Bayer-Symposium VI Experimental Models of Chronic Inflammatory Diseases Edited by L. E. Glynn· H. D. Schlumberger With 142 Figures Springer-Verlag Berlin Heidelberg New York 1977 Dr. LEONARD ELEAZAR GLYNN The Mathilda and Terence Kennedy Institute of Rheumatology Bute Gardens, Hammersmith, London W6 7DW, Great Britain Professor Dr. HORST DIETER SCHLUMBERGER Bayer Pharma-Forschungszentrum, Institut fUr Immunologie und Onkologie Aprather Weg, 5600 Wuppertal 1, Fed. Rep. of Germany Bayer-Symposium VI held at Grosse Ledder near Cologne, Germany, May 20-22, 1976 ISBN-13: 978-3-642-66575-2 e-ISBN-13: 978-3-642-66573-8 DOl: 10.1007/978-3-642-66573-8 Library of Congress Cataloging In PublIcatIOn Data. Bayer-SymposIUm, 6th, Grosse Ledder, 1976. Experimental models of chromc inflammatory diseases.!. InflammatIOn-Congresses. 2. InflammatIOn-EtIOlogy-Congresses. 3 Dlseases-Ammals models-Congresses. 4. Rheumatism EtIOlogy-Congresses. I. Glynn, Leonard Eleazar. II. Schlumberger, Horst Dieter, 1933- [DNLM: 1. Diseases models, Ammal-Congresses. 2. Lupus erythematosus, Systemic Congresses. 3. Rheumatism-Congresses. 4. ArthrItis-Congresses. 5. Immune complex dIsease-Congresses. W3 BA266 1976e/WE344 B357 1976e] RBI31.B39 1976 616.047 76-30736. This work is subject to COPYrIght. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translatIOn, reprIntIng, re-use of IllustratIOns, broadcastIng, reproductIon by photocopying machine or similar means, and storage in data banks. Under § 54 of the German CopYrIght Law, where copies are made for other than prIvate use, a fee IS payable to the publisher, the amount of the fee to be determIned by agreement With the publisher © by SprInger-Verlag Berlin Heidelberg 1977. Softcover reprint of the hardcover 1 st edition 1977 The use of registered names, trademarks, etc. In thIS publicatIOn does not Imply, even In the absence of a speCIfic statement, that such names are exempt from the relevant protective laws and regulatIOns and therefore free for general use. Preface With the introduction of antibiotics acute inflammatory disease has ceased to be the dominant problem in general medical practice and its place is now increasingly occupied by chronic inflamma tory disease of which the rheumatic diseases constitute the most important group. lwo aspects of these diseases need to be consid ered, their aetiology and their pathogenesis. In some respects the latter is more important since even when the aetiology is known, as for example the haemolytic streptococcus in rheumatic fever, the mechanism by which the infecting agent accomplishes the development of the lesions that characterise the disease are still largely unknown. Still more so is this the case in rheuma toid arthritis and other chronic inflammations where the aetio logical agents are unknown. In an attempt to clarify the pathogenic mechanisms involved, sev eral attempts have been made to induce comparable lesions in ex perimental animals, partly to test underlying hypotheses, and partly to provide test situations for the trial of new therapeu tic agents. In view of the deficiencies in the current drug treat ment of chronic inflammatory disease there are many who feel that this is largely due to the inadequacy of the models avail able for test purposes. In other words, are any of the available models sufficiently close to their natural counterparts in man to justify their use either as indicators of pathogenic mechanisms or as subjects for therapeutic trial? With these questions in the foreground