interferons and, 195 DNA cytokine receptors and, 115 interferon-γ and, 75 recombinant human transforming growth factor-/3l and, 65 soluble IFN-γ receptor and, 144 Dosage interferon-γ and, 76-86, 90, 93, 96, 99 interferons and, 196-198, 200-202, 206 mean toxic dose, 200 leukemia inhibitory factor and, 71 recombinant human GM-CSF and, 210-211, 213-215 recombinant human transforming growth factor/31 and, 50-54, 60, - 6 soluble cytokine receptors and, 125, 127, 131, 134 tumor necrosis factor and, 12, 16-17 Dysmyelopoiesis, recombinant human GM-CSF and, 212, 216 Edema bacterial meningitis and, 187, 189, 191 interleukin-8 (IL-8) and, 35, 40 recombinant human transforming growth factor-j8l and, 65 tumor necrosis factor and, 17 Electrocardiogram, interferon-γ and, - 7 Embryos, recombinant human transforming growth factor-/3l and, 44 Encephalomyocarditis virus (EMCV), soluble IFN-γ receptor and, 141 Endothelium bacterial meningitis and, 187, 191 cytokine receptors and, 110, 113 inflammation and, interleukin-8 (IL-8) and, 28-29, 34 recombinant human transforming growth factor-/3l and, 44 soluble IFN-γ receptor and, 138 tumor necrosis factor and, 10, 13-14, 17, 161, 163, 166, 168 Endotoxic shock, bacterial meningitis and, 183 Endotoxin bacterial meningitis and, 184—185 inflammation and, interleukin-8 (IL-8) and, 30, 34, 39 tumor necrosis factor and, 8, 10—11, 17, 162 Endotoxinemia bacterial meningitis and, 186 tumor necrosis factor and, 161, 163 Enostosis, recombinant human transforming growth factor-/3l and, 64 Enzymes cytokine receptors and, 106, 109 interferon-γ and, 74 interleukin-8 (IL-8) and, 39 recombinant human transforming growth factor/31 and, 52, 60 soluble IFN-γ receptor and, 138 Index Eosinophilopoiesis, cytokine receptors and, 112 Eosinophils, interleukin-8 (IL-8) and, 30, 35 Epidermal growth factor bacterial meningitis and, 186 receptors, 114—115 recombinant human transforming growth factor-ßl and, 43 soluble IFN-γ receptor and, 145 Epithelium interferon-γ and, 83, 90 interleukin-8 (IL-8) and, 28, 31 pulmonary fibrosis and, 176 recombinant human transforming growth factor-ßl and, 44, 46, 49, 53, 66 tumor necrosis factor and, 13, 19, 161, 163, 165, 168 Epitopes interferons and, 204 soluble IFN-γ receptor and, 139 Erythrocytes interferon-γ and, 80, 83, 85 recombinant human GM-CSF and, 213 tumor necrosis factor and, 161 Erythroid cells interferon-γ and, 77, 80, 97 recombinant human transforming growth factor/31 and, 60, 65 Erythropoietin, receptors, 114 Escherichia coli interferons and, 194 leukemia inhibitory factor and, - recombinant human GM-CSF, 209-216 soluble cytokine receptors and, 125, 129 tumor necrosis factor and, 10 Extracellular matrix pulmonary fibrosis and, 173 recombinant human transforming growth factor-ßl and, 53, 63 Fas antigen, cytokine receptors and, 106-107 Fatigue interferon-γ and, 97 interferons and, 200 recombinant human GM-CSF and, 215 Fatty acids, bacterial meningitis and, 184 Fetal development, interferon-γ and, 93-96 Fever interferons and, 200 221 recombinant human GM-CSF and, 214 tumor necrosis factor and, 12 Fibrin, tumor necrosis factor and, 17 Fibroblast growth factors, pulmonary fibrosis and, 175 Fibroblasts cytokine receptors and, 106, 110-111, 113-115 interferon-γ and, 73 interferons and, 194 interleukin-8 (IL-8) and, 28, 35, 37 pulmonary fibrosis and, 174-175, 178 recombinant human transforming growth factor-ßl and, 43-44, 60, 65 soluble IFN-γ receptor and, 141 — 142 tumor necrosis factor and, 161, 163, 165-166 Fibrogenic cytokines, pulmonary fibrosis and, 174-176, 178-179 Fibronectin, cytokine receptors and, 113 Fibrosis interferon-γ and, 80 pulmonary, 173-179 recombinant human GM-CSF and, 214 recombinant human transforming growth factor-01 and, 50, 52, 60, 65 tumor necrosis factor and, 162, 165, 168 Flow cytometry, tumor necrosis factor and, 10-11 Food