Leukocyte Trafficking – Molecular Mechanisms, Therapeutic Targets and Methods

Professor Alf Hamann is leader of the liaison group Experimental Rheumatology located at the German Arthritis Research Centre and the Charite Hospital in Berlin. He established the research group in 1998 with a focus on basic and pathophysiological aspects of lymphocyte trafficking and immunoregulation. Professor Britta Engelhardt started her career as research group leader at the Max--Planck Institute of Vascular Cell Biology in Munster, Germany, studying the molecular mechanisms of leukocyte migration into the central nervous system. Since 2003 shehas been director of the renowned Theodor--Kocher--Institute at the University of Bern, Switzerland.

Preface. List of Authors. Movies on the included CD. Color Plates. Part I: Molecular Mechanisms. 1. The Multistep Model of Leukocyte Trafficking: A Personal Perspective from 15 Years Later (Eugene C. Butcher). Acknowledgments. References. 2. Capture and Rolling: Selectins and Their Ligands (Claudine S. Bonder and Paul Kubes). 2.1 Introduction. 2.2 Selectins. 2.3 P Selectin Glycoprotein Ligand 1 and Other Ligands of Selectins. 2.4 Glycosyltransferases. 3. Chemokines and Their Receptors: Biochemical, Structural and Biological Properties (Martin Oppermann and Reinhold Forster). 3.1 Introduction. 3.2 Chemokines. 3.3 Chemokine Receptors. 3.4 Role of Chemokines in Lymphocyte and Dendritic Cell Trafficking to and Within Primary and Secondary Lymphoid Organs. 4. Mechanisms of Leukocyte Integrin Activation (Gabriela Constantin and Carlo Laudanna). 4.1 Introduction. 4.2 Modalities of Integrin Activation and the Role of Chemokines. 4.3 Signaling Mechanisms Controlling Rapid Integrin Activation. 4.4 Chemokines, Integrins and Concurrency in Leukocyte Recruitment. 4.5 The Way Ahead. 5. Mechanisms of Leukocyte Transmigration: Role of Immunoglobulin Superfamily Molecules (Federica M. Marelli Berg and Sussan Nourshargh). 5.1 Introduction. 5.2 Leukocyte Migration Through Endothelial Cells. 5.3 Endothelial Cell Junctional Molecules. 5.4 Role of Immunoglobulin Superfamily Cell Adhesion Molecules in Leukocyte Transmigration. 5.5 Intercellular Adhesion Molecules. 5.6 Junctional Adhesion Molecules. 5.7 PECAM 1 (CD31). 5.8 Role of Additional Molecules in Regulation of Leukocyte Transmigration. 5.9 Summary and Future Directions. 6. The Endothelial Cell Basement Membrane and Its Role in Leukocyte Extravasation (Lydia M. Sorokin). 6.1 Introduction. 6.2 Extracellular Matrix of Blood Vessels. 6.3 Function of Endothelial Cell Basement Membranes. 6.4 Conclusion. Part II: Trafficking in vivo. 7. Control of Homing Receptor Expression during Lymphocyte Differentiation, Activation, and Function (Daniel J. Campbell). 7.1 Introduction. 7.2 Developing Lymphocytes Undergo Programmed Changes in Homing Receptor Expression. 7.3 Control of Homing Receptor Expression During Lymphocyte Activation and Effector Cell Differentiation. 7.4 Homing Receptor Expression by Effector/Memory Lymphocytes: Lineage or Lifestyle? 7.5 Selection vs. Instruction. 7.6 Transcriptional Control of Homing Receptor Expression. 7.7 Concluding Remarks. 8. Trafficking of Lymphocyte Subpopulations (Alf Hamann, Carrie N. Arnold, and Gudrun F. Debes). 8.1 Major Lymphocyte Lineages. 8.2 Impact of Activation on Trafficking of T Cells. 8.3 Trafficking of Effector/Memory T Cells. 8.4 Specialized Effector/Memory T Cell Subsets Defined by their Expression of Chemokine Receptors 159 8.5 Differential Trafficking of Functional Subsets: Th1, Th2, and Regulatory T Cells. 8.6 Summary. 9. Trafficking of B Cells (Rudolf A. Manz). 9.1 Introduction. 9.2 B1 Cells. 9.3 B Cell Precursors and Immature B Cells. 9.4 Peripheral B Cells. 9.5 Germinal Center B Cells and Memory B Cells. 9.6 Plasma Cells 179 10. Trafficking of Dendritic Cells (Nikolaus Romani, Sandra Holzmann, Christoph H. Tripp, Michael Sixt, and Patrizia Stoitzner). 10.1 Introduction. 10.2 Pathways and Morphology of Dendritic Cell Trafficking. 10.3 Regulation of Dendritic Cell Trafficking. 10.4 Functional Implications of Dendritic Cell Trafficking. Part III: Inflammation. 11. Molecular and Cellular Contributions to Selectin Dependent Leukocyte Adhesion Under Flow (Rodger P. McEver). 11.1 Introduction. 11.2 Structure of Selectins. 11.3 Regulation of Expression of Selectins. 11.4 Selectin Ligands. 11.5 Regulation of Cell Rolling Under Flow. 11.6 Signaling Through Selectins or Selectin Ligands. 