Synthetic Immunology

"This book reviews the emerging studies of synthetic immunology, including the development and regeneration of immune cells, immune organ development and artificial regeneration, and the synthetic approach towards understanding human immune system. Immunology has developed rapidly over the last 50 years through the incorporation of new methods and concepts in cell and molecular biology, genetics, genomics and proteomics. This progress is the result of works by many excellent researchers all over the world. Currently, immunological research has accumulated detailed knowledge on basic mechanisms of immunity and is in the process to change medical practices. Yet, due to the enormous complexity of the immune system, many aspects on the regulation and function of this system remain unknown. Synthetic biology uses gain-of-function rather than loss-of-function approaches. The goals of synthetic biology can be described in a simple phrase ?rebuild, alter, and understand,? namely, to rebuild minimal functional systems using well-defined parts from nature and then to perturb the system to understand its working principles. Given the richness of accumulated knowledge in molecular and cellular mechanisms of the immune system, we now begin adapting the concepts of synthetic biology to immunology. An immune response is a spatiotemporal phenomenon occurring at a given time and at a specialized place in the body. One goal of synthetic immunology is to reconstruct artificial microenvironments for better understanding of an immune response. We hope this yet-to-be-experimental approach of synthetic immunology and the compilation of this book will aid our further understanding of the immune system and future devising the tools to manipulate the immune system for therapy and prevention of the diseases."--Publisher's website Preface for Synthetic Immunology 6 Contents 8 Editors and Contributors 10 Chapter 1: Development and Regeneration of Hematopoietic Stem Cells 13 Introduction 14 Developmental Mimicking 16 Embryonic Development of HSCs 17 Pluripotent Stem Cell Differentiation Along Developmental Pathways 22 HSC Generation in vivo 26 Transdifferentiation 30 Future Directions 33 References 34 Chapter 2: Generation and Regeneration of T Cells 43 Introduction 44 Developmental Pathway from HSCs to T Cell Progenitors 44 Proposal of Myeloid Based Model 44 Myeloid Based Model as a Map of Developmental Potentials 46 Myelo-Lymphoid Progenitor Stage (M-T-B Progenitor Status) 46 Prethymic Pathway of T Cell Development 46 Myeloid-T Progenitors 47 Myeloid Potential of T Cell Progenitors is Terminated in the Midst of the DN2 Stage 49 Identification of a Developmental Checkpoint for Production of the T Cell Lineage 51 Environmental Factors That Support T Cell Development 51 Factors Required for Thymic Colonization 51 Notch Signal is Essential for T Cell Development 53 Expression of Unique Peptides in Cortical Thymic Epithelial Cells (cTECs) is Required for Positive Selection 53 Approaches Based on the Concept of Synthetic Biology 54 In Vivo Recapitulation of the Phylogeny of Thymus 54 In Vitro Recapitulation of T Cell Development 55 Fetal Thymic Organ Culture 55 Co-Culture with Stromal Cells 55 Developmental Arrest-Restart Controlling Culture System 56 Recapitulation of DN1 Stage Development Using the Arrest-Restart Controlling Culture System 57 Feeder-Free Culture System 59 Toward Clinical Application 60 Currently Ongoing Efficient Strategies in Cancer Immunotherapy 60 Cloning of Antigen-Specific T Cells by Using iPSC Technology 60 Production of iPSCs from Tumor Antigen-Specific CTLs 61 Regeneration of Tumor Antigen-Specific CTLs from iPSCs 62 Allogeneic Transfusion Setting is Preferable 63 Concluding Remarks 64 References 65 Chapter 3: Strategies for Thymic Regeneration: Recent Advances Towards Clinical Therapy 69 Introduction 72 An Overview of the Thymus 72 The Thymus and T Cell Development 73 Thymus Organogenesis 75 Forkhead-Box Transcription Factor n1 (Foxn1) 77 Thymus Ageing 78 The Clinical Impact of Thymus Ageing and Strategies for Its Regeneration to Replenish the Peripheral T Cell Pool 80 Reactivation of the Endogenous Thymus 81 Sex Steroid Ablation 81 Cytokine and Growth Factor Supplementation 82 Hormone Therapy 84 Reactivation of Resident