Progress in Inflammation Research Series Editor Prof. Dr. Michael J. Parnham PLiVA Research Institute Prilaz baruna Filipovica 25 10000 Zagreb Croatia Published titles: T Cells in Arthritis, P. Miossec, W. van den Berg, G. Firestein (Editors), 1998 Chemokines and Skin, E. Kownatzki, J. Norgauer (Editors), 1998 Medicinal Fatty Acids, J. Kremer (Editor), 1998 Inducible Enzymes in the Inflammatory Response, D.A. Willoughby, A Tomlinson (Editors), 1999 Cytokines in Severe Sepsis and Septic Shock, H. Redl, G. Schlag (Editors), 1999 Fatty Acids and Inflammatory Skin Diseases, J.-M. Schroder (Editor), 1999 Immunomodulatory Agents from Plants, H. Wagner (Editor), 1999 Cytokines and Pain, L. Watkins, S. Maier (Editors), 1999 In Vivo Models of Inflammation, D. Morgan, L. Marshall (Editors), 1999 Pain and Neurogenic Inflammation, S.D. Brain, P. Moore (Editors), 1999 Anti-Inflammatory Drugs in Asthma, AP. Sampson, M.K. Church (Editors), 1999 Novel Inhibitors of Leukotrienes, G. Folco, B. Samuelsson, R.C Murphy (Editors), 1999 Vascular Adhesion Molecules and Inflammation, J.D. Pearson (Editor), 1999 Metalloproteinases as Targets for Anti-Inflammatory Drugs, K.M.K. Bottomley, D. Brad- shaw, J.S. Nixon (Editors), 1999 Free Radicals and Inflammation, P.G. Winyard, D.R. Blake, CH. Evans (Editors), 1999 Gene Therapy in Inflammatory Diseases, CH. Evans, P. Robbins (Editors), 2000 New Cytokines as Potential Drugs, S. K. Narula, R. Coffmann (Editors), 2000 High Throughput Screening for Novel Anti-inflammatories, M. Kahn (Editor), 2000 Immunology and Drug Therapy of Atopic Skin Diseases, CAF. Bruijnzeel-Komen, E.F. Knol (Editors), 2000 Inflammatory Processes. Molecular Mechanisms and Therapeutic Opportunities, L.G. Letts, DW. Morgan (Editors), 2000 Forthcoming titles: Cellular Mechanisms in Airway Inflammation, C Page, K. Banner, D. Spina (Editors), 2000 Inflammatory and Infectious Basis of Atherosclerosis, J.L. Mehta (Editor), 2001 Novel Cytokine Inhibitors Gerry A. Higgs Brian Henderson Editors Springer Basel AG Editors Dr. Gerry A. Higgs Prof. Brian Henderson Celltech Chiroscience Cellular Microbiology Research Group 216 Bath Road Eastman Dentallnstitute University College London Slough Berkshire SL 1 4EN 256 Gray's Inn Road London WC1X 8LO UK UK Deutsche Bibliothek Cataloging-in-Publication Data Novel cytokine inhibitors / ed. by Gerry A. Higgs ; Brian Henderson - Basel ; Boston; Berlin: Birkhăuser, 2000 (Progress in inflammation research) The publisher and editor can give no guarantee for the information on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use. ISBN 978-3-0348-9572-9 ISBN 978-3-0348-8450-1 (eBook) DOI 10.1007/978-3-0348-8450-1 This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on micro- films or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained. © 2000 Springer Basel AG Origina1ly published by Birkhăuser Verlag, Base!, Switzerland in 2000 Printed on acid-free paper produced from chlorine-free pulp. TCF 00 Cover design: Markus Etterich, Basel Cover iIIustration: The cover picture shows the ribbon strueture of a monoclonal antibody binding to two molecules of tumour necrosis factor (TNF). The antibody, CDP571 (HUMICADETM), is effective in reducing the signs and symptoms of rheumatoid arthritis and inflammatory bowel disease (see chapters 6 and 7) and has been genetically engineered to prevent immunogenicity in patients. This picture is reproduced by kind permission of Dee Athwal and Celltech, UK. 987654321 Contents List of contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. vii Brian Henderson and Gerry A. Higgs Targets for modulating cytokine responses in inflammatory and infectious diseases . 1 Mary Lee MacKichan and Anthony L. DeFranco Cell signaling and cytokine induction by lipopolysaccharide. . . . . . . . . . . . . . . . . 9 Rodger A. Allen and Stephen E. Rapecki Regulation of cytokine production by inhibitors of cell signalling 43 Stanley T. Crooke Oligonucleotide-based drugs in the control of cytokine synthesis. . . . . . . . . . . . . .. 83 Peter I. Croucher, Ingunn Holen and Philip G. Hargreaves Inhibiting cytokine-processing enzymes . .. .... 103 Amanda Suitters and Roly Foulkes Cytokine-neutralizing therapeutic antibodies 123 Ravinder N. Maini The debut of anti-TNF therapy of rheumatoid arthritis in the clinic 145 Anthony Meager Blockade of cytokine activity by soluble cytokine receptors 157 Michael F. Smith Jr. Interleukin-1 receptor antagonist 177 Raymond J. Owens and Simon Lumb Therapeutic regulation of cytokine signalling by inhibitors of p38 mitogen-activated protein kinase . 201 Christian Bogdan, Yoram Vodovotz and John Letterio TGFp and IL-10: inhibitory cytokines regulating immunity and the response to infection 217 Brian Henderson Therapeutic control of cytokines: lessons from microorganisms ................. 