Novel Strategies for Immune Therapy of Arthritis
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Novel strategies for immune therapy of arthritis - Towards sustained disease remission - About the cover Het tweeluik “Amistad entrega felicidad” van Angeles Nieto (“Vriendschap brengt geluk”). Copyright © 2006 by Future Rheumatology for chapter 2 Copyright © 2002 by Arthritis and Rheumatism for chapter 3 Copyright © 2006 by PLoS ONE for chapter 4 Copyright © 2008 by Blood for chapter 6 Copyright © 2008 by Autoimmunity for chapter 7 Copyright © 2009 by S. Roord for all other chapters All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means without prior permission of the author. Cover Angeles Nieto Layout and Printing Gildeprint Drukkerijen, Enschede, The Netherlands ISBN 978-94-901-2206-5 Address of correspondence Sarah Teklenburg-Roord, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Department of Pediatric Immunology, PO Box 85090, 3508 AB Utrecht, The Netherlands. [email protected]. Novel strategies for immune therapy of arthritis - Towards sustained disease remission - Nieuwe strategieën voor immuun therapie van arthritis - Op weg naar blijvende ziekte remissie - (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 9 april 2009 des middags te 2.30 uur door Sarah Theresa Anne Roord geboren op 23 juni 1974 te Utrecht Promotoren: Prof. dr. B.J. Prakken Prof. dr. W. Kuis Co-promotoren: Dr. N. Wulffraat Dr. F. van Wijk The printing of this thesis was supported by Abbott BV, Amgen BV, BD Biosciences, Boehringer Ingelheim, Eijkman Graduate Fonds, GlaxoSmithKline BV, J.E. Jurriaanse Stichting, Pfizer BV, Phadia BV, Reumafonds (Dutch Arthritis Association), Roche Nederland BV, Schering Plough BV, Stichting Kind en Afweer, Wyeth Pharmaceuticals, ZonMW. Voor mijn ouders TABLE OF CONTENTS Chapter 1 General introduction 9 PART 1 Tolerance induction by antigen specific immunomodulation Chapter 2 Present and future of combination therapy of autoimmune diseases 29 Chapter 3 Inhibition of adjuvant-induced arthritis by interleukin-10-driven 41 regulatory cells induced via nasal administration of a peptide analog of an arthritis-related heat-shock protein 60 T cell epitope Chapter 4 Modulation of T cell function by combination of epitope specific 65 and low dose anticytokine therapy controls autoimmune arthritis PART 2 Tolerance induction by autologous bone marrow transplantation Chapter 5 Autologous bone marrow transplantation specifically 87 suppresses auto antibody and IL-17 production in proteoglycan induced arthritis Chapter 6 Autologous bone marrow transplantation in autoimmune 109 arthritis restores immune homeostasis through CD4+CD25+ Foxp3+ regulatory T cells Chapter 7 Regulatory T cells in autologous stem cell transplantation 131 for autoimmune disease Chapter 8 Summary and general discussion 147 Nederlandse samenvatting 169 Dankwoord 179 Curriculum Vitae 187 List of publications 191 List of abbreviations 195 Colour Figures 199 1General introduction regel 1 PART 1: Tolerance induction of arthritis by antigen specific regel 2 immunomodulation regel 3 regel 4 Current treatment of rheumatological diseases: non-specific regel 5 immunosuppression regel 6 Juvenile Idiopathic Arthritis (JIA) and Rheumatoid Arthritis (RA) are among the most common regel 7 autoimmune diseases worldwide1. They are characterized by chronic, systemic inflammatory regel 8 episodes that target synovial joints and have a relapsing-remitting course. In recent years, regel 9 extensive research in this field has focused on in depth analysis of the underlying mechanisms regel 10 involved in the disease processes. The diseases seem to consist of an initial T cell directed regel 11 stage, followed by self-reverberating cycles of non-specific inflammation, eventually leading to regel 12 joint damage. Likely, local antigens in joints and synovium play a role in this process, however regel 13 the ‘one’ disease-triggering antigen has not been found yet, and probably does not exist either. regel 14 Treatment of JIA and RA can be a major challenge and those diseases are known to lead to regel 15 significant morbidity and even mortality. regel 16 Treatment of JIA and RA has thus far mainly focused on the second inflammatory stage regel 17 of disease. Induction of disease remission can be achieved by the early use of powerful regel 18 immunosuppressants and cytostatic drugs, such as high dose corticosteroids and regel 19 methotrexate (MTX)2;3. Unfortunately, persistent disease remission is still exceptional and regel 20 even then progression of joint damage is hard to prevent. In addition, due to the fact that they regel 21 induce a generalized and non-specific inhibition of immune response and inflammation, these regel 22 agents can have considerable side effects. regel 23 regel 24 Modulation of the immune response by targeting molecules that are involved regel 25 1 Chapter in disease pathogenesis- the innate immune response regel 