Stem Cells Using Small RNAs 85 Creating de novo Thymic Tissue 87 Adult Stem and Progenitor Cells 87 Embryonic and Induced Pluripotent Stem Cells 88 Regeneration via Bioengineered Matrices 89 Supporting Role of Extracellular Matrices in the Thymus 90 Biomaterials as Scaffolds for Thymus Regeneration 90 Conclusion 92 References 93 Chapter 4: Artificial Thymus: Recreating Microenvironmental Cues to Direct T Cell Differentiation and Thymic Regeneration 107 Introduction 108 T Cell Development in Vitro 109 Use of Ex Vivo Tissue Fetal Thymic Organ Cultures (FTOC) 109 Requirement of Notch Signaling for T Cell Development 112 Hematopoietic Stem/Progenitor Cell (HSPC)-Derived T-Cells Using OP9-DL Cells 113 OP9-DL1 vs OP9-DL4 Cells 115 Adoptive Transfer of Progenitor T Cells 116 Human T Cell Generation in Vitro 117 Use of Alternative Stromal Cells to Generate T Cells in Vitro 119 Cell-Free Support System DL-Fc 119 Artificial Thymus Development 122 FoxN1 and Nude Mice: A Model for Discovery 122 Thymus Regeneration: FoxN1 Master Regulatory Transcription Factor for Reprogramming 124 Pluripotent Stem Cells (PSC) and Thymus Regeneration 126 References 128 Chapter 5: Spleen Development and the Origin of Stromal Diversity 133 Spleen Morphogenesis 134 Genetic and Transcriptional Control of Spleen Mesenchymal Cell Specification 136 Hematopoietic-Cell Colonization and the Establishment of Lymphoid Compartments 138 Spleen Stromal Cells and the Origin of Stromal Diversity 139 From Spleen Development to the Generation of Artificial Lymphoid Tissues 141 Concluding Remarks 142 References 142 Chapter 6: Controlling Lymphoid Development 146 Introduction 146 Secondary Lymphoid Organs (SLO) 146 Tertiary Lymphoid Organs (TLO) 148 Role of Fα in Lymphoid Organogenesis 152 Conclusions 155 References 157 Chapter 7: Synthesis of Functional Tertiary Lymphoid Organs 162 Introduction 163 Roles of Lymphoid Tissue Inducer (LTi) Cells and Organizer (LTo) Cells in Development of SLO and TLO 164 Mesenchymal Stromal (LTo) Cells in SLO and TLO 165 Regulatory Role of LTo in Immune Responses 166 Contribution of Chemokines in Generation of TLO 167 Other Factors and Cells Required for Maintaining a Microenvironment for Lymphoid Tissue Organization 168 Scaffolds for Generation of Artificial Lymphoid Tissues 169 Generation of Tissue-Engineered Spleen and Mucosal Lymphoid Tissues 170 Generation of Artificial Lymph Node Tissues (aLN) in Mouse by Using Stromal Cells 170 Generation of Artificial Tertiary Lymphoid Tissues (TLOs) Without Using Stromal Cells (Figs.7.1, 7.2, and 7.3) 171 Attempts to Generate Human Peripheral Lymphoid Tissues 174 Conclusion 175 References 175 Chapter 8: Growing a Surrogate Organ in Lymph Node 181 Growing a Surrogate Liver in a Lymph Node 182 Problems Facing Patients with Liver Disease 182 Intraperitoneal Injection of Hepatocytes Rescues a Mouse Model of Lethal Liver Disease 183 Targeting the Lymph Node for Transplantation 184 Conclusion 185 Growing a Surrogate Thymus in a Lymph Node 185 Therapeutic Advantages of Growing a Surrogate Thymus 185 Remodeling a Thymus in a Lymph Node 185 Rebuilding a Thymus in a Nude Mouse 186 Synopsis 187 References 189 Chapter 9: Engineering of Artificial Lymph Node 191 Overview of Current Situation of Tissue Engineering and Biofabrication 192 Research Related to Tissue Engineering 192 Biofabrication: Tissue Engineering Through Development and Use of Machine Technology 193 Currently Available 3D Printers for AM 195 Background of Synthetic Immunology 199 Research of Immune System 199 Synthetic Immunology 199 Artificial LNs 200 Artificial LNs Development as a Major Target of Synthetic Immunology 200 Previous Research of Artificial LNs 200 Synthesized Chemokines 202 Biofabrication of Artificial LNs 203 Strategy for Development of Synthetic LNs (Fig.9.10) 203 Designing Artificial LNs Based on Immunological Background 204 Artificial LNs with and Without Cells 204 Artificial LNs with Chemokines 204 Biofabrication Using Inkjet 3D Bioprinter 205 Biofabrication by Extrusion Using Micro-Manufactured Spinneret Nozzles 206 Application of Spinneret Nozzle 206 Experimental Design Using Micro-Fabricated Spinneret Nozzles 207 Results of Experiments With Sea-Island Nozzle 208 Conclusion and Future Perspectives for Engineering of Artificial LNs 208 