Table Of ContentProgress in Inflammation Research
Series Editor
Prof. Michael J. Parnham PhD
Director of Preclinical Discovery
CEMDD
GSK Research Centre Zagreb Ltd.
Prilaz baruna Filipovic´a 29
HR-10000 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.)
The Immune Synapse as a
Novel Target for Therapy
Luis Graca
Editor
Birkhäuser
Basel · Boston · Berlin
ggrraaccaa..iinndddd iiiiii
Editor
Luis Graca
Unidade de Imunologia Celular
Instituto de Medicina Molecular
Faculdade de Medicina da Universidade de Lisboa
Av. Professor Egas Moniz
1649-208 Lisboa
Portugal
Library of Congress Control Number: 2007934182
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ISBN 978-3-7643-8295-7 Birkhäuser Verlag AG, Basel – Boston – Berlin
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© 2008 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 (cid:39)
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 978-3-7643-8295-7 e-ISBN 978-3-7643-8296-4
9 8 7 6 5 4 3 2 1 www.birkhauser.ch
Contents
List of contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Emmanuel Donnadieu
The immune synapse and T cell activation: regulation by chemokines . . . . . . . . . . 1
Luis Graca
The induction of regulatory T cells by targeting the immune synapse . . . . . . . . . . . 15
Paul J. Fairchild
Infiltrating the immunological synapse: prospects for the use of altered
petide ligands for the treatment of immune pathology . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Herman Waldmann, Elizabeth Adams and Stephen Cobbold
Targeting CD4 for the induction of dominant tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Damien Bresson and Matthias von Herrath
Anti-CD3: from T cell depletion to tolerance induction . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Yuan Zhai and Jerzy W. Kupiec-Weglinski
Immune modulation by CD40L blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Mark R. Nicolls and Rasa Tamosiuniene
Adhesion molecules as therapeutic targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
DCoalnipte Jn.Sts. Sirinathsinghji and Ray G. Hill
Irene Puga and Fernando Macian
E3 ubiquitin ligases and immune tolerance: targeting the immune synapse
from within? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Ramireddy Bommireddy and Thomas Doetschman
Transforming growth factor-(cid:96): from its effect in T cell activation to a role
in dominant tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Wang-Fai Ng and John D. Isaacs
From mice to men: the challenges of developing tolerance-inducing
biological drugs for the clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
vi
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 19104-6082, USA
Ramireddy Bommireddy, BIO5 Institute and Department of Immunobiology, Uni-
versity of Arizona, PO Box 245217, Tucson, AZ 85724-5217, USA;
e-mail: [email protected]
Damien Bresson, La Jolla Institute for Allergy and Immunology, Department of
Developmental Immunology 3, 9420 Athena Circle, La Jolla, CA 92037, USA;
e-mail: [email protected]
Amy Brown, Pathology and Laboratory Medicine, University of Pennsylvania, 252
John Morgan, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, 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, 75014 Paris, France; e-mail: [email protected]
Thomas Doetschman, BIO5 Institute and Department of Cell Biology and Anatomy
and Arizona Cancer Center, University of Arizona, PO Box 245217, Tucson, AZ
85724-5217, USA; e-mail: [email protected]
Paul J. Fairchild, University of Oxford, Sir William Dunn School of Pathology,
South Parks Road, Oxford, OX1 3RE, UK; e-mail: [email protected]
vii
List of contributors
Francesca Fallarino, Dept. of Experimental Medicine, Section of Pharmacology,
University of Perugia, Via del Giochetto, 06126 Perugia, Italy; e-mail: [email protected]
Stefania Gizzi, Dept. of Experimental Medicine, Section of Pharmacology, Univer-
sity of Perugia, Via del Giochetto, 06126 Perugia, Italy
Mark I. Greene, Pathology and Laboratory Medicine, University of Pennsylvania,
252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA;
e-mail: [email protected]
Ursula Grohmann, Dept. of Experimental Medicine, Section of Pharmacology, Uni-
versity of Perugia, Via del Giochetto, 06126 Perugia, Italy
John D. Isaacs, Musculoskeletal Research Group, Institute of Cellular Medicine,
University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK;
e-mail: [email protected]
Makoto Katsumata, Pathology and Laboratory Medicine, University of Pennsylva-
nia, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA 19104-6082,
USA
Jerzy W. Kupiec-Weglinski, The Dumont-UCLA Transplant Center, Department of
Surgery, David Geffen School of Medicine at UCLA, 10833 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 19104-6082, USA
Fernando Macian, Albert Einstein College of Medicine, Department of Pathology,
1300 Morris Park Avenue, Bronx, NY 10461, USA;
e-mail: [email protected]
Wan-Fai Ng, Musculoskeletal Research Group, Institute of Cellular Medicine, Uni-
versity of Newcastle, Newcastle upon Tyne, NE2 4HH, UK
Mark R. Nicolls, Veterans Administration Palo Alto, Health Care System, Medi-
cal Service (111), and Division of Pulmonary and Critical Care Medicine, Stanford
University, 3801 Miranda Ave., Palo Alto, CA 94304, USA;
e-mail: [email protected]
Maria T. Pallotta, Dept. of Experimental Medicine, Section of Pharmacology, Uni-
versity of Perugia, Via del Giochetto, 06126 Perugia, Italy
viii
List of contributors
Paolo Puccetti, Dept. of Experimental Medicine, Section of Pharmacology, Univer-
sity of Perugia, Via del Giochetto, 06126 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 Pennsylva-
nia, 252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA 19104-6082,
USA
Sandra J. Saouaf, Pathology and Laboratory Medicine, University of Pennsylvania,
252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA
Yuan Shen, Pathology and Laboratory Medicine, University of Pennsylvania, 252
John Morgan, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA
Xiaomin Song, Pathology and Laboratory Medicine, University of Pennsylvania,
252 John Morgan, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA
Rasa Tamosiuniene, Veterans Administration Palo Alto, Health Care System, Medi-
cal 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, Univer-
sity of Perugia, Via del Giochetto, 06126 Perugia, Italy
Claudia Volpi, Dept. of Experimental Medicine, Section of Pharmacology, Univer-
sity of Perugia, Via del Giochetto, 06126 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;
e-mail: [email protected]
Yuan Zhai, The Dumont-UCLA Transplant Center, Department of Surgery, David
Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA
90095, USA; e-mail: [email protected]
Geng Zhang, Pathology and Laboratory Medicine, University of Pennsylvania, 252
John Morgan, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA
ix
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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 transplanta-
tion tolerance. Fallarino and colleagues discuss the targeting of CD28 by CTLA-4-Ig
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