consumption interferon-γ and, 85 recombinant human transforming growth factor-ßl and, 50 Fusion protein, soluble cytokine receptors and, 131, 134 G protein, cytokine receptors and, 108, 115-116 Ganciclovir, recombinant human GM-CSF and, 214 Gastrointestinal tract interferon-γ and, 80, 83, 90, 97 interferons and, 201 Gene expression interferon-γ and, 75 interférons and, 193, 197 interleukin-8 (IL-8) and, 29 Genes cytokine receptors and, 111, 113, 116 interferons and, 194-195 222 Index Globulin, interferon-γ and, 83 Glomerulitis, interferon-γ and, 83 Glomerulonephritis interferon-γ and, 97, 99 soluble IFN-γ receptor and, 144-145 Glomeruluar disease, tumor necrosis factor and, 168 Glucose bacterial meningitis and, 184 interferon-γ and, 85 recombinant human transforming growth factor-jÖl and, 50 Glycosylation leukemia inhibitory factor and, 69 recombinant human GM-CSF and, 209, 211 soluble cytokine receptors and, 124, 134 soluble IFN-γ receptor and, 139 Graft-versus-host disease (GVHD) soluble IFN-γ receptor and, 142-144, 146 tumor necrosis factor and, 161-166, 168 Granulation tissue, recombinant human transforming growth factor/31 and, 45, 48-49, 66 Granulocyte colony-stimulating factor (G-CSF) bacterial meningitis and, 186 leukemia inhibitory factor and, 70-71 receptors, 113 Granulocyte—macrophage colony-stimulating factor (GM-CSF) pulmonary fibrosis and, 175 receptor, 106, 109, 112 recombinant human, 209-210, 215-216 dysmyelopoisis, 212—214 myeloid hypoplasia, 210-211 tolerability, 214-215 transplantation, 211-212 tumor necrosis factor and, 165, 167 Granulocytes bacterial meningitis and, 186-187 cytokine receptors and, 113 inflammation and, 4—5 interferons and, 196, 198 interleukin-8 (IL-8) and, 31 soluble IFN-γ receptor and, 138 Granulomas, tumor necrosis factor and, 163-165, 167 GRO-a, interleukin-8 (IL-8) and, 28-30, 34-35, 39-40 GTP, cytokine receptors and, 108, 113 Haemophilus influenzae, bacterial meningitis and, 184, 187 Hairy cell leukemia, interferons and, 196-199, 202-203 Heart interferon-γ and, 80 soluble cytokine receptors and, 127, 130 soluble IFN-γ receptor and, 145 tumor necrosis factor and, 14 Hematocrit, interferon-γ and, 80, 83, 85 Hematology interferon-γ and, 76-79, 83, 85-86, 96-98 interferons and, 195, 201 interleukin-8 (IL-8) and, 37 Hematopoiesis cytokine receptors and, 112—113 inflammation and, interferon-γ and, 77, 86 leukemia inhibitory factor and, - recombinant human GM-CSF and, 209, 211, 213 soluble cytokine receptors and, 123 Hematopoietic factor receptor family, 105-107, 109-114 Hemoglobin interferon-γ and, 80, 83, 85 interferons and, 198 Hemorrhage interleukin-8 (IL-8) and, 35 tumor necrosis factor and, 160, 162 Hemorrhagic necrosis, bacterial meningitis and, 184 Hepatocytes cytokine receptors and, 112 leukemia inhibitory factor and, 69, 72 Herpes simplex virus, interferons and, 196-197 Histiocytes, interferon-γ and, 90, 93 Histology interleukin-8 (IL-8) and, 31, 34-35 tumor necrosis factor and, 18, 20 Histones, interferons and, 204 Histopathology interferon-γ and, - 7 , - , , - , 97-98 tumor necrosis factor and, 162 Homology cytokine receptors and, 106,109,112-113, 115 Index inflammation and, 3—5 interferon-γ and, 74-75, - 9 interferons and, 194 leukemia inhibitory factor and, 69 soluble IFN-γ receptor and, 139 Hormones, interferon-γ and, 95 Human serum albumin, interferon-γ and, 77, 80 Hybridization, soluble IFN-γ receptor and, 145 Hydrogen peroxide, bacterial meningitis and, 189 Hydropathy, soluble IFN-γ receptor and, 139 Hydrophobicity, soluble IFN-γ receptor and, 139 Hyperplasia interferon-γ and, 80, 83, - soluble IFN-γ receptor and, 143 Hypersensitivity, soluble IFN-γ receptor and, 146 Hypertension bacterial meningitis and, 184 pulmonary fibrosis and, 173 Hypertrophy, interferon-γ and, 80, 83, 86, 90, 93,97 Hypoplasia recombinant human GM-CSF and, 209-211, 