Progress in Inflammation Research

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3 Progress in Inflammation Research Series Editor Prof. Michael J. Parnham PhD Director of Preclinical Discovery CEMDD GSK Research Centre Zagreb Ltd. Prilaz baruna Filipovića 29 HR Zagreb Croatia Advisory Board G. Z. Feuerstein (Wyeth Research, Collegeville, PA, USA) M. Pairet (Boehringer Ingelheim Pharma KG, Biberach a. d. Riss, Germany) W. van Eden (Universiteit Utrecht, Utrecht, The Netherlands) Forthcoming titles: The Resolution of Inflammation, A.G. Rossi, D.A. Sawatzky (Editors), 2007 Angiogenesis in Inflammation: Mechanisms and Clinical Correlates, M.P. Seed, D.A. Walsh (Editors), 2008 New Therapeutic Targets in Rheumatoid Arthritis, P.-P. Tak (Editor), 2008 Inflammatory Cardiomyopathy (DCM) Pathogenesis and Therapy, H.-P. Schultheiß, M. Noutsias (Editors), 2008 Matrix Metalloproteinases in Tissue Remodelling and Inflammation, V. Lagente, E. Boichot (Editors), 2008 (Already published titles see last page.)

4 The Immune Synapse as a Novel Target for Therapy Luis Graca Editor Birkhäuser Basel Boston Berlin

5 Editor Luis Graca Unidade de Imunologia Celular Instituto de Medicina Molecular Faculdade de Medicina da Universidade de Lisboa Av. Professor Egas Moniz Lisboa Portugal Library of Congress Control Number: Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the internet at ISBN Birkhäuser Verlag AG, Basel Boston Berlin 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. This work is subject to copyright. All 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 microfilms or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained Birkhäuser Verlag AG, P.O. Box 133, CH-4010 Basel, Switzerland Part of Springer Science+Business Media Printed on acid-free paper produced from chlorine-free pulp. TCF Cover design: Markus Etterich, Basel Cover illustration: The immune synapse is often visualized by microscopy using reagents that put in evidence the spatial segregation of molecules involved in antigen-recognition, co-stimulation and adhesion. Visually it resembles a target-like structure with concentric rings. Artist Marta de Menezes created a visual representation of the immune synapse with an image of an eyespot of a Byciclus anynana butterfly. Printed in Germany ISBN e-isbn

6 Contents List of contributors Preface vii xi Emmanuel Donnadieu The immune synapse and T cell activation: regulation by chemokines Luis Graca The induction of regulatory T cells by targeting the immune synapse Paul J. Fairchild Infiltrating the immunological synapse: prospects for the use of altered petide ligands for the treatment of immune pathology Herman Waldmann, Elizabeth Adams and Stephen Cobbold Targeting CD4 for the induction of dominant tolerance Damien Bresson and Matthias von Herrath Anti-CD3: from T cell depletion to tolerance induction Yuan Zhai and Jerzy W. Kupiec-Weglinski Immune modulation by CD40L blockade Francesca Fallarino, Carmine Vacca, Claudia Volpi, Maria T. Pallotta, Stefania Gizzi, Ursula Grohmann and Paolo Puccetti CTLA-4-immunoglobulin and indoleamine 2,3-dioxygenase in dominant tolerance Mark R. Nicolls and Rasa Tamosiuniene Adhesion molecules as therapeutic targets

7 Dalip Contents J.S. Sirinathsinghji and Ray G. Hill Irene Puga and Fernando Macian E3 ubiquitin ligases and immune tolerance: targeting the immune synapse from within? Bin Li, Xiaomin Song, Arabinda Samanta, Kathryn Bembas, Amy Brown, Geng Zhang, Makoto Katsumata, Yuan Shen, Sandra J. Saouaf and Mark I. Greene FOXP3 biochemistry will lead to novel drug approaches for vaccines and diseases that lack suppressor T cells Ramireddy Bommireddy and Thomas Doetschman Transforming growth factor- : from its effect in T cell activation to a role in dominant tolerance Wang-Fai Ng and John D. Isaacs From mice to men: the challenges of developing tolerance-inducing biological drugs for the clinic Index vi