it was decided to devote the Sixth Bayer-Symposium to a discussion of experimental models of chronic inflammatory disease and this volume contains the original contributions in full, together with a considerably condensed version of the final session which was devoted entirely to a free discussion of the major problems that emerged from the more formal presentation. It became evident during the course of the symposium that four main phenomena are at present under consideration as underlying the persistence of a chronic inflammatory state: 1. persistent viral infection, 2. retention of enzyme-resistant bacterial resi dues, 3. inappropriate activation of lymphocytes, 4. autoimmunity. The present volume provides a discussion in depth of these four major possibilities. London - Wuppertal L.E. GLYNN - H.D. SCHLUMBERGER Contents Welcome H.D. SCHLUMBERGER Experimental Models of Rheumatoid Lesions Chairman: D. C • DUMONDE •.•.•.•...••.....•...........•.•...• 3 Experimental Models of Rheumatoid Inflammation D.C. DUMONDE, ELIZABETH H. JONES, R.H. KELLY, and CAROLYN M. OATES. With 4 Figures ..•....••...•....•.•....•. 4 Persistence of Antigen in Experimental Allergic Mono arthritis H.E. JASIN and T.D. COOKE .•.....•••....•...•......•....••. 28 Experimental Suhcutaneous Granulomata Simulating R.A. Nodules L.E. GLYNN ....................................•........... 33 Studies on the Mitotic Responsiveness of "T" Cells After Stimulation with Contact Sensitizing Agents. A.J.S. DAVIES, V.J. WALLIS, E. LEUCHARS, I. GERY, and T. PALMER. With 2 Figures .•.•...•...•.•...•...•.•.....•..• 35 Rheumatoid-Type Lymph Node Changes in Animals Exhibiting Immunoregulatory Defects R.H. KELLY. With 6 Figures .•....•....•.•.•.•......•.••.... 41 Experimental Models and Systemic Lupus Chairman: N. TALAL •••..........•.•.•....•....••...•..•..•. 51 Autoimmunity: A Problem of Disordered Immunologic Regulation N. TALAL, J.R. ROUBINIAN, R. PAPOIAN, and R.J. PILLARISETTY 52 Chronic Infections of C-Type RNA Viruses NATALIE M. TEICH and R.A. WEISS •............•......•..•..• 59 Evidence for a Virus in Canine Systemic Lupus Erythematosus R.M. LEWIS .•...•....•.•...•...•..................••.•..... 71 VIII Viral Replication in Lymphocytes and the Pathogenesis of Connective Tissue Diseases A.M. DENMAN, D.J. APPLEFORD, R.C. IMRIE, M.J. KINSLEY, B.K. PELTON, and T. SCHNITZER. With 8 Figures ••••..••••••• 77 Recent Approaches to Experimental Immune Complex Disease and Allergic Vasculitis Chairman: P. M. HENSON •••••••.•...••••.•.•.•.•..•..•..••.•• 93 Immune Complex Diseases: Cellular Mediators and the Patho genesis of Inflammatory Tissue Injury Produced by Immune Complexes P.M. HENSON. With 1 Figure ••••....•.••...•.••.•..•..•..... 94 Antibody Affinity, Macrophage Function and Immunoregulation in Murine Immune Complex Disease M.W. STEWARD. With 4 Figures .................•.......••... 107 Features of Human Spontaneous Vasculitis Reproduced Experimentally in Animals. Effects of Antiglobulins, C-Reactive Protein and Fibrin W.E. PARISH ...•...•........•.....•....................•... 117 Mechanisms Involved in Clinical Allergic Vasculitis J. J. CREAM •••••••••••••••••••••••••••••••••••••••••••••••• 1 S2 Significance of Anti-IgG Antibodies in Experimental Arthritis K. FEHR, M. VELVART, and A. BUNI. With 5 Figures .....•.... 164 Immune Complex Arthritis - In Man and Experimental Animals G. LOEWI. With 2 Figures ............................•...•. 182 Arthritis During the Course of Experimental or Natural Infection Chairman: B. P. MARMION ••.