216 soluble IFN-γ receptor and, 143 Hypotension recombinant human GM-CSF and, 215 tumor necrosis factor and, 12 Hypoxia, recombinant human GM-CSF and, 215 Immune complex glomerulonephritis (ICGN), soluble IFN-γ receptor and, 144-145 Immune-mediated injury in bacterial meningitis, 183-191 Immune response interferon-γ and, 77 pulmonary fibrosis and, 175, 178 tumor necrosis factor and, 23, 161, 163 Immune system interferon-γ and, 73, 97 interferons and, 196 soluble cytokine receptors and, 123-124 223 Immunogenicity interferons and, 203-206 soluble IFN-γ receptor and, 141-142 Immunoglobulin, soluble IFN-γ receptor and, 144 Immunoglobulin A cytokine receptors and, 113 interferons and, 199 Immunoglobulin E cytokine receptors and, 109 soluble IFN-γ receptor and, 138 Immunoglobulin G interferons and, 205 soluble cytokine receptors and, 125 soluble IFN-γ receptor and, 138 tumor necrosis factor and, 161 Immunoglobulin M cytokine receptors and, 110—111 tumor necrosis factor and, 161 Immunoglobulin supergene family, 105—106, 113-115 Immunomodulation interferons and, 193, 195, 197 soluble IFN-γ receptor and, 138 Immunopathology, tumor necrosis factor and, 159-168 Immunosuppression, soluble IFN-γ receptor and, 145 Infection interferons and, 198, 200 recombinant human GM-CSF and, 209, 212-214 Infectious disease inflammation and, interferons and, 197, 205 tumor necrosis factor and, 162, 167 Inflammation bacterial meningitis and, 189-190 cytokine receptors and, 110 cytokines and, 3-4 interferon-γ and, 90 interferons and, 197 interleukin-8 (IL-8) and, 27-28, 30-32, 35, 39-40 leukemia inhibitory factor and, 70 recombinant human GM-CSF and, 215 soluble cytokine receptors and, 123, 134 soluble IFN-γ receptor and, 138 tumor necrosis factor and, 8, 10, 12-14, 17, 23, 160, 166, 168 224 Index Influenza virus, interferons and, 193, 196 Inhibitors bacterial meningitis and, 191 cytokine receptors and, 108 inflammation and, interferon-γ and, 74 interferons and, 193, 196, 203 leukemia inhibitory factor and, 69—72 pulmonary fibrosis and, 175-176,178-179 soluble cytokine receptors and, 124 soluble IFN-γ receptor and, 138, 141-142, 145 tumor necrosis factor and, 21-23, 163, 165 Inositol triphosphate, cytokine receptors and, 110-112 Insulin bacterial meningitis and, 189 receptor, 114 soluble IFN-γ receptor and, 145 Insulin-like growth factor receptor, 114 Interferon, bacterial meningitis and, 189 Interferon family, clinical experiences with, 193-195, 206 efficacy, 198-200 pharmacology, 195-198 toxicity, 200-206 Interferon-α (IFN-a) clinical experiences with, 193-194, 206 efficacy, 198-200 pharmacology, 195-197 toxicity, 200-205 comparative pathology of, 73-75, 97 recombinant human GM-CSF and, 212 Interferon-ß (IFN-/3), comparative pathology of, 73-75, 97 Interferon-y (IFN-γ) comparative pathology of, 73-75, - 9 acute toxicity, 76—77 multidose toxicity, 77-85 reproductive toxicity, 93—96 subchronic toxicity, 83, - inflammation and, - pulmonary fibrosis and, 175-176, 179 receptors, 105-106, 109, 115-116 soluble receptor, 137-141, 144-146 GVHD modulation, 142-144 human IFN-γ, 138-139, 141-142 immunogenicity, 141-142 mouse IFN-γ, 139, 141-144 pharmacokinetics, 141—142 tumor necrosis factor and, 165 Interleukin-1 (IL-1) bacterial meningitis and, 184, 186, 189-190 induction, 28-29, 39 inflammation and, interferon-γ and, 75 pulmonary fibrosis and, 174, 176, 178 receptor, 106, 110, 114-115 soluble, 124-127, 134 tumor necrosis factor and, 9, 16 Interleukin-2 (IL-2) interferon-γ and, 75 interferons and, 194 pulmonary fibrosis and, 175 receptors, 105-106, 109-112, 115-116 soluble IFN-γ receptor and, 137, 145 tumor necrosis factor and, 165-166 Interleukin-3(IL-3) biological activities, 30 receptors, 105-106, 109, 112 tumor necrosis factor and, 165, 167 Interleukin-4(IL-4) receptor, 105, 109-112, 145 soluble, 124-129, 131 