Progress in Inflammation Research

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2 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.)

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

4 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

5 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

6 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

7 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

8 List of contributors Francesca Fallarino, Dept. of Experimental Medicine, Section of Pharmacology, University ; fllfnc@tin.it Stefania Gizzi, Dept. of Experimental Medicine, Section of Pharmacology, University Mark I. Greene, Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA , USA; greene@reo.med.upenn.edu Ursula Grohmann, Dept. of Experimental Medicine, Section of Pharmacology, University John D. Isaacs, Musculoskeletal Research Group, Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK; j.d.isaacs@newcastle.ac.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; fmacianj@aecom.yu.edu 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; mnicolls@stanford.edu Maria T. Pallotta, Dept. of Experimental Medicine, Section of Pharmacology, University viii

9 List of contributors Paolo Puccetti, Dept. of Experimental Medicine, Section of Pharmacology, University 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 Claudia Volpi, Dept. of Experimental Medicine, Section of Pharmacology, University 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

10 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

11 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