8 List of contributors Elizabeth Adams, Sir William Dunn School of Pathology, Oxford University, South Parks Road, Oxford OX1 3RE, UK Kathryn Bembas, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA Ramireddy Bommireddy, BIO5 Institute and Department of Immunobiology, University of Arizona, PO Box , Tucson, AZ , USA; Damien Bresson, La Jolla Institute for Allergy and Immunology, Department of Developmental Immunology 3, 9420 Athena Circle, La Jolla, CA 92037, USA; Amy Brown, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA Stephen Cobbold, Sir William Dunn School of Pathology, Oxford University, South Parks Road, Oxford OX1 3RE, UK Emmanuel Donnadieu, Département de Biologie Cellulaire, Institut Cochin, 22 rue méchain, Paris, France; Thomas Doetschman, BIO5 Institute and Department of Cell Biology and Anatomy and Arizona Cancer Center, University of Arizona, PO Box , Tucson, AZ , USA; Paul J. Fairchild, University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK; vii

9 List of contributors Francesca Fallarino, Dept. of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia, Italy; Stefania Gizzi, Dept. of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia, Italy Mark I. Greene, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA; Ursula Grohmann, Dept. of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia, Italy John D. Isaacs, Musculoskeletal Research Group, Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK; Makoto Katsumata, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA Jerzy W. Kupiec-Weglinski, The Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Le Conte Avenue, Los Angeles, CA 90095, USA Bin Li, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA Fernando Macian, Albert Einstein College of Medicine, Department of Pathology, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Wan-Fai Ng, Musculoskeletal Research Group, Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK Mark R. Nicolls, Veterans Administration Palo Alto, Health Care System, Medical Service (111), and Division of Pulmonary and Critical Care Medicine, Stanford University, 3801 Miranda Ave., Palo Alto, CA 94304, USA; Maria T. Pallotta, Dept. of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia, Italy viii

10 List of contributors Paolo Puccetti, Dept. of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia, Italy Irene Puga, Albert Einstein College of Medicine, Department of Pathology, 1300 Morris Park Avenue, Bronx, NY 10461, USA Arabinda Samanta, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA Sandra J. Saouaf, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA Yuan Shen, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA Xiaomin Song, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA Rasa Tamosiuniene, Veterans Administration Palo Alto, Health Care System, Medical Service (111), and Division of Pulmonary and Critical Care Medicine, Stanford University, 3801 Miranda Ave., Palo Alto, CA 94304, USA Carmine Vacca, Dept. of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia, Italy Claudia Volpi, Dept. of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia, Italy Matthias von Herrath, La Jolla Institute for Allergy and Immunology, Department of Developmental Immunology 3, 9420 Athena Circle, La Jolla, CA 92037, USA Herman Waldmann, Sir William Dunn School of Pathology, Oxford University, South Parks Road, Oxford OX1 3RE, UK; Yuan Zhai, The Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Le Conte Avenue, Los Angeles, CA 90095, USA; Geng Zhang, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA ix

11 Preface It is now accepted that T cell activation by an antigen-presenting cell requires the organization of a supramolecular structure the immune synapse. This structure, with different types of molecules spatially segregated, is involved in the delivery of quantitative and qualitative signals critical for T cell activation, and therefore in controlling the nature of the immune response. This volume discusses the progress in manipulating components of the immune synapse as a strategy to regulate the immune response in immune pathology, such as transplantation, autoimmunity and allergy. Donnadieu reviews the current knowledge on the molecular composition and organization of the immune synapse and how the formation of this structure can be modulated by chemokines. It is also known that the immune synapse formation is critical for the activation of naive T cells, as well as their functional polarization. The second chapter discusses the conversion of naive T cells into regulatory T cells (Treg) when components of the immune synapse are manipulated in such a way that the T cells receive suboptimal activation signals. One way to interfere with the immune synapse s ability to activate T cells is by using altered peptide ligands (APLs). Fairchild reviews the state of the art of immune-modulation with APLs. Several different monoclonal antibodies (mabs) have been shown to be effective in inducing immune tolerance associated with a dominant role of Treg cells. One of the pioneers of the concept of reprogramming the immune system with non-depleting mabs is Herman Waldmann. His chapter reviews the use of mabs targeting CD4 to achieve immune tolerance, giving an historical perspective of the developments in this field. Another T cell co-receptor the CD3 has been recently used as a target for tolerogenic mabs, after many years being mainly used as a target for mabs leading to T cell depletion, or T cell activation. Bresson and von Herrath review the recent developments in anti-cd3 therapy, with a special emphasis on the treatment of type 1 diabetes. Tolerance has also been achieved following co-stimulation blockade. Zhai and Kupiec-Weglinski describe how CD40L blockade can lead to long-term transplantation tolerance. Fallarino and colleagues discuss the targeting of CD28 by CTLA-4-Ig xi