Interleukin-5(IL-5) receptor, 105-106, 109, 112 Interleukin-6 (IL-6) bacterial meningitis and, 186, 189 inflammation and, leukemia inhibitory factor and, 70-71 receptor, 105-106, 109-110, 112-113 Interleukin-7(IL-7) receptor, 105, 109-112, 145 Interleukin-8 (IL-8) inflammation and, pathophysiology of, 27-28, 37, - formation, 28-29 leukocytes, 30 local application, 34-37 methods, 30-34 neutrophils, 29-30 systemic application, 35, 37—38 Intestines interferon-γ and, 90 tumor necrosis factor and, 12-15, 17-18, 20, 23 Intracranial pressure (ICP), bacterial meningitis and, 187, 189 IRAP (IL-1 receptor agonist protein), 114-115 Irritation, interferon-γ and, - 7 Index Kaposi's sarcoma, interferons and, 199 Keratitis, interferons and, 196 Kidney leukemia inhibitory factor and, 70 soluble cytokine receptors and, 126-130, 134 soluble IFN-γ receptor and, 146 tumor necrosis factor and, 17 Kinetics cytokine receptors and, 110 soluble cytokine receptors and, 126, 129-130 tumor necrosis factor and, 18 Kupffer cells, tumor necrosis factor and, 168 Lactate dehydrogenase, interferon-γ and, 80, 83, 85, 97 Large granular lymphocytes, tumor necrosis factor and, 165-166 Lesions interferon-γ and, 80, 82-84, 86, 89-90, 97-99 tumor necrosis factor and, 160-164, 167 Leukemia, interferons and, 196-199, 202-203 Leukemia inhibitory factor, pathology induction by, 69—72 Leukocyte inhibition factor receptor, 109, 113 Leukocytes bacterial meningitis and, 184-186, 189 interferon-γ and, 73, 80, 85 interferons and, 197 interleukin-8 (IL-8) and, 27, 30-31 leukemia inhibitory factor and, 71 pulmonary fibrosis and, 173, 176 recombinant human GM-CSF and, 215 tumor necrosis factor and, 161 — 162, 164-165, 167-168 Leukocytosis bacterial meningitis and, 186-187 interferons and, 199 Leukopenia interferon-γ and, 97 interferons and, 201 Leukostasis, interleukin-8 (IL-8) and, 35 Ligands cytokine receptors and, 106-110,113-115 inflammation and, 225 leukemia inhibitory factor and, 71 soluble cytokine receptors and, 124-125, 131 tumor necrosis factor and, 166 Lipids, interleukin-8 (IL-8) and, 28 Lipopolysaccharide (LPS) bacterial meningitis and, 186, 189 cytokine receptors and, 110 inflammation and, interleukin-8 (IL-8) and, - tumor necrosis factor and, 8,10—12,17—18, 20-23, 160, 165, 167 Listeria monocytogenes, bacterial meningitis and, 184 Liver interferon-γ and, 83, 85, 97 interferons and, 201 leukemia inhibitory factor and, 70 soluble cytokine receptors and, 126—131, 134 tumor necrosis factor and, 16, 165, 168 Low-affinity nerve growth factor receptor, 106-108 Lung interferon-γ and, 80, 86, 93 interleukin-8 (IL-8) and, 35, 37, - pulmonary fibrosis and, 174, 178 soluble cytokine receptors and, 127, 129-130 tumor necrosis factor and, 16-17, 20, 23 Lungs, tumor necrosis factor and, 164-165 Lupus nephritis, tumor necrosis factor and, 168 Lymph nodes interferon-γ and, 80, 88 leukemia inhibitory factor and, 70 Lymphocytes, see also B lymphocytes; T lymphocytes interferon γ and, 74-75, 80, 88, 90 interferons and, 194, 197 interleukin-8 (IL-8) and, 28, 30, 37, 39 soluble IFN-γ receptor and, 143, 145 tumor necrosis factor and, 9, 18, 163, 165-166 Lymphocytic choriomeningitis virus (LCMV), bacterial meningitis and, 185 Lymphoid cells interferon-γ and, 80, 88, 98 leukemia inhibitory factor and, 69 soluble IFN-γ receptor and, 142 226 index Lymphoid organs, tumor necrosis factor and, 167-168 Lymphoid tissues, tumor necrosis factor and, 165 Lymphoma interferons and, 196, 199, 203 recombinant human GM-CSF and, 210 Lymphopenia, tumor necrosis factor and, - U , 17-18 Lymphotoxin cytokine receptors and, 107 tumor necrosis factor and, 164 Macrophage-activating factor (MAF), interferon-γ and, 74-75, 80, 97 Macrophage colony-stimulating factor, bacterial meningitis and, 186 Macrophage inflammatory protein-1 (MIP-1) bacterial meningitis and, 186-187 interleukin-8 (IL-8) and, 28 Macrophage inflammatory protein-2 (MIP-2), bacterial meningitis and, 186-187 Macrophages, see also Granulocyte-macrophage colony-stimulating factor (GM-CSF) bacterial meningitis and, 187, 189 cytokine receptors and, 115 inflammation and, - interferon-γ and, 74-75, 86 interleukin-8 (IL-8) and, 28 pulmonary fibrosis and, 176 soluble IFN-γ receptor and, 138 tumor necrosis factor and, 163—168 Major histocompatibility complex (MHC) cytokine receptors and, 115 inflammation and, interferon-γ and, 74 interferons and, 197 pulmonary fibrosis and, 178 soluble IFN-γ receptor and, 143, 145 Malaria, tumor necrosis factor and, 163-168 Malignancy inflammation and, interferons and, 199-200, 205 Mast cells, interleukin-8 (IL-8) and, 39 Mean toxic dose, interferons and, 200 Megakaryocytes leukemia inhibitory factor and, 70-72 recombinant human GM-CSF and, 210, 213 Megakaryopoiesis, leukemia inhibitory factor and, 71 Melanoma interferons and, 200 interleukin-8 (IL-8) and, 28 Melanoma growth-stimulatory activity (MGSA), interleukin-8 (IL-8) and, 28 Meningitis, bacterial, 183-191 Microscopy interferon-γ and, 83 tumor necrosis factor and, 12-13, 19 Mineralization, interferon-γ and, 90 Mitogens interferon-γ and, 73 interferons and, 194 leukemia inhibitory factor and, 69 Mixed leukocyte reaction, tumor necrosis factor and, 161 Monoclonal antibodies soluble IFN-γ receptor and, 139, 145 tumor necrosis factor and, 164-165, 167-168 Monocyte chemotactic peptide-1 (MCP-1 ), interleukin-8 and, 28 Monocytes bacterial meningitis and, 186 cytokine receptors and, 110 interferons and, 196 interleukin-8 (IL-8) and, 28, 30, 37, 39 soluble IFN-γ receptor and, 138 tumor necrosis factor and, Mortality bacterial meningitis and, 183 interferons and, 200 recombinant human GM-CSF and, 210 soluble IFN-γ receptor and, 143-144 tumor necrosis factor and, 165 mRNA cytokine receptors and, 111, 113 pulmonary fibrosis and, 176, 178 tumor necrosis factor and, 18, 163—168 Multiple sclerosis, tumor necrosis factor and, 167 Mutations, cytokine receptors and, 113 Mycobacteria bacterial meningitis and, 189 tumor necrosis factor and, 163 Mycobacterium bovis, tumor necrosis factor and, 162-164, 167 Myelodysplastic syndrome (MDS), recombinant human GM-CSF and, 209, 211, 216 Myeloid cells cytokine receptors and, 106-107 Index interferon-y and, 77, 80, 83, 97 recombinant human GM-CSF and, 212 Myeloid leukemia, leukemia inhibitory factor and, 69 Myeloma cytokine receptors and, 112 interferons and, 199 Myelosclerosis, leukemia inhibitory factor and, 70 Myelosuppression, recombinant human GM-CSF and, 210 Myelotoxicity, recombinant human GM-CSF and, 210-211, 216 Natural killer cells interferon-γ and, 74 interferons and, 197 soluble IFN-γ receptor and, 137 tumor necrosis factor and, 10 Nausea, interferons and, 200-201 Necrosis bacterial meningitis and, 184 leukemia inhibitory factor and, 70 tumor necrosis factor and, 13, 16, 19, 160-163 Neisseria meningitidis, bacterial meningitis and, 184 Nerve growth factor receptor, 106 Neurological sequelae, bacterial meningitis and, 184, 189, 191 Neurological syndromes, tumor necrosis factor and, 162-163 Neuronal cells bacterial meningitis and, 189-191 leukemia inhibitory factor and, 70 Neurotoxicity bacterial meningitis and, 189 interferons and, 200—201 Neurotrophins, cytokine receptors and, 108 Neutropenia interferon-γ and, 80, 83 recombinant human GM-CSF and, 210-211, 214-215 Neutrophil-activating peptide-1 (NAP-1), interleukin-8 and, 28 Neutrophil-activating peptide-2 (NAP-2), interleukin-8 and, 28-30, 34-35, - Neutrophilia, tumor necrosis factor and, 9,11, 13, 17-18 Neutrophils inflammation and, 227 interferon-γ and, 98 interferons and, 198 interleukin-8 (IL-8) and, 28-32, 35, 37, 39-40 leukemia inhibitory factor and, 71 tumor necrosis factor and, 9, 17-18, 20, 23 Nucleotides, interferon-γ and, 75 