References 209 Annotation This book reviews the emerging studies of synthetic immunology, including the development and regeneration of immune cells, immune organ development and artificial regeneration, and the synthetic approach towards understanding human immune system. Immunology has developed rapidly over the last 50 years through the incorporation of new methods and concepts in cell and molecular biology, genetics, genomics and proteomics. This progress is the result of works by many excellent researchers all over the world. Currently, immunological research has accumulated detailed knowledge on basic mechanisms of immunity and is in the process to change medical practices. Yet, due to the enormous complexity of the immune system, many aspects on the regulation and function of this system remain unknown. Synthetic biology uses gain-of-function rather than loss-of-function approaches. The goals of synthetic biology can be described in a simple phrase rebuild, alter, and understand, namely, to rebuild minimal functional systems using well-defined parts from nature and then to perturb the system to understand its working principles. Given the richness of accumulated knowledge in molecular and cellular mechanisms of the immune system, we now begin adapting the concepts of synthetic biology to immunology. An immune response is a spatiotemporal phenomenon occurring at a given time and at a specialized place in the body. One goal of synthetic immunology is to reconstruct artificial microenvironments for better understanding of an immune response. We hope this yet-to-be-experimental approach of synthetic immunology and the compilation of this book will aid our further understanding of the immune system and future devising the tools to manipulate the immune system for therapy and prevention of the diseases." This book reviews the emerging studies of synthetic immunology, including the development and regeneration of immune cells, immune organ development and artificial regeneration, and the synthetic approach towards understanding human immune system. Immunology has developed rapidly over the last 50 years through the incorporation of new methods and concepts in cell and molecular biology, genetics, genomics and proteomics. This progress is the result of works by many excellent researchers all over the world. Currently, immunological research has accumulated detailed knowledge on basic mechanisms of immunity and is in the process to change medical practices. Yet, due to the enormous complexity of the immune system, many aspects on the regulation and function of this system remain unknown. Synthetic biology uses gain-of-function rather than loss-of-function approaches. The goals of synthetic biology can be described in a simple phrase 2rebuild, alter, and understand," namely, to rebuild minimal functional systems using well-defined parts from nature and then to perturb the system to understand its working principles. Given the richness of accumulated knowledge in molecular and cellular mechanisms of the immune system, we now begin adapting the concepts of synthetic biology to immunology. An immune response is a spatiotemporal phenomenon occurring at a given time and at a specialized place in the body. One goal of synthetic immunology is to reconstruct artificial microenvironments for better understanding of an immune response. We hope this yet-to-be-experimental approach of synthetic immunology and the compilation of this book will aid our further understanding of the immune system and future devising the tools to manipulate the immune system for therapy and prevention of the diseases Front Matter....Pages i-xi Development and Regeneration of Hematopoietic Stem Cells....Pages 1-30 Generation and Regeneration of T Cells....Pages 31-56 Strategies for Thymic Regeneration: Recent Advances Towards Clinical Therapy....Pages 57-94 Artificial Thymus: Recreating Microenvironmental Cues to Direct T Cell Differentiation and Thymic Regeneration....Pages 95-120 Spleen Development and the Origin of Stromal Diversity....Pages 121-133 Controlling Lymphoid Development....Pages 135-150 Synthesis of Functional Tertiary Lymphoid Organs....Pages 151-169 Growing a Surrogate Organ in Lymph Node....Pages 171-180 Engineering of Artificial Lymph Node....Pages 181-200