12. Mechanisms of Inflammation: Neutrophils (Markus Sperandio and Barbara Walzog). 12.1 Formation and Differentiation of Neutrophils. 12.2 Regulation of Neutrophil Homeostasis in the Circulation. 12.3 Neutrophil Activation and Recruitment. 12.4 Phagocytosis by Neutrophils. 12.5 Neutrophil Apoptosis. 12.6 Resolution of Inflammation. 13. Chemokines Drive Inflammatory Leukocyte Recruitment (Stefan Floess and Antal Rot). 13.1 Introduction. 13.2 Inflammatory and Homeostatic Chemokines. 13.3 Chemokine "Redundancy". 13.4 Chemokine Presentation by GAGs. 13.5 Chemokine Interceptors. 13.6 Chemokines on Blood Tissue Interface. 13.7 In Vivo Veritas. 13.8 CCR1. 13.9 CCR2. 13.10 CCR3. 13.11 CCR4. 13.12 CCR5. 13.13 CCR6. 13.14 CCR8. 13.15 CCR9. 13.16 CXCR2. 13.17 CXCR3. 13.18 CXCR6. 13.19 CX3CR1. 13.20 Concluding Remarks. 14. Mechanism of Inflammation: Activation of the Endothelium (Matthias Clauss and Carolyn E. Patterson). 14.1 Introduction. 14.2 Effects of Endothelial Activation. 14.3 Cell Activating Factors and Principles. 14.4 Signaling of Endothelial Activation. 14.5 Role of Reactive Oxygen Species in Endothelial Activation. 14.6 Chronic Endothelial Cell Activation. Part IV: Trafficking Mechanisms as Therapeutic Targets. 15. Integrins as Therapeutic Targets for Inflammatory Disease (Michael J. Briskin). 15.1 Introduction 339 15.2 Preclinical Studies 340 15.3 Humanization of Anti integrin mAbs. 15.4 Clinical Trials with Humanized Anti alpha4 Integrin mAbs. 15.5 Clinical Studies of Humanized Anti CD11a. 15.6 Other Approaches: Antisense Antagonists. 15.7 Final Remarks. 16. Chemokine Receptor Antagonists: From the Bench to the Clinic (Sofia Ribeiro and Richard Horuk). 16.1 Introduction. 16.2 Chemokines and Their Receptors. 16.3 CC Chemokine Receptor Antagonists. 16.4 CXC Chemokine Receptor Antagonists. 16.5 Conclusion. Part V: Methods to Study Cell Trafficking. 17. Leukocyte Endothelial Cell Cell Interactions in Vitro: Static Assays and Adhesion under Shear Stress (Markus Hammel, Olaf Zilles, and Rupert Hallmann with a contribution from Silke Jennrich, Kerstin Siegmund, and Alf Hamann). 17.1 Introduction. 17.2 Adhesion of Leukocytes to High Endothelial Venules: The HEV Assay. 17.3 Adhesion of Leukocytes to Cultured Endothelium, With or Without Shear. 17.4 Adhesion Assay under Static Conditions in Microtiter Plates. 18. Chemotaxis Assay: Analysis of Migration of Lymphocyte Subsets (Kerstin Siegmund, Gudrun F. Debes, and Alf Hamann). 18.1 Introduction. 18.2 Basic Protocol. 19. In Vitro Transendothelial Migration Assay (Ruth Lyck and Britta Engelhardt). 19.1 Introduction. 19.2 Methods for the Investigation of Transendothelial Migration in Vitro. 19.3 Experimental Details. 19.4 Protocol. 20. Real Time in Vitro Assays for Studying Leukocyte Transendothelial Migration Under Physiological Flow Conditions (Ronen Alon, Guy Cinamon, and Francis W. Luscinskas). 20.1 Background. 20.2 Introduction. 20.3 Disadvantages of Analysis of Leukocyte TEM Without Provision for Shear Flow. 20.4 An Alternative System for Real Time Analysis of Leukocyte TEM. 20.5 Spatial and Temporal Analysis of Leukocyte Adhesion Molecules and Endothelial Junctional Molecules During Leukocyte TEM. 20.6 Drawbacks of Present Flow Chamber Technologies. 20.7 Open Questions and Extended Tools for Studying Leukocyte TEM In Vitro. 21. Intravital Microscopy and In Vitro Flow Chamber: Techniques to Study Leukocyte Adhesion Under Flow and in Real Time (Jens V. Stein). 21.1 Introduction. 21.2 Hemodynamics. 21.3 In Vitro Flow Chamber. 21.4 Advantages and Limitations of FCAs. 21.5 IVM: Past and Present. 21.6 Practical IVM. 21.7 Observing Endogenous Versus Exogenous Cells. 21.8 Advantages and Limitations of IVM. 21.9 Emerging Applications for FCA and IVM. 21.10 Conclusion. 22. Immune Processes in the Light of Two Photon Microscopy (Alexander Flugel and Naoto Kawakami). 22.1 Introduction. 22.2 Two Photon Live Microscopy: Basic Principles. 22.3 Two Photon Analyses of Immune Processes. 22.4 Conclusions. 23. Use of Labeled Lymphocytes to Analyze Trafficking In Vivo (Kerstin Siegmund and Alf Hamann). 23.1 Introduction. 23.2 Protocols for Labeling with Radioisotopes. 23.3 Homing Procedure: Injection of Labeled Cells and Determination of Radioactivity Recovered. 23.4 Use of Antibodies Against Adhesion Molecules in Homing Experiments. 23.5 Protocols for Labeling with Fluorescent Dyes. Index.