Oncogenes, cytokine receptors and, 113 Oncology, interferons and, 198 Open reading frames, cytokine receptors and, 106 Organ injury, tumor necrosis factor and, 12-16, 23 Osteoblasts, leukemia inhibitory factor and, 70 Ovary, interferon-γ and, 94 Oxygen, bacterial meningitis and, 184, 187, 189-190 Pancreas, leukemia inhibitory factor and, 70 Pancytopenia, recombinant human GM-CSF and, 212-213 Parasitemia, tumor necrosis factor and, 162-163 Parasites, interferons and, 197 Parenchyma, interleukin-8 (IL-8) and, 31 Pathogenesis bacterial meningitis and, 184, 187, 189 pulmonary fibrosis and, 179 soluble cytokine receptors and, 131, 134 tumor necrosis factor and, Pathology of IFN-γ, 73-75, - 9 acute toxicity, 76—77 multidose toxicity, 77—85 reproductive toxicity, 93—96 subchronic toxicity, 83, - induction by leukemia inhibitory factor, 69-72 leukemia inhibitory factor and, 69—72 of recombinant human transforming growth factor/31, 43-46, 60, - 6 dermal toxicity, - intravenous toxicity, 49—64 soluble IFN-γ receptor and, 146 Pathophysiology of interleukin-8 (IL-8), see Interleukin-8 (IL-8), pathophysiology of 228 Index of tumor necrosis factor, see Tumor necrosis factor, pathophysiology of Pericarditis, recombinant human GM-CSF and, 215 Peripheral blood interferon-γ and, 97 recombinant human GM-CSF and, 212 tumor necrosis factor and, - , - , 23 Peripheral blood lymphocytes, interferons and, 197 Phagocytes, interferons and, 200 Pharmacodynamics, interferons and, 201, 203 Pharmacokinetics soluble cytokine receptors and, 124-128, 130, 134-135 soluble IFN-γ receptor and, 141-142, 146 Pharmacology interferon-γ and, 75, 96, - 9 interferons and, 195 leukemia inhibitory factor and, 71 Phenotype pulmonary fibrosis and, 178 soluble IFN-γ receptor and, 145 Phosphate-buffered saline (PBS) interleukin-8 (IL-8) and, 31 soluble cytokine receptors and, 125 Phosphorylation, cytokine receptors and, 108, 110, 112-113, 115-116 Plasma interferon-γ and, 77 interleukin-8 (IL-8) and, 27 soluble cytokine receptors and, 125 tumor necrosis factor and, 20-21, 163 Plasmacytomas, cytokine receptors and, 112 Plasmodium falciparum, tumor necrosis factor and, 163 Platelet-activating factor (PAF) interleukin-8 and, 27, 30, 32, 39 tumor necrosis factor and, 20 Platelet-derived growth factor (PDGF) interleukin-8 and, 39 pulmonary fibrosis and, 175-176 receptor, 114 Platelet factor-4, interleukin-8 (IL-8) and, 28 Platelets interleukin-8 (IL-8) and, 28-29 leukemia inhibitory factor and, 70-71 tumor necrosis factor and, 17 Pleocytosis, bacterial meningitis and, 187 Pneumococcal meningitis, bacterial meningitis and, 187—188 Pneumoconiosis, pulmonary fibrosis and, 178 Pneumonia, recombinant human GM-CSF and, 214 Polymyxin B, tumor necrosis factor and, 10 Progenitors leukemia inhibitory factor and, - recombinant human GM-CSF and, 209 Proteases, bacterial meningitis and, 189 Protein bacterial meningitis and, 184—185 cytokine receptors and, 105-116 inflammation and, 3, interferon-γ and, 74-75, 99 interferons and, 194, 204 leukemia inhibitory factor and, 69—70 pulmonary fibrosis and, 173, 176 soluble cytokine receptors and, 124-125, 129-131, 134 soluble IFN-γ receptor and, 139, 141-142, 146 tumor necrosis factor and, 20 Protein kinase A, cytokine receptors and, 115 Protein kinase C, cytokine receptors and, 108, 110, 116 Proteolysis cytokine receptors and, 107, 110 interleukin-8 (IL-8) and, 39 soluble cytokine receptors and, 124 soluble IFN-γ receptor and, 139 Pulmonary damage, tumor necrosis factor and, 20 Pulmonary fibrosis cytokines and, 173-179 tumor necrosis factor and, 163—164 Pyrogen-free saline (PFS), interleukin-8 ( IL-8) and, 30, 32 Recombinant DNA, interferon-γ and, 75 Recombinant human GM-CSF, clinical experience with, 209-216 Recombinant human interferon-γ, 96—99 toxicity acute, 76-77 multidose, 77-85 reproduction, 93—96 Recombinant human