26 10 Since conventional treatments mainly focus on the general inflammatory pathogenic regel 27 component of the disease, they do not focus on specific components that play a role in disease regel 28 pathogenesis. In this respect, recently introduced biologics have contributed an important regel 29 step forward, targeting for example cytokines that play a role in disease pathogenesis in the regel 30 innate immune response (Table 1)1;4;5. Several biological agents have been identified that regel 31 can block pro-inflammatory cytokines. Etanercept®, a soluble TNF receptor fusion protein, regel 32 Infliximab®, a chimeric anti TNFα antibody, and Adalimumab®, a recombinant human anti regel 33 TNFα antibody, can target TNFα; Anakinra®, an IL-1 receptor antagonist, neutralizes IL-1; and regel 34 MRA® (a humanized IL-6 receptor antibody) targets IL-6. The use of these agents has shown regel 35 clinical efficacy in several clinical trials in JIA and RA patients and they are currently approved regel 36 for treatment of RA and/or JIA1;4. However, unfortunately, persistent disease remission can only be achieved as long as the drugs are administered and only then progression of joint regel 1 damage can be prevented. Therefore, it does not lead to a permanent remission of disease or regel 2 a cure. In addition, due to the fact that most of these agents induce a generalized inhibition of regel 3 immune response and inflammation, they can cause considerable immunodepression, leading regel 4 to possibly severe side effects, such as malignancies and infections, including tuberculosis, regel 5 and the induction of other autoimmune diseases4;6-10. regel 6 regel 7 Table 1. Selection of cytokine targets in RA and JIA therapy regel 8 regel 9 Targeted molecule Agents Drug name regel 10 TNFα * Antibodies regel 11 -Chimeric MAB (mouse x human) Infliximab® regel 12 -Humanized murine CDR3-engrafted MAB CDP571 -Human MAB D2E7 (Adalimumab®) regel 13 -PEG-linked Fab fragment CDP870 regel 14 -Recombinant human methionyl TNF binding protein TNFbp regel 15 PEGylated dimer * Soluble TNFR:Fc Fusion Proteins regel 16 -Recombinant soluble p75 TNFR-Fc fusion protein Etanercept® regel 17 -Recombinant soluble p55 TNFR-Fc fusion protein Lenercept® regel 18 -Pegylated Truncated p55 TNF-R regel 19 -PEG soluble TNF Receptor Type 1 Pegsunercept® regel 20 IL-1 rHuIL-1 receptor antagonist Anakinra® rHuIL-1 receptor inhibitor regel 21 IL- 6 Humanized anti IL-6 receptor MAB Atlizumab (MRA)® regel 22 Anti IL-6 MAB B-E8 regel 23 IL-15 Anti IL-15 MAB Hu-MAX IL-15/AMG-714 regel 24 IL-12 Anti IL-12 MAB ABT-874/J-695 General introduction General IFNγ rHuIFNγ regel 25 IFNβ rHuIFNβ 11 regel 26 IL-11 rHuIL-11 regel 27 IL-10 rHuIL-10 regel 28 IL-4 rHuIL-4 Current biological agents and agents in development and/or suggested for treatment of human arthritis. regel 29 Agents currently in use in clinical practice are depicted in bold face. MAB=Monoclonal Antibody. regel 30 TNFR=TNF receptor. rHu=recombinant human. regel 31 regel 32 regel 33 regel 34 regel 35 regel 36 regel 1 Modulation of the immune response by targeting molecules that are involved regel 2 in disease pathogenesis- the adaptive immune response regel 3 Other attempts have focused on several arms of the specific, adaptive immune response. regel 4 Table 2 summarizes a selection of the efforts targeting the adaptive immune response in regel 5 autoimmune diseases, such as RA, JIA, Multiple Sclerosis (MS) and type 1 diabetes. Those regel 6 attempts range from inhibition of leukocytes trafficking into the joint by targeting adhesion regel 7 molecules, to depletion of all CD3+ and CD4+ T cells or B cells. Other efforts target only regel 8 pathogenic T cells, e.g. cells expressing OX-40, or target molecules that are involved in CD4+ regel 9 signaling pathways, such as co stimulatory molecules CD28, CD80, and CTLA411;12. Lastly, regel 10 some attempts aim to modulate only the response to a pathogenic antigen present at the regel 11 site of inflammation by either immunization to this antigen or mucosal tolerance induction regel 12 to such an antigen. Some of these attempts have led to encouraging results in clinical trials, regel 13 and as a consequence some drugs have become readily available on the market. Abatacept®, regel 14 a recombinant CTLA-4Ig fusion protein that blocks the co stimulatory signal mediated by regel 15 the CD28-CD80/86 pathway, and Rituximab®, an anti CD20 MAB, are currently in use for RA. regel 16 Natalizumab®, an anti α4 integrin monoclonal antibody (MAB), is being used for adult MS regel 17 patients. regel 18 On the contrary, the first attempts that focused on targeting CD4+ T cells showed that, in order regel 19 to achieve therapeutic levels within the joints, the required dose would lead to an unacceptably regel 20 profound CD4 lymphopenia with the subsequent risk of severe immune suppression and have regel 21 therefore been abandoned as a therapeutic strategy in RA13-16.