•.•....•........••.••.•.....•.... 187 Rheumatoid Arthritis and the Virus Hypothesis B.P. MARMION and J.M.K. MACKAY. With 3 Figures •.•.••...••• 188 Teno-Synovitis (Viral Arthritis) of Chickens G• A . CULLEN ..•.........•...•......•.•...•....•.•.••••.•..• 2 1 2 Hemostasis, Fibrin Incorporation and Local Mesenchymal Reaction in Erysipelothrix Infection as a Model for Rheumatism Research L.Cl. SCHULZ, H. EHARD, B. HERTRAMPF, W. DROMMER, D. SEIDLER, and K.H. BUHM. With 18 Figures ••.....•..•...•• 215 Erysipelothrix Arthritis in Rabbits L. E. GLYNN .................•..•....•.....•....••.•.....•.. 238 Mycoplasma Infection and Arthritis of Chickens G. A . CULLEN ........•...•..•.•.........•.....••...•........ 2 40 IX Experimental Models of streptococcal Arthritis: Pathoge netic Role of Streptococcal Products and Prostaglandins and Their Modification by Anti-Inflammatory Agents I. GINSBURG, U. ZOR, and Y. FLOMAN. With 20 Figures .•...•• 256 Control Mechanisms in Inflammatory Responses Chairman: R. VAN FURTH •.•......•.•...••.....•••..••....•.• 301 The Regulation of the Participation of Mononuclear Phago cytes in Inflammatory Responses R. VAN FURTH, D. VAN WAARDE, J. THOMPSON, and A.E. GASSMANN With 10 Figures .••...•....•........•.....•.•.•...•.••.••.. 302 The Kinetics of Chronic Inflammatory Cellular Infiltrates W.G. SPECTOR .••....•..•.••.•....•.•••.•.•...•..•..•..•..•. 327 Pathology of Lymphoid Tissue in Rheumatoid Arthritis and Allied Diseases B. SCHNITZER. With 16 Figures •....•...•.....•...•...•..•.. 331 Lymphocyte Infiltration and Proliferation of Stroma Cells of Synovial Tissue in Rheumatoid Arthritis H. G. FASSBENDER. With 6 Figures ....•.•..•..•......•..•..•. 349 Aspects of Synovial Biodegradation D.P. PAGE-THOMAS. With 15 Figures .•.•.....•.•....•.•...•.. 353 An Effect of Joint Fluid on Blood Monocytes G. LOEWI and J. REYNOLDS. With 1 Figure .•.....•.•••....•.• 366 Should We Stimulate or Suppress the Inflammatory Response? Chairman: D.A. WILLOUGHBY ..•...•••....•..••••.•.••.••.•••. 369 Should We Suppress or Stimulate the Immune Response in Inflammation? D.A. WILLOUGHBY, C.J. DUNN, P.A. DIEPPE, and E.C. HUSKISSON Wi th 3 Figures ......•.•........•.....•..•..........•.••..• 370 The Action of Anti-Inflammatory Drugs on the Lymphocyte Macrophage Axis J. MORLEY, M.A. BRAY, and D. GORDON. With 3 Figures ..•.... 376 Problems in Analysing the Actions of Immunosuppressive Agents in Immuno-Inflammatory Disease M.C. BERENBAUM. With 4 Figures •....••.•.•.••.•...•..•...•. 391 Influence of Anti-Inflammatory Drugs on Connective Tissue Metabolism H. GREILING, A.M. GRESSNER, and H.W. STUHLSATZ With 11 Figures •...•••.••.......•.•...•..•.......•..•....• 406 Final General Discussion and Resume Chairman: L. E. GLYNN ........•............................. 421 Subject Index •.......•.....•.........................••... 443 List of Participants BERENBAUM, M. C. St. Mary's Hospital, Medical School, Praed Street, Paddington, London W2 lPG, Great Britain CREAM, J.J. Dept. of Dermatology, Charing Cross Hos pital, Medical School, Fulham Palace Road, London W6 8RF, Great Britain CULLEN, G.A. Central Veterinary Laboratory, Ministry of Agriculture, Weybridge, Surrey, Great Britain DAVIES, A.J.S. Institute of Cancer Research, Royal Cancer Hospital, Chester Beatty Research Institute, Fulham Road, London SW3 6JB, Great Britain DENMAN, A.M. Clinical Research Centre, Division of Immunology, Watford Road, Harrow, Middlesex HA1 3UJ, Great Britain DUMONDE, D.C. The Mathilda and Terence