Over the last decade, enormous progress in the understanding of T-cell homing has made it possible to identify the multitude of molecules involved, such as cytokines, chemokines, and adhesion molecules, and to unravel their complex interactions resulting in controlled, non-random T-cell recirculation. These insights are now being explored therapeutically, with several compounds close to approval. Highlighting key findings in the field, Lymphocyte Homing to the Skin: Immunology, Immunopathology, and Therapeutic Perspectives brings insight to the physiology and pathophysiology of T-cell homing as a process, as well as to the manipulation of this process for therapeutic benefit. The book begins with a review of the role of T-lymphocytes in skin biology, followed by coverage of the process of lymphocyte recruitment, and lymphocyte homing to the skin. Subsequent chapters describe in vitro techniques to investigate lymphocyte extravasation, in vivo methods to study lymphocyte homing to the skin, and cutaneous T-lymphocytic infiltrates in skin pathology. The text concludes with discussions on translating cutaneous T-cell recruitment to patients. Providing a timely update on T-cell homing, this book clarifies our understanding of this complex process and offers guidance on potential therapies. It fulfills the needs of those involved in skin biology, skin toxicology, and dermatology, and proposes new directions for innovative research.
Author(s): Wolf-Henning Boehncke
Edition: 1
Publisher: Informa Healthcare
Year: 2004
Language: English
Pages: 224
Front cover......Page 1
Preface......Page 6
Editor......Page 8
Contributors......Page 10
Table of Contents......Page 12
1.1 A Brief View on T-Cells in the Immune System......Page 14
1.2.1 Tethering and Rolling - The First Steps of Leukocyte Evtravasation......Page 17
1.2.2 Lymphocyte Extravasation - Teamwork of Chemokines and Adhesion Molecules......Page 20
1.2.3 Epidermal T-Cell Localization - The Endpoint of a Long Journey......Page 24
1.3 Psoriasis - A Model Disorder for Studying Cutaneous T-cell Recruitment......Page 27
1.3.2 Transcriptional Regulation of Selectin Functions......Page 30
REFERENCES......Page 31
2.1 The Multistep Paradigm......Page 42
2.2.1 Selectins and their Receptors......Page 44
2.2.2 Selectin Signaling......Page 46
2.3.1 Chemokines and Chemokine Receptors......Page 48
2.3.2 Integrins and Integrin Receptors......Page 50
2.3.3 Affinity and Avidity Modulation......Page 52
2.4 Transendothelial Migration......Page 54
2.4.1 Cell Spreading and Locomotion......Page 55
2.4.2 Cell Junctions......Page 56
2.5 Chemotaxis......Page 57
References......Page 58
Lymphocyte Homing to the Skin......Page 66
3.1 Adhesion Molecules and the Skin-Specific Migration of Lymphocytes......Page 67
3.1.1.1 Selectins......Page 69
3.1.1.2 Selectin Ligands......Page 72
3.1.1.3 CLA on Skin-Homing Lymphocytes......Page 74
3.1.1.4 Other Molecules Mediating Rolling Interactions......Page 75
3.1.2.1 Core 2 Branching Enzymes......Page 76
3.1.2.2 Fucosyltransferases......Page 77
3.1.2.4 Sulfotransferases......Page 78
3.1.3.1 Integrins......Page 79
3.1.3.3 Immunoglobulin Superfamily Members as Integrin Ligands......Page 81
3.1.4 Adhesion Molecules in Transmigration of Lymphocytes......Page 82
3.1.6 Epidermal Localization of Lymphocytes......Page 84
3.2.1 Chemokines in Lymphocyte Trafficking......Page 86
3.2.2.1 Chemokine Presentation on Endothelium......Page 87
3.2.2.2 Skin-Specific Chemokines......Page 89
3.2.3 Chemokines in Transmigration of Lymphocytes......Page 90
3.2.4 Chemokines and Lymphocyte Migration within the Skin......Page 91
References......Page 92
In Vitro Techniques to Investigate Lymphocyte Extravasation......Page 102
4.1 Introduction......Page 103
4.2.2.1 Chemokines Regulate Cell-Cell Interaction - Binding of Immune Cells to EC and Other Tissue Cells......Page 105
4.2.2.2 Specific Considerations with Respect to Chemokines......Page 108
4.2.2.3 The Stamper-Woodruff Adherence Assay under Static or Shear Flow Conditions......Page 109
4.3.1 Single-Cell Tracking......Page 113
4.3.2 Wound Healing Assays......Page 114
4.3.3.1 The Boyden Chamber......Page 115
4.3.3.2 Chemokinesis: Mathematics of Random Migration......Page 119
4.3.4.1 TEM under Static Conditions......Page 120
4.3.4.3 Under-Agarose Migration Assay......Page 124
4.4 Tethering, Adhesion, and Migration Under Flow Conditions......Page 127
4.4.3 Transmigration under Flow Conditions......Page 128
4.4.3.1 Dynamic Systems......Page 129
REFERENCES......Page 134
In Vivo Methods to Study Lymphocyte Homing to the Skin......Page 142
5.1.2 Extravasation of Endogenous Lymphocytes......Page 143
5.1.2.1 Choosing a Model......Page 144
5.1.2.2 Injection of the Fluorescent Dye Rhodamine 6G......Page 150
5.1.2.3 Data Acquisition and Evaluation......Page 151
5.1.3.1 Lymphocyte Isolation and Staining......Page 152
5.1.3.3 Data Acquisition and Evaluation......Page 156
5.1.4 Microscope and Recording Equipment......Page 157
5.1.5 Data Evaluation......Page 158
5.2.1 Rationale for the Use of Animal Models......Page 160
5.2.2 Cutaneous Inflammation in Wild-Type Animals......Page 161
5.2.3.1 Cutaneous Inflammation Triggered by External Stimuli......Page 164
5.2.3.2 Cutaneous Inflammation as Part of the Phenotype......Page 165
5.2.4 Cutaneous Inflammation in Xenogeneic Skin Transplantation Models......Page 168
5.2.5.1 The Psoriasis SCID Mouse Model as Tool for Drug Discovery......Page 169
References......Page 174
6.1 Introduction......Page 182
6.2.1.1 Atopic Dermatitis......Page 183
6.2.1.2 Other Endogenous Eczemas (Seborrhoeic, Discoid, Stasis)......Page 184
6.2.1.3 Exogenous Eczemas (Allergic Contact and Irritant Contact Dermatitis)......Page 185
6.2.2 Psoriasis......Page 186
6.2.4 Cutaneous Organ-Specific Autoimmune Disease: Alopecia Areata and Vitiligo......Page 187
6.3.1 Nonmelanoma Skin Cancer......Page 188
6.3.2 Melanoma......Page 189
References......Page 190
From Bench to Bedside: Bringing Understanding of Cutaneous T-Cell Recruitment to Patients......Page 198
7.1 Emerging Targets for Interfering with T-Cell Trafficking......Page 199
7.2 Targeting Lymphocyte Rolling along the Blood Vessel Wall......Page 200
7.3 Blockade of Chemokine-Chemokine Receptor Interaction......Page 203
7.5 Challenges of Targeting Lymphocyte Skin Homing......Page 206
References......Page 208
