Immunologic Signatures of Rejection (eBook)

Contents 6
Part I:Preamble 10
From the “Delayed Allergy Reaction” to the “Immunologic Constant of Rejection” 11
From the Delayed Allergy Reaction to the Immunologic Constant of Rejection 11
Interferon Regulatory Factor (IRF)-1: Master Switch of Inflammation 13
The Recurrent Themes Defining the Signatures of Rejection 13
References 14
Part II:The Immune Biology of Rejection:Basic Principles 17
The Yin Yang of Cancer RelatedInflammation 18
Introduction 18
Recruitment of TAM 19
Plasticity of TAM and Promotion of Metastasis 19
Protective Inflammation and Macrophage Activation 20
References 20
The Immune Rejection: Lessonsfrom Experimental Models 24
Introduction 24
Rejection of Intestinal Microbiota 25
Rejection of Acute Infections 26
Chronic Inflammation in Obesity 27
Tumor Rejection 28
Concluding Remarks 30
References 30
Turning on and off the Immunological Switch: Immune Response Polarization and Its Control by IL-10 and STAT3 33
T Helper Cell Lineages 33
Differentiation and Activation of T Helper Lineages 35
Function and Plasticity of Th and Treg Lineages In Vivo 36
IL-10 Controls Inflammation 37
Regulation of IL-10 Production 39
IL-10 Signaling and Role of STAT3 in its Regulatory Functions 40
IL-10 has Superior Anti-Inflammatory Activity Compared with Other STAT3-Signaling Cytokines: Role of SOCS3 42
Molecular Mechanisms of the IL-10-Mediated Anti-Inflammatory Effects 43
Roles of STAT3 in Health and Disease 46
Roles of STAT3 