transforming growth factor/81, pathology of, 43-46, 60, 63-66 dermal toxicity, 46—49 intravenous toxicity, 49—64 Index Recombinant murine interferon-γ, 98—99 toxicity reproduction, 96 subchronic, 83, - Red blood cells, tumor necrosis factor and, 14, 17 Regional cerebral flow, bacterial meningitis and, 187 Reproduction, interferon-γ and, 93-96, 99 Respiratory distress syndrome, interleukin-8 (IL-8) and, 40 Reticuloendothelial cells, interferon-γ and, 80, 83, 86 Reticuloendothelial system interferon-γ and, 80, 86, - tumor necrosis factor and, 12 Rheumatoid arthritis, interleukin-8 (IL-8) and, 39 RNA pulmonary fibrosis and, 176 tumor necrosis factor and, 163 Sarcoidosis, pulmonary fibrosis and, 173 Second messengers, cytokine receptors and, 113, 116 Sequences cytokine receptors and, 105-106, 112 inflammation and, interferon-γ and, 74-75 Serum amyloid protein (SAP), soluble IFN-γ receptor and, 143 Sex, interferons and, 205 Signal transduction, cytokine receptors and, 110, 115-116 Small bowel damage, tumor necrosis factor and, 18-20 Small cell lung cancer, recombinant human GM-CSF and, 210 Soluble cytokine receptors, see Cytokine receptors, soluble Soluble IFN-γ receptor, 137-146 Spleen cytokine receptors and, 109 interferon-γ and, 83, 86, 88, 97 interferons and, 197 leukemia inhibitory factor and, 70 soluble cytokine receptors and, 127, 130 soluble IFN-γ receptor and, 143 229 Splenomegaly cytokine receptors and, 114 interferons and, 199 Streptococcus pneumoniae, bacterial meningitis and, 184, 187 Superoxide, bacterial meningitis and, 189 Systemic lupus erythematousus (SLE), soluble IFN-γ receptor and, 144-145 T cells cytokine receptors and, 106, 108—112, 115 interferons and, 194 interleukin-8 (IL-8) and, 30 soluble IFN-γ receptor and, 144 tumor necrosis factor and, 10, 161, 164-167 T lymphocytes inflammation and, - interferon-γ and, 73, 75, 97 interferons and, 194 pulmonary fibrosis and, 178 soluble IFN-γ receptor and, 137 tumor necrosis factor and, 160, 162, 164, 166-168 Testes, interferon-γ and, 80 Thrombocytes, interferons and, 198 Thrombocytopenia interferon-γ and, 80, 83, 97 interferons and, 201 leukemia inhibitory factor and, 71 recombinant human GM-CSF and, 213-215 Thrombocytosis, interferons and, 199 Thymocytes cytokine receptors and, 111 — 112, 114 tumor necrosis factor and, 161 Thymus interferon-γ and, 80, 88 leukemia inhibitory factor and, 70 tumor necrosis factor and, 160 Tissue damage, tumor necrosis factor and, 167 Tissue distribution, soluble cytokine receptors and, 127-130 Toxicity bacterial meningitis and, 190 cytokine receptors and, 108 interferon-γ and, 75, 96—99 acute toxicity, - 7 multidose toxicity, 7 - reproductive toxicity, 93—96 subchronic toxicity, 83, 85—95 230 Index interferons and, 200-206 leukemia inhibitory factor and, 70-72 recombinant human GM-CSF and, 210, 212 tumor necrosis factor and, 10, 13, 15-17, 21-23, 161 Transcription, tumor necrosis factor and, 165 Transcription factors, cytokine receptors and, 115 Transfection, cytokine receptors and, 107 Transforming growth factor-ß bacterial meningitis and, 187-188, 191 cytokine receptors and, 109 pulmonary fibrosis and, 176 Transforming growth factor-ß 1, recombinant human, 43-46, 60, - 6 dermal toxicity, 46—49 intravenous toxicity, 49—64 Transplantation, bone marrow, recombinant human GM-CSF and, 211-212, 215-216 Tropomyosin receptor kinase (trk) receptor, 106, 108 Tumor necrosis factor immunopathology, 159-160 immune response, 161 induction, 164-167 overproduction, 162-164 properties, 160—161 T lymphocytes, 167-168 tissue damage, 167 inflammation and, - interferons and, 197 interleukin-8 (IL-8) and, 28-29, 39 leukemia inhibitory factor and, 71 pathophysiology of, - , 23 endogenous production, 17-18 organ injury, 12—16 peripheral blood alterations, 9—11, 18-19 pulmonary changes, 20 recombinant human TNF, 9-16, 