Molecular Immunotoxicology E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 724

Veröffentlichungsjahr: 2014

Beschreibung

The human immune system is constantly exposed to chemical contaminants, whether from food, water or air. Some chemicals directly elicit an immune response, while others indirectly activate or deactivate components within the immune system. Thus when tracking or predicting the effect of a chemical on the immune system, many different pathways and modes of action need to be considered.
Following an introduction to the various pathways and toxicity mechanisms from a systemic perspective, the main part of this comprehensive reference surveys individual molecular mechanisms of important immunotoxicants, from PAHs to biopharmaceuticals, and from receptor-mediated toxicity to nanoparticle toxicity, using analyses based on molecular effects rather than on animal models.
Taken together, the knowledge presented here provides an up-to-date overview of this hot topic that can be directly applied to the prediction and characterization of immunotoxic effects in drugs, chemicals, and environmental contaminants.

Leseprobe

Table of Contents

Cover

Related Titles

Title Page

Copyright

Preface

List of Contributors

Chapter 1: The Evolution of Immunotoxicology

1.1 Introduction

1.2 Immune-Mediated Environmental Lung Diseases

1.3 Immunotoxic Drug Reactions

1.4 Autoimmunity

1.5 Immunosuppression

1.6 Allergic Contact Dermatitis (ACD)

1.7 Summary

References

Chapter 2: Overview on the Mechanisms Underlying Chemical-Induced Immunotoxicity

2.1 Introduction

2.2 Mechanisms of Immunotoxicity

2.3 Conclusions

References

Chapter 3: Use of Toxicogenomics in Immunotoxicology

3.1 Introduction

3.2 Toxicogenomics

3.3 Bioinformatics and Data Analysis

3.4 Multiple Omic Approaches in the Evaluation of Immunosuppressive Compounds

3.5 Summary and Conclusions

References

Chapter 4: Breakdown of the Molecular Processes Driving the Adverse Outcome Pathways (AOPs) of Skin and Respiratory Sensitization Induction in Humans Exposed to Xenobiotics and Proteins

4.1 Introduction

4.2 The AOP for Skin Sensitization

4.3 The Molecular Processes in the MOA for Sensitization Induction

4.4 Summary

References

Chapter 5: Chemical Allergen-Induced Skin Cell Activation

5.1 Introduction

5.2 Breaching the Barriers

5.3 Role of the Extracellular Matrix in Skin Inflammation

5.4 Cytoprotective Responses and Skin Inflammation

5.5 Skin Dendritic Cells – Tolerance versus Immunity

5.6 DC Activation and Migration

5.7 The Role of Danger Signals

5.8 Inappropriate/Compromised DC Activation

5.9 T-Cell Activation and Immune Regulation

5.10 Allergic Contact Dermatitis as a (Sterile) “Infection” – Implications

Abbreviations

References

Chapter 6: The Aryl Hydrocarbon Receptor (AhR) as a Mediator of Adverse Immune Reactions

6.1 Introduction

6.2 The Arylhydrocarbon Receptor – a Sensor of Chemicals and a Link to Our Chemical Environment

6.3 Immunotoxicity of TCDD, the Paradigm Ligand of AhR

6.4 AhR-Deficient Animal Models to Study AhR Function in the Immune System

6.5 Concluding Remarks

Acknowledgments

Abbreviations

References

Chapter 7: Immunotoxicological Effects of Pharmaceuticals on Signal Transduction in Innate and Adaptive Immunity

7.1 Introduction

7.2 Drug Affecting Signal Transduction in Innate Immunity

7.3 Drug Affecting Signal Transduction in Adaptive Immunity

References

Chapter 8: Promises and Challenges with Immunomodulatory Biologics

8.1 Introduction

8.2 Adaptive Immunity in the Control of Tumors

8.3 Recent Developments in Oncology Immunotherapy – Case Examples

8.4 Conclusions

References

Chapter 9: The Nonclinical Evaluation of Biotechnology-Derived Pharmaceuticals, Moving on after the TeGenero Case

9.1 The TeGenero (TGN1412) Case

9.2 The EU CHMP Risk Mitigation Document

9.3 MABEL versus NOAEL Approach

9.4 Predictivity of Antibody Properties, Pharmacodynamics, Pharmacokinetics, and Toxicology

9.5 New Developments in Biological Testing:

In Vitro

Approaches?