12 Preface and how the tolerance state thus induced appears to relate with changes on tryptophan catabolism triggered by indoleamine 2,3-dioxygenase (IDO) induction. The formation of the immune synapse also requires the participation of cellular adhesion molecules. Nicolls and Tamosiuniene review anti-adhesion therapies namely with mabs targeting LFA-1 and ICAM-1 as immune modulators. In recent years it became apparent that ubiquitination is an important mechanism in regulating cellular processes. Several E3 ubiquitin ligases, such as Cbl-b, GRAIL and Itch, have been reported as key players in the regulation of immune tolerance. Puga and Macian describe how E3 ubiquitin ligases may modulate the activity of key signaling molecules therefore targeting the immune synapse from within the T cell. Li and colleagues discuss Foxp3 biochemistry, and how drugs interfering with post-translational modification of Foxp3 may control Treg function. Bommireddy and Doetschman review the role of TGF- in immune-pathology and in Treg cell function. TGF- has been reported as a critical cytokine for Treg cell induction in the periphery, as well as being able to function by increasing the threshold necessary for full activation of T cells. In the final chapter Ng and Isaacs discuss the challenges for translating the knowledge acquired with animal models into tolerance-inducing drugs for the clinic. I am grateful to all contributors to this volume, who have shared their expertise from basic science to clinical trials. I do hope all readers will be as excited as myself with the promising developments in this field. Lisboa, August 2007 Luis Graca xii

13 The immune synapse and T cell activation: regulation by chemokines Emmanuel Donnadieu Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, and Inserm, U567, Paris, France Initial descriptions of the immune synapse The initiation of an immune response requires that cells communicate with each others to ensure an appropriate protection against pathogens. T cells do not see free antigens, recognizing them only after processing and presentation by professional antigen-presenting cells (APCs), such as dendritic cells (DCs). This cell-cell contact enables T cells to engage their T cell receptors (TCRs) with cell surface peptide-mhc (pmhc) complexes. Together with signals from costimulation molecules, the antigenic signal leads to T cell activation and differentiation. The importance of cell communication in the initiation of an immune response was underestimated for a long time. T cell activation was mainly studied using biochemical tools on T cell lines stimulated with antibodies directed against surface molecules. Although these approaches have been very fruitful to dissect the various signaling pathways triggered following TCR stimulation, they did not provide spatio-temporal information at the single-cell level. However, within the past 15 years, progress in imaging technologies has made it possible to monitor the early consequences of the interaction between T cells and APCs. Initial studies were focused on immediate downstream events triggered in APC-stimulated T cells, including Ca 2+ responses and shape changes [1, 2]. In 1998, Avi Kupfer and his colleagues [3], using 3-D confocal microscopy, made the striking observation that TCR, other receptors and signaling molecules display a distinct clustering at the T-APC interface. The classical immune synapse (IS) was first characterized in T cell-b cell contacts as a central clustering of small signaling molecules, such as the TCR, CD28 and protein kinase C, that the authors named c-smac (for central supramolecular activation cluster), surrounded by a ring of larger adhesion molecules such as the integrin LFA-1, named p-smac (for peripheral supramolecular activation cluster). This report was shortly followed by a study performed with lipids bilayers bearing pmhc complexes and adhesion molecules used as a surrogate for a live APC [4]. This model, although artificial, provided a dynamic view of receptors cluster- The Immune Synapse as a Novel Target for Therapy, edited by Luis Graca 2008 Birkhäuser Verlag Basel/Switzerland 1