18, 20 small bowel damage, 18-20 toxicity, 16-17 vascular permeability, 20—21 pulmonary fibrosis and, 174-176, 179 receptor, 105-109, 115 soluble receptor, 125, 129-131, 134 Tumor necrosis factor« bacterial meningitis and, 184-187, 189-191 inflammation and, Tumors cytokine receptors and, 106 interferons and, 195-200, 203 leukemia inhibitory factor and, 69 recombinant human GM-CSF and, 211 soluble IFN-γ receptor and, 145 Tyrosine, cytokine receptors and, 112-113 Tyrosine kinase, cytokine receptors and, 108, 110-111 Uterus interferon-γ and, 88, 94 tumor necrosis factor and, 16 Vacuolization, tumor necrosis factor and, 13, 17 Vascular leak, tumor necrosis factor and, 13-16, 162 Vascular permeability, tumor necrosis factor and, 20-21 Vascularity, interleukin-8 (IL-8) and, 39 Viral infection bacterial meningitis and, 184 interferon-γ and, 73 Viruses, interferons and, 193, 196-198, 200, 205 Weight, see Body weight White blood cells, recombinant human GM-CSF and, 214 Wound healing, pulmonary fibrosis and, 175 Zidovudine, recombinant human GM-CSF and, 214 Contents of Recent Volumes VOLUME 31 Transition Metal Toxicity Iron Toxicosis Philip Aisen, Gerald Cohen, and Jae O Kang Host Defences against Copper Toxicity Dennis R Winge and Rajesh K Mehra Chromium Toxicity and Carcinogenesis Joy A Alcedo and Karen E Wetterhahn The Chemistry of Dioxygen Species (0 , - - , H00*, and HOOH) and Their Activation by Transition Metals Donald T Sawyer Transition Metal Ions and Oxygen Radicals Sara Goldstein and Gidon Czapski The Cytopathology of Metal Overload Elaine R Alt, Irmin Sternlieb, and Sidney Goldfischer VOLUME 32 Molecular Cell Pathology Applications of in Situ Hybridization Gerald Niedobitek and Herman Herbst Interactions between Endothelial Cells and the Cells of the Immune System Druie E Cavender Molecular Biology of Cytokine Effects on Vascular Endothelial Cells Hiroshi Suzuki and Heihachiro Kashiwagi Interphase Nucleolar Organizer Regions in Cancer Cells Massimo Derenzini and Dominique Ploton Antineutrophil Cytoplasmic Autoantibodies: Disease Associations, Molecular Biology, and Pathophysiology J Charles Jennette, Linda A Charles, and Ronald J Falk Apoptosis: Mechanisms and Roles in Pathology Mark J Arends and Andrew H Wyllie 231 232 Contents of Recent Volumes Molecular Events in Measles Virus Infection of the Central Nervous System Peggy T Swoveland VOLUME 33 Progress in Hodgkin's Disease Differential Diagnosis between Hodgkin's Disease and Non-Hodgkin's Lymphoma Nancy L Harris Diagnosis and Grading of Nodular Sclerosing Hodgkin's Disease: A Study of 2190 Patients K A MacLennan, M H Bennett, B Vaughan Hudson, and G Vaughan Hudson Lymphocyte-Predominance Hodgkin's Disease Sibrand Poppema Immunophenotype of Reed-Sternberg Cells Judith Hugh and Sibrand Poppema The Nature and Function of the Hodgkin's Cell Lectin and Its Role in Lymphocyte Agglutination Elisabeth Paietta Role of T Cells in the Pathogenesis of Hodgkin's Disease E Maggi, P Parronchi, D Macchia, M.-P Piccinni, C Simonelli, and S Romagnani Gene Analysis and Epstein-Barr Viral Genome Studies of Hodgkin's Disease Lawrence M Weiss Hodgkin's Disease: Analysis of Cell Line Data Christof v Kalle and Volker Diehl ISBN 0-15-3t,iH3S-A 90065 ll 780123"649355 .. .International Review of EXPERIMENTAL φ PATHOLOGY Volume 34 CYTOKINE- INDUCED PATHOLOGY PART B: Inflammatory Cytokines, Receptors, and Disease Edited by G W Richter Department of Pathology. .. fication of a number of endogenous and exogenous chemoattractants, such International Review of Experimental Pathology, Volume 3 4B Copyright © 1993 by Academic Press, Inc All rights of reproduction... cross-reactivity of the biological effects of human and mouse IFN-γ In contrast, the homology International Review of Experimental Pathology, Volume J 4B Copyright © 1993 by Academic Press, Inc All rights of