9.6 Cytokine Release Assays

9.7 Conclusions

References

Chapter 10: Glucocorticoid-Induced Immunomodulation

10.1 Introduction

10.2 Mechanism of Action

10.3 GC Resistance

10.4 GC Effects on the Immune System

10.5 GC, Inflammation, and Immunosuppression

10.6 GC and Autoimmunity

10.7 Conclusions and Perspectives

References

Chapter 11: Particulate Matter-Induced Immune Activation

11.1 Background and Introduction

11.2 The Human Evidence

11.3 Do Physical or Chemical Particle Components Mediate Immune Stimulation?

11.4 Particle Adjuvant Effect – the Primary and Secondary Response

11.5 Particle Properties and Adjuvant Effect – Size is a Critical Factor

11.6 Interactions of Particles with the Immune System

11.7 Genetic Factors

11.8 Mechanisms of Particle Adjuvanticity

11.9 Oxidative Stress

11.10 Summary and Conclusions

References

Chapter 12: Genotoxic Mechanisms of PAH-Induced Immunotoxicity

12.1 Introduction

12.2 General Chemical Structure of PAHs

12.3 Aryl Hydrocarbon Receptor (AhR)-Mediated Immunotoxicity Pathways

12.4 PAH-Induced Immunotoxicity via AhR-Independent Pathway

12.5 Microsomal Epoxide Hydrolase (mEH)

12.6 Genotoxic Pathways

12.7 PAH-Induced Apoptosis Pathways in T Cells, B Cells, and Macrophages

References

Chapter 13: Immunotoxic Effects of Perfluoroalkylated Compounds: Mechanisms of Action

13.1 Introduction

13.2 Immune Effects of PFOA and PFOS in Animal Models

13.3 Immune Effects of PFOA and PFOS in Humans

13.4 Mechanisms of Action

13.5 Conclusions

References

Chapter 14: Pesticide-Induced Immunotoxicity: Molecular Targets

14.1 Introduction

14.2 Summary

References

Chapter 15: Mode of Action of Organotins in Immune Cells

15.1 Introduction to Tributyltin Compounds

15.2 Findings on Immunotoxicity of TBTs Based on Animal Studies

15.3 Differential Effects of TBTs on Prenatal, Postnatal, or Adult Rats

15.4 Lactational Transfer of TBT

15.5 Effects of Organotin Compounds on the Immune Function of Aquatic Organisms

15.6 Modes of Action of TBTO as Assessed by Cytological and Biochemical Assays

15.7 Toxicogenomics Studies on the Modes of Action of TBTs

15.8 Summary

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Chapter 1: The Evolution of Immunotoxicology

List of Illustrations

Figure 2.1

Figure 2.2

Figure 3.1

Figure 3.2

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Figure 4.6

Figure 4.7

Figure 5.1

Figure 6.1

Figure 6.2

Figure 7.1

Figure 7.2

Figure 7.3

Figure 7.4

Figure 7.5

Figure 7.6

Figure 7.7

Figure 8.1

Figure 8.2

Figure 8.3

Figure 8.4

Figure 8.5

Figure 8.6

Figure 9.1

Figure 9.2

Figure 9.3

Figure 10.1

Figure 11.1

Figure 11.2

Figure 12.1

Figure 12.2

Figure 12.3

Figure 12.4

Figure 12.5

Figure 14.1

Figure 14.3

Figure 14.2

Figure 14.4

Figure 15.1

Figure 15.2

List of Tables

Table 3.1

Table 3.2

Table 4.1

Table 4.2

Table 6.1

Table 6.2

Table 6.3

Table 6.4

Table 7.1

Table 12.1

Table 13.1

Table 13.2

Table 13.3

Table 14.1

Table 14.2

Table 14.3

Related Titles

Matthiessen, P. (ed.)

Endocrine Disrupters

Hazard Testing andAssessment Methods

2013

Print ISBN: 978-0-470-93209-4

Pohjanvirta, R. (ed.)

The AH Receptor in Biology and Toxicology

2012

Print ISBN: 978-0-470-60182-2

Anzenbacher, P., Zanger, U.M. (eds.)

Metabolism of Drugs and Other Xenobiotics

2012

Print ISBN: 978-3-527-32903-8

Casciano, D.A., Sahu, S.C. (eds.)

Handbook of Systems Toxicology

2 Volume Set

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Print ISBN: 978-0-470-68401-6

Edited by Emanuela Corsini and Henk van Loveren

Molecular Immunotoxicology

The Editors

Prof. Emanuela Corsini

University of Milan

School of Pharmacy

Via Balzaretti 9

20133 Milan

Italy

Prof. Henk van Loveren

Maastricht University

Dept. of Toxicogenomics

6200 MD Maastricht

Netherlands

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

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Print ISBN: 978-3-527-33519-0

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Preface

In the era of Tox21 a book on molecular immunotoxicology is timely.