14 Emmanuel Donnadieu ing with a good spatio-temporal resolution. It confirmed the partitioning of several surface and intracellular signaling molecules at the c-smac and p-smac. Subsequent experiments with green fluorescent protein (GFP)-tagged proteins expressed in T cells have given access to direct dynamic information at the IS and shown some subtle movements of a number of surface and signaling molecules including CD4, CD28, Lck and PI3K [5, 6]. Plasticity of the immune synapse After these seminal observations performed with B cells as APCs or with planar bilayers, it appeared that the architecture and the composition of the IS were more diverse than initially thought. Several studies established that the characteristics of the IS are dependent on the nature of the T cells. Hence, immature thymocytes have been shown, in bilayer experiments, to form multiple, small transient clusters of the TCR, but have no central clustering of the TCR or lipid rafts [7]. In addition, murine primary Th1 and Th2 cells differ in the organization of the IS, with Th1 cells, but not Th2 cells, clustering signaling molecules at the T cell/b cell synapse site [8]. Furthermore, the structure of the IS is very dependent on the nature of the APCs. Initial observation of the IS were made with B cells, which in resting state are inefficient APCs. T cells form long-lasting contacts with B cells and as outlined above, c-smac and p-smac are observed at the interface of both cells. The situation is strikingly different when one uses DCs, which are the most potent APCs. First, DCs possess a unique ability to trigger multiple signals in the absence of antigen. More than 20 years ago, Nussenzweig and Steinman reported the formation of antigen-independent T-DC conjugates leading to a low level of T cell proliferation [9]. Since this initial description, studies have demonstrated the formation of a functional antigen-independent synapse with the recruitment of surface and signaling molecules at the interface between T cells and DCs [10 13]. Using primary human T cells and autologous DCs, my colleagues and I have shown that DCs are very potent for inducing T lymphocyte motility [14, 15]. Initially round and static, T lymphocytes overlaid onto a monolayer of DCs rapidly adopt a polarized morphology with a leading edge and a uropod. This step is followed by an active motility of T cells that successively interact with multiple DCs. We also found that a fraction of T cells display small and transient Ca 2+ responses during their migration. Importantly, these antigen-independent signals promote T cell survival [16]. They are also supposed to prime T cells and maintain them in a state of functional alertness ready to detect and rapidly respond to rare expressed cognate antigens [17]. A second feature of the DCs is the absence of a classical c-smac and p-smac synapse at the contact site with T cells. Of note, in the presence of a cognate anti- 2

15 The immune synapse and T cell activation: regulation by chemokines gen, the structure of the synapse formed between murine DCs and naive T cells is multifocal and composed of tight appositions of a few tens of nm in diameter [18]. Interestingly, these numerous tight appositions are reminiscent of the microclusters of TCRs and essential signaling molecules that have been recently described in different models including lipid bilayers [19, 20]. Third, T cells and DCs, even in the presence of a cognate antigen, have a tendency to form dynamic interactions that contrast with the very stable contact between T cells and B cells. By looking at the interaction between T cells and DCs embedded in a collagen matrix, Gunzer et al. [21] showed that T cells only formed short-lived interaction with antigen-loaded DCs. Interestingly, these transient interactions were sufficient to trigger a full T cell activation. However, more recent data indicate that the T-DC contact duration time analyzed in a collagen matrix is very much controlled by the concentration of antigen [22]. Hence, there is a clear positive relation between the amount of antigen and the stability of the interaction between both cell types. As outlined above, the dynamics and composition of the IS have been studied extensively and a clear picture is emerging from these works. However, there is still considerable debate as to the purpose of the IS. I refer readers to several reviews covering this topic [23, 24]. Studying immune synapse formation and T cell activation in vivo All the studies summarized below were realized in culture systems. Although the in vitro condition is convenient and easy to dissect experimentally, the findings obtained in these systems might not always be applicable to the in vivo condition. In particular, they did not take into account the complexity of the lymphoid milieu. Since 2002, the use of two-photon microscopy has enabled several groups to visualize the behavior of T cells and APCs deep within secondary lymphoid organs such as lymph nodes (LNs). These studies indicate that in a non-inflammatory steady-state condition, T cells in LNs migrate rapidly in an apparently random manner [25 27]. This continuous scan may explain the remarkable ability of rare antigen-specific T cells and APCs to find one another to produce an effective immune response. In the presence of a cognate antigen, a stable T-DC contact lasting for several hours is, in most of the published studies, preceded by transient interactions [26, 28, 29]. The rules that control the transition from these brief to stable contacts are not known at present. One can hypothesize that T cells have to reach a certain threshold to make long-lived interactions with DCs. During their transient interactions, T cells would collect and integrate multiple antigen signals but also input from the LN environment. The avidity of the antigen, both its concentration and affinity, is also likely to regulate the duration of the T-DC interaction. At a very high antigen concentration, and similarly to studies performed in culture systems, 3