243 Index.......................... .. ..263 List of contributors Rodger A. Allen, Celltech Chiroscience, 216 Bath Road, Slough, Berkshire SLl 4EN, UK; e-mail: List of contributors John J. Letterio, Lab of Cell Regulation and Carcinogenesis, Building 41, Room C629, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA; e-mail: Targets for modulating cytokine responses in inflammatory and infectious diseases 1 2 Brian Henderson and Gerry A. Higgs 1Cellular Microbiology Research Group, Eastman Dental Institute, University College London, 256 Gray's Inn Road, London WC1X 8LD, UK; 2Research Division, Celltech Chiroscience, 216 Bath Road, Slough, Berkshire, SL1 4EN, UK Introduction Cytokines were discovered in the 1950s by workers studying fever and by those interested in cellular anti-viral defences and in the 1960s by immunologists inter- ested in monocyte-lymphocyte interactions. Further discoveries and rediscoveries were made in the 1970s and 1980s and the term cytokine (first introduced by Cohen in the 1970s) now describes a very large number of proteins and glycoproteins. These proteins are part of the cell-to-cell signalling requirements of the multicellu- lar organism in order to maintain homeostasis. The importance of cytokines is increasingly being delineated by the development of animals in which one or more selected cytokine genes have been disrupted (knocked out) by homologous recom- bination. Many of these knockout animals show increased sensitivity to infectious microorganisms. Others, such as those where interleukin-2 (IL-2) or interleukin-10 (IL-10) genes have been knocked out, reveal severe local inflammatory responses which appear to be due to aberrant responses to the animal's commensal micro- flora. The major impetus to the study of cytokines and the reason that the world's pharmaceutical industry is ploughing billions of dollars into research of cytokines is that these cell-regulatory proteins have been identified as being key mediators of the pathology of human and animal diseases. Much of our understanding of cytokines has come from the study of prototypic diseases such as rheumatoid arthritis, septic shock and atherosclerosis. In these diseases, pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor a (TNFa), interleukin-6 (IL-6), chemokines and growth factors such as transforming growth factor ~ (TGF~), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), are implicated as being important in disease pathology. It is these, and many other, cytokines that represent the therapeutic targets for the treatment of human and ani- mal diseases. In this book the various means that are being utilised, or could be utilised, to treat infectious and idiopathic diseases through the medium of cytokine Novel Cytokine Inhibitors. edited by Gerry A. Higgs and Brian Henderson © 2000 Birkhauser Verlag Basel/Switzerland Brian Henderson and Gerry A. Higgs manipulation will be discussed. This brief chapter is designed to give an overview of the biology of cytokines and the potential means by which their synthesis or activi- ty can be therapeutically manipulated. The reader is referred to earlier reviews on this topic [1-5]. Cytokines: a brief overview In a world awash with communication (radio, television, telephone, E-mail), it should not be difficult to convince the reader of the importance of correct commu- nication, and the problems arising when our communication systems go wrong. It is now recognised that all cells, including bacteria, have cell-to-cell communication systems. In mammals three major cell-to-cell communication systems are recog- nised: neuronal, endocrine and cytokine. It is becoming recognised that these three systems mesh to produce a homeostatic control system. However, the details of the ways these systems mesh still await elucidation. It is probably still too early to make any sweeping statements about the overall physiological role of cytokines. In spite of this, it is probably safe to say that, in contrast to neuronal and endocrine sig- nalling, cytokines are generally important in local cell-to-cell signalling. Of course, this statement, like many general statements about cytokines, will have numerous counter-examples. In general terms, cytokines are proteins or glycoproteins produced by one cell and able to activate (or inhibit) that cell, another similar cell or distinct cells by virtue of binding to specific high-affinity receptors on the target cell. Thus cytokines can indulge in three types of interaction with cells (Fig. 1). If the producing cell responds to the cytokine, this is known as autocrine signalling. If the cells respond- ing are in the neighbourhood of the producing cell, then we have paracrine sig- nalling (para: nearby). Cytokines such as IL-6 may also have a hormone-like role, passing into the blood stream and acting on remote tissues. Interaction of a cytokine with its specific receptor can induce a variety of cellular changes that are shown dia- grammatically in Figure 2. This includes activation of the cell with the switching-on of particular patterns of gene transcription. This can result in a variety of cellular changes, including the target cell entering the cell cycle and proliferating, or prolif- erating and differentiating. Alternatively, cells responding to cytokines, such as members of the TNF family, may undergo apoptosis. The most recently discovered group of cytokines are the chemokines which are important in leukocyte trafficking. Cytokine nomenclature The first requirement to understand the "zoology" of cytokines is to learn their names and the "families" to which they belong. This brings the first problem in 2