Immunotoxicity can result from exposure to a wide variety of unrelated chemicals. Traditionally, immunotoxicology studies are performed in experimental models, which utilize a tiered approach that includes standard toxicity testing, characterization of specific immune cell populations, and evaluation of functional parameters and host resistance, which is not typically as well understood as are the mechanisms of action. Driven by the Seventh Amendment to the EU Cosmetic Directive, the EU policy on chemicals (the REACH system), the update of the European legislation on the protection of animals used in research, and emerging visions and strategies for predicting toxicity (i.e., Tox21, Toxcast, etc.), in vitro methods are likely to play a major role in the near future. Combined with new technologies, such as toxicogenomics, in vitro methods will offer the opportunity for a better understanding of chemical-induced immunotoxicity.

For the vast majority, these compounds directly interact with immunocompetent cells, interfering with signal transduction and resulting in alteration in the status and/or functionality of the immune system. Overall, it is the understanding of the mechanisms by which xenobiotics alter adaptive and natural immune responses that might shed light on the etiology of environmental and occupational immune diseases. There are examples of immunotoxic compounds interfering with all basic signal transduction pathways.

This book aims to facilitate a better hazard identification and a mechanistically based risk assessment of immunotoxicity. As examples, the effects of well-characterized immunotoxic compounds, including dioxins, drugs, pesticides, and particulate matters, are presented. The characterization of specific interference with cell signaling induced by immunotoxicants leads to a better understanding of their molecular mechanism of action. With the identification of the mechanism of immunotoxic action a more reliable species-to-species extrapolation is possible, which will result in better risk assessment for human beings.

Prof. Emanuela Corsini

University of Milan, Italy

Prof. Henk van Loveren

Maastricht University, The Netherlands

List of Contributors

John B. Barnett

West Virginia University

Department of Microbiology

Immunology, and Cell Biology

School of Medicine

One Medical Center Drive

Morgantown, WV 26506

USA

Scott W. Burchiel

The University of New Mexico

Department of Pharmaceutical Sciences

College of Pharmacy

Marble Street

Albuquerque, NM 87131-001

USA

Emanuela Corsini

Università degli Studi di Milano

Laboratory of Toxicology, DiSFeB

School of Pharmacy

Via Balzaretti 9

Milan 20133

Italy

Jamie C. DeWitt

East Carolina University

Department of Pharmacology and Toxicology

Moye Boulevard

Greenville, NC 27834

USA

Charlotte Esser

Leibniz-Institute for Environmental Medical Research

Molecular Immunology

Auf'm Hennekamp 50

Düsseldorf

Germany

Philipp R. Esser

University of Medical Center Freiburg

Department of Dermatology and Venereology

Allergy Research Group

Hauptstrasse 7

D-79104 Freiburg

Germany

Rachel Frawley

National Institute of Environmental Health Sciences

National Toxicology Program

Morrisville

NC 27560

USA

Jun Gao

TA43, Bldg01

Bioscience Division

Los Alamos National Laboratory

Los Alamos NM

NM

USA

Dori Germolec

National Institute of Environmental Health Sciences

National Toxicology Program

Morrisville

NC 27560

NC

USA

Peter J.M. Hendriksen

RIKILT-Institute of Food Safety

Wageningen University and Research Centre

Akkermaalsbos 2

AE Wageningen

The Netherlands

Carla Herberts

Medicines Evaluation Board

Section on Pharmacology

Toxicology

and Biotechnology

P.O Box 8275

RG Utrecht

The Netherlands

David Jones

Medicines and Healthcare Products Regulatory Agency (MHRA)

Licensing Division

Buckingham Palace Road

SW1W 9SZ

London

UK

Deborah E. Keil

Montata State University

Department of Microbiology

P.O Box 173520

Bozeman

MT 59717

USA

Jan Willem van der Laan

Medicines Evaluation Board

Section on Pharmacology

Toxicology

and Biotechnology

P.O Box 8275

RG Utrecht

The Netherlands

Henk van Loveren

Maastricht University

Department of Toxicogenomics

MD Maastricht

The Netherlands

and

National Institute of Public Health and the Environment

Laboratory for Health Protection Research

Bilthoven

Utrecht

The Netherlands

Martinus Lovik

Norwegian University of Science and Technology (NTNU)

Faculty of Medicine

Institute of Cancer Research and Molecular Medicine

P.O Box 8905

N-7491 Trondheim

Norway

Michael I. Luster

West Virginia University

School of Public Health

Quail Road

Morgantown, WV 26508

USA

Stefan F. Martin

University of Medical Center Freiburg

Department of Dermatology and Venereology

Allergy Research Group

Hauptstrasse 7

D-79104 Freiburg

Germany

Graziella Migliorati

Perugia University

Department of Medicine

Section of Pharmacology

P.le Severi

Perugia 06100

Italy

Kazuichi Nakamura

Shionogi & Co., Ltd.