Kennedy Institute of Rheumatology, Bute Gardens, Hammersmith, London W6 7DW, Great Britain FASSBENDER, H.G. Zentrum fUr Rheuma-Pathologie, Kleine WindmUhlenstraBe 2 1/10, 6500 Mainz, Fed. Rep. of Germany FEHR, K. Universitats-Rheumaklinik, Gloria-StraBe 25, CH 8006 ZUrich, Switzerland VAN FURTH, R. Department of Infectious Diseases, Uni versity Hospital, Leiden, The Netherlands GINSBURG, I. Department Oral Biology, Faculty of Dental Medicine, Hebrew University-Hadassah, Medical Centre, POB 1171, Jerusalem, Israel GLYNN, L.E. The Mathilda and Terence Kennedy Institute of Rheumatology, Bute Gardens, Hammersmith London W6 7DW, Great Britain XII GREILING, H. Klinisch-chem. Zentrallaboratorium der Medizinischen Fakultat der Technischen Hochschule, Goethe-StraBe 27-29, 5100 Aachen, Fed. Rep. of Germany HENSON, P.M. Department of Immunopathology, Scripps Clinic and Res. Foundation, 476 Prospect Street, La Jolla, CA 92037, USA HEWLETT, G. Institut fUr Immunologie und Onkologie, Bayer AG, Friedrich Ebert-Str. 217, 5600 Wuppertal 1, Fed. Rep. of Germany JASIN, H.E. Rheumatic Diseases Unit, University of Texas, Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA KELLY, R.H. Clinical Immunopathology Unit, Department of Pathology, Scaife Hall, University of Pittsburgh, Medical School, Pittsburgh, PA 15261, USA LEMMEL, E.M. Institut fUr Med. Mikrobiologie der Universitat, Langenbeck-StraBe 1, 6500 Mainz, Fed. Rep. of Germany LEWIS, R.M. Department of pathology, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA LOEWI, G. Clinical Research Centre, Northwick Park Hospital, Watford Road, Harrow, Middlesex HAl 3UJ, Great Britain MARMION, B.P. Department of Bacteriology, University Medical School, Teviot Place, Edinburgh EH8 9AG, Great Britain MORLEY, J. Cardiothoracic Institute, Department of Clinical Pharmacology, Fulham Road, London SW3 6HP, Great Britain OPITZ, H.G. Zentrum fUr klinische Grundlagenforschung der Universitat, Park-StraBe 10/11, 7900 Ulm, Fed. Rep. of Germany PAGE-THOMAS, D.P. Strangeways Research Laboratory, Wort's Causeway, Cambridge, CBl 4RN Great Britain PARISH, W.E. Environmental Safety Division, Unilever Research, Colworth House, Sharnbrook, Bedford MK44 lLQ, Great Britain XIII PEARSON, C.M. University of California, Department of Medicine, School of Medicine, The Center for the Health Sciences, Los Angeles, CA 90024, USA SCHLUMBERGER, H.D. Institut fUr Immunologie und Onkologie, Bayer AG, Friedrich-Ebert-StraBe 217, 5600 Wuppertal 1, Fed. Rep. of Germany· SCHNITZER, B. The University of Michigan, Medical School, Department of Pathology, Pathology Building, 1335 E.Catherine Street, Ann Arbor, MI 48104, USA SCHULZ, L. Cl. Institut fUr Pathologie der Tierarztlichen Hochschule, Bischofsholer Damm 15, 3000 Hannover, Fed. Rep. of Germany SPECTOR, W.G. Department of Histopathology, St. Bartholo mew's Hospital, Medical College, West Smith field, London EC1A 7BE, Great Britain STEWARD, M.W. The Mathilda and Terence Kennedy Institute of Rheumatology, Bute Gardens, Hammersmith, London \V'6 7DW, Great Britain TALAL, N. Veterans Administration Hospital, 4150 Clement Street, San Francisco, CA 94121, USA TEICH, N.M. Imperial Cancer Research Fund Laboratories, Lincoln's Inn Fields, London WC2A 3PX, Great Britain WEISS, R.A. Imperial Cancer Research Fund Laboratories, Lincoln's Inn Fields, London WC2A 3PX, Great Britain WILLOUGHBY, D.A. Rheumatology and Experimental Pathology Department, St. Bartholomew's Hospital, Medical College, West Smithfield, London EC1A 7BE, Great Britain