Molecular Immunotoxicology

354 Pages·2014·4.952 MB·English

by  Emanuela Corsini, Henk Van Loveren

Editedby
EmanuelaCorsiniand
HenkVanLoveren
MolecularImmunotoxicology
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EditedbyEmanuelaCorsiniandHenkVanLoveren
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V
Contents
Preface XIII
ListofContributors XV
1 TheEvolutionofImmunotoxicology 1
MichaelI.Luster
1.1 Introduction 1
1.2 Immune-MediatedEnvironmentalLungDiseases 1
1.3 ImmunotoxicDrugReactions 3
1.4 Autoimmunity 3
1.5 Immunosuppression 4
1.6 AllergicContactDermatitis(ACD) 6
1.7 Summary 7
References 7
2 OverviewontheMechanismsUnderlyingChemical-Induced
Immunotoxicity 11
EmanuelaCorsini
2.1 Introduction 11
2.2 MechanismsofImmunotoxicity 13
2.2.1 InterferencewithCellularSignaling 14
2.2.1.1 Receptor-MediatedImmunotoxicity 14
2.2.1.2 Non-receptor-MediatedImmunotoxicity 20
2.2.2 AdductsFormationandRoleofROS 21
2.3 Conclusions 22
References 22
3 UseofToxicogenomicsinImmunotoxicology 27
RachelFrawley,DoriGermolec,andHenkvanLoveren
3.1 Introduction 27
3.2 Toxicogenomics 28
3.2.1 ProfilingGeneExpression 30
3.2.2 PathwayArrays 35
3.2.3 ComparativeEvaluationofImmunotoxicants 36
VI Contents
3.2.4 miRNAandsiRNA,GeneExpressionRegulators 39
3.2.5 mRNASplicing 41
3.2.6 RNA-Seq 41
3.2.7 Proteomics 42
3.2.8 MolecularGenomics 43
3.2.9 PhenotypicAnchoring,DoseResponse,TimeCourse 45
3.3 BioinformaticsandDataAnalysis 46
3.3.1 EffectMarkersandMachineLearning 47
3.4 MultipleOmicApproachesintheEvaluationofImmunosuppressive
Compounds 48
3.4.1 MultipleOmicApproachesintheStudyofHypersensitivity 52
3.5 SummaryandConclusions 54
References 56
4 BreakdownoftheMolecularProcessesDrivingtheAdverseOutcome
Pathways(AOPs)ofSkinandRespiratorySensitizationInductionin
HumansExposedtoXenobioticsandProteins 67
ErwinL.Roggen
4.1 Introduction 67
4.2 TheAOPforSkinSensitization 68
4.3 TheMolecularProcessesintheMOAforSensitization
Induction 68
4.3.1 Bioavailability:theCompoundAcquiresAccessto
theSystem 68
4.3.2 Haptenation:theChemicalReactsCovalentlywitha
“CarrierProtein” 69
4.3.3 Inflammation:InnateRecognitionofHaptensFollowedbyActivation
ofInnateImmunity 70
4.3.3.1 HaptensEngageToll-LikeReceptors(TLR)2and4 71
4.3.3.2 ReactiveOxygenSpecies(ROS)andOxidativeStressPlayaRolein
ChemicalAllergen-InducedSkinCellActivation 73
4.3.3.3 EpithelialROSProductionResultsinDegradationofEndogenous
HA,andTLR2andTLR4Activation 75
4.3.3.4 ROSSignaltheNLRP3InflammosomeResultinginIL-1β,IL-18,and
IL-33Activation 75
4.3.4 DendriticCellActivation:fromInnateResponsestoDC
Maturation 77
4.3.5 DendriticCellMigration:TranslatingtheMessageintoSpecific
Actions 80
4.3.6 T-CellPrimingandProliferation:theTurning-Pointbetween
SensitizationandEffect 82
4.4 Summary 83
References 84
Contents VII
5 ChemicalAllergen-InducedSkinCellActivation 91
StefanF.MartinandPhilippR.Esser
5.1 Introduction 91
5.2 BreachingtheBarriers 92