Global Regulatory Affairs Department

2-17-5 Shibuya

Shibuya-ku

Tokyo 150-8673

Japan

Margie M. Peden-Adams

Montata State University

Department of Microbiology

P.O Box 173520

Bozeman

MT 59717

USA

Ad A. Peijnenburg

RIKILT-Institute of Food Safety

Wageningen University and Research Centre

Akkermaalsbos 2

AE Wageningen

The Netherlands

Rafael A. Ponce

Amgen Inc.

Amgen Court West

Seattle, WA 98119

USA

Carlo Riccardi

Perugia University

Department of Medicine

Section of Pharmacology

P.le Severi

Perugia 06100

Italy

Erwin L. Roggen

3Rs Management and Consulting ApS

Asavaenget 14

Lyngby

Denmark

and

Novozymes AS

Department of Toxicology and Product Safety

Krogshoejvej 36

Bagsvaerd

Denmark

Simona Ronchetti

Perugia University

Department of Medicine

Section of Pharmacology

P.le Severi

Perugia 06100

Italy

Peter C.J. Schmeits

RIKILT-Institute of Food Safety

Wageningen University and Research Centre

Akkermaalsbos 2

AE Wageningen

The Netherlands

Jia Shao

RIKILT-Institute of Food Safety

Wageningen University and Research Centre

Akkermaalsbos 2

AE Wageningen

The Netherlands

Richard Stebbings

National Institute for Biological Standards and Control

Biotherapeutics Group

Blanche Lane

Potters Bar

Hertfordshire EN6 3QG

UK

Robin Thorpe

National Institute for Biological Standards and Control

Biotherapeutics Group

Blanche Lane

Potters Bar

Hertfordshire EN6 3QG

UK

Susan J. Thorpe

National Institute for Biological Standards and Control

Biotherapeutics Group

Blanche Lane

Potters Bar

Hertfordshire EN6 3QG

UK

and

Tsuguto Toda

Shionogi & Co., Ltd.

Development Research Laboratories

3-1-1 Futaba-cho

Toyonaka

Osaka 561-0825

Japan

1The Evolution of Immunotoxicology*

Michael I. Luster

1.1 Introduction

The origins of immunotoxicology surprisingly date back to the seventeenth century when Bernardino Ramazzini, an Italian medical professor, described lung disease associated with various occupations including baking, grain handling, and mining [1]. It was not until the early 1900s, however, that the immune system was implicated and the causative agents first identified. Since then various pharmaceutical, occupational, and environmental agents have been shown to potentially influence many facets of immune-mediated diseases including allergy, immunosuppression, autoimmunity, and chronic inflammation. The following is a brief historical perspective of what we now refer to as immunotoxicology.

1.2 Immune-Mediated Environmental Lung Diseases

The most studied environmentally induced lung disease is occupational asthma, which was first described by Henry Slater in 1866 as “hyperresponsiveness provoked by exposure to chemical and mechanical irritants, as well as to particular atmospheres” [2]. It was Ehrlich, however, who described the presence of eosinophils in the sputum of workers, which is now considered a hallmark of immune-mediated asthma (reviewed by Hirsch et al. [3]). In the mid-twentieth century, it was shown that occupational asthma can be caused by two distinct groups of agents. The first group consists of proteins such as alanase, an enzyme found in soap detergent, latex, and flour, the cause of baker's asthma [4]. The second group represents small molecular weight, highly reactive chemicals that behave as haptens, such as various anhydrides and isocyanates [5]. Our understanding of how allergic responses can occur from low molecular weight chemicals originated from the pioneering studies of Landsteiner and Jacobs [6] who showed that when these chemicals covalently bind to host proteins they become antigenic (i.e., act as haptens). Late in the twentieth century, based initially on epidemiological observations of increasing asthma rates in industrialized cities and shortly after on experimental animal studies, it was shown that many common air pollutants do not cause allergic asthma but can exacerbate existing asthma by acting as adjuvants [7]. This seminal finding was followed by epidemiological studies suggesting that co-exposure to bacterial endotoxins early in life leads to a reduced likelihood of developing asthma, often referred to as the hygiene hypothesis [8] and suggested that early stimulus of the immune system is important for its normal maturation.

Immune-mediated environmental lung diseases also exist that are not Type 1 (IgE) reactions. For example, chronic beryllium disease (CBD), first described by Sterner and Eisenbud in 1951 [9], is a granulomatous lung disease representing a Type 4 immune reaction. CBD occurs most often in beryllium workers who possess the HLA DPB1 genotype with glutamic acid at amino acid position 69 [10]. This was an important observation as genetic testing is now often conducted in workers in industries that use beryllium to help identify those individuals that may be at high risk of developing the disease. Hypersensitivity pneumonitis, caused by microbes, animal and plant proteins, and low molecular weight chemicals, leads to Type 3 and 4 immune reactions involving immune complexes and complement. First identified in the 1930s [11], it produces noncaseating lung granulomas and is the cause of pigeon breeder's lung, among others.