This book has the objective to provide a reference text for toxicologists, materials scientists, and regulators by covering the key issues that define interaction of nanomaterials with the immune system. Altering immune responses can lead to many kinds of pathologies; therefore, it is important to make adequate assessments before new nanomaterials are introduced in the market. On the other hand, negative perception and excessive concerns, based on incomplete or misleading results, need to be avoided by communicating existing knowledge and by defining in the future clear endpoints and thresholds for immunosafety regulations.
Nanotoxicology investigations often focus on toxicity leading to death of cells or organisms, while important immune parameters can be affected much earlier and at much lower doses. Some aspects of immunity, for example allergic sensitivity and heightened danger for risk persons with a frail immune system, are usually not covered at all. This gap in nanosafety assessment needs to be filled, not only from a scientific point of view but also for a better implementation of relevant safety regulations. A friend and nanotoxicologist, Jan Mats, told us once: “if we do not consider immunity, we keep studying the mouse without seeing the elephant in the room.” To increase the awareness of the importance of immunity in nanotoxicology, several years ago we started the Immunosafety Focus Group within the Working Group “Hazard” of the EU-supported NanoSafety Cluster, and this book intends to disseminate knowledge gained by the research community in this field.
The book covers several issues that all stakeholders in nanotechnology should be a ware of: identification of endpoints that are relevant for assessing hazard, evaluating impact on immunologically frail populations, considering allergic responses, and how to evaluate chronic/cumulative effects. In addition, the book addresses a very important issue, that is how to shape and turn the immunomodulating properties of nanomaterials to our advantage for preventive strategies (such as vaccination) or for therapeutic approaches in diseases where immunostimulation is desired(infections, tumors) or where immunosuppression in needed (inflammatory diseases, allergies, autoimmunity).
Our goal is to raise awareness about the effects of nanomaterials on our immune system, in order to ensure a safe design or safe use of such materials. We also want to emphasize an especially useful role of the immune system：it has been optimized by evolution to identify whether or not specific foreign materials are dangerous to the body. Finding that out is also the key question in nanosafety, so knowing the opinion of the professional immune cells should be of particular interest to us.

Preface ix

Acknowledgments xi

Contributors xiii

Chapter 1 How Innate and Adaptive Immunity Work 1

1.1 The Immune System: Protecting the Body from Damage 1

1.2 Innate Immunity 2

1.3 Adaptive Immunity 5

1.4 Nanoparticles and the Immune System 6

Reference 7

Chapter 2 Nanoparticles and Innate Immunity 9

2.1 The Innate Immune System 9

2.2 The Innate Immune Cells 10

2.3 Sensing of Nanoparticles by Innate Immune Cells 11

2.4 Interaction of Nanoparticles with Innate Immune Cells 17

2.5 Interaction with Innate Immune Factors 19

2.6 Innate Immune Reaction to Nanoparticles: Healing Versus Chronic Inflammation 26

References 29

Chapter 3 Nanoparticles and Adaptive Immunity 33

3.1 Adaptive Immunity—Differences and Cooperation with Innate Immunity 33

3.2 DeNovo Induction of Adaptive Immunity: MHC Complexes and Dendritic Cells 37

3.3 T Cell Subtypes 39

3.4 Regulating Adaptive Immunity: Regulatory T Cells and Anergy Versus Inflammatory T Cells 41

3.5 B Cells and Antibodies 46

3.6 Toxicity at the Level of Specific Immune Cell Types: Does it Exist? 48

References 49

Chapter 4 Nanoparticles and Allergy 55

4.1 Allergy: A Special Case of Immune Reaction 55

4.2 Nanoparticles in the Sensitization Phase of Allergy 58

4.3 Nanoparticles and the Response Against Allergens 61

4.4 Sensitizers, Contact Allergy, Delayed-Type Allergy 63

4.5 Therapeutic Perspectives 65

References 65

Chapter 5 Nanoparticles and Immunological Frailty 69

5.1 When Does Immunological Frailty Occur? 69

5.2 Disease 71

5.3 Aging 72

5.4 Interaction of Nanoparticles with Frail Immune Systems 73

References 74

Chapter6 Nanoparticlesin Medicine: Nanoparticle Engineering for Macrophage Targeting and Nanoparticles that Avoid Macrophage Recognition 77

6.1 Introduction 77

6.2 Macrophage Distribution, Activation, and Heterogeneity 80

6.3 Macrophage Recognition of Nanoparticles 84

6.4 Macrophage Avoidance of Nanoparticles 85

6.5 Other Challenges 86

References 87

Chapter 7 The Invertebrate Immune System as a Model for Investigating the Environmental Impact of Nanoparticles 91

7.1 Brief Overview of Invertebrate Immunity 91

7.2 Invertebrate Immunity as a Target for Environmental Nanoparticles 97

7.3BivalveMolluscsasan Invertebrate Model for Investigating the Effects of Nanoparticles on InnateImmunity in Aquatic Environments 98

7.4 Earthworms as a Model for Investigating the Effects of Nanoparticles on Innate Immunity on Terrestrial Invertebrates 102

7.5 Conclusions 107

References 108

Chapter 8 Summary and Outlook 113

8.1 The Role of Immunity in Nanosafety 113

8.2 Challenges for the Further Development of the Field 115

8.3 Understanding Molecular Mechanisms 117

8.4 Applying Nanotechnology in Immunology 119

References 120

Glossary 123

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