5.3 RoleoftheExtracellularMatrixinSkinInflammation 94
5.4 CytoprotectiveResponsesandSkinInflammation 95
5.5 SkinDendriticCells–ToleranceversusImmunity 97
5.6 DCActivationandMigration 98
5.7 TheRoleofDangerSignals 100
5.8 Inappropriate/CompromisedDCActivation 102
5.9 T-CellActivationandImmuneRegulation 102
5.10 AllergicContactDermatitisasa(Sterile)
“Infection”–Implications 103
Abbreviations 104
References 105
6 TheArylHydrocarbonReceptor(AhR)asaMediatorofAdverse
ImmuneReactions 117
CharlotteEsser
6.1 Introduction 117
6.1.1 RecognitionandResponse–theBasicFeaturesoftheImmune
System 117
6.1.2 TheConceptof“AdverseReaction”inImmunotoxicology 118
6.1.2.1 ChemicalsCausingHaptenation,Neo-antigens,andCryptic
Antigens 118
6.1.2.2 Chemical-InducedImmunosuppression 120
6.1.2.3 ImmunosuppressiveChemicalsandMetals 120
6.2 TheArylhydrocarbonReceptor–aSensorofChemicalsandaLink
toOurChemicalEnvironment 122
6.2.1 BiochemistryofAhRSignaling 122
6.2.2 TheRealmofAhRLigands 124
6.2.3 AhR-MediatedGeneExpressionisCellSpecific 124
6.3 ImmunotoxicityofTCDD,theParadigmLigandofAhR 126
6.3.1 GenerationofDioxinsintheEnvironment 126
6.3.2 ImmunotoxicityofTCDD 127
6.3.2.1 AnimalStudies 127
6.3.2.2 HumanExposureData 127
6.3.2.3 HumanImmunotoxicEffects–EpidemiologyandInVitro
Studies 129
6.4 AhR-DeficientAnimalModelstoStudyAhRFunctioninthe
ImmuneSystem 129
6.4.1 InfectionModels 130
6.4.2 AdaptiveImmunity:RegulatoryTCells(Treg)andTh17 131
6.4.3 DendriticCells(DCs) 131
6.4.4 BarrierImmunity–γδTCellsandILC3 132
VIII Contents
6.4.5 OtherImmuneCells–Macrophages,Neutrophils,andMore 133
6.5 ConcludingRemarks 134
Acknowledgments 134
Abbreviations 134
References 135
7 ImmunotoxicologicalEffectsofPharmaceuticalsonSignal
TransductioninInnateandAdaptiveImmunity 145
TsugutoTodaandKazuichiNakamura
7.1 Introduction 145
7.2 DrugAffectingSignalTransductionin
InnateImmunity 146
7.2.1 TLRSignalingPathways 146
7.2.2 RLRSignalingPathways 149
7.3 DrugaffectingSignalTransductioninAdaptiveImmunity 150
7.3.1 TCRandCostimulatorySignalingPathways 150
7.3.1.1 MechanismofActionofCyclosporinAandTacrolimus 151
7.3.1.2 MechanismofCytokineReleaseSyndrome 152
7.3.1.3 EffectsofTofacitinibonJAK/STATSignalingPathway 153
7.3.2 BCRSignalingPathways 155
References 156
8 PromisesandChallengeswithImmunomodulatoryBiologics 159
RafaelA.Ponce
8.1 Introduction 159
8.1.1 LocalDisease,SystemicTreatment 160
8.1.2 Context 161
8.1.3 TippingPoints 161
8.2 AdaptiveImmunityintheControlofTumors 162
8.2.1 AdaptiveAntitumorImmunity 162
8.2.2 CD8+T-CellEffectorActivityisEstablishedbyProperlyActivated
DCwithCD4+T-CellHelp 165
8.2.3 VariousFactorsRegulateDCActivation 166
8.2.4 RegulationofT-CellActivation 166
8.3 RecentDevelopmentsinOncologyImmunotherapy–Case
Examples 167
8.3.1 CaseStudy1:ImmuneCheckpointBlockade 169
8.3.1.1 NonclinicalSafetyAssessmentofAnti-CTLA-4 172
8.3.2 Bi-specificT-CellEngagement(RedirectedLysis) 173
8.3.3 OncolyticViralTherapy 175
8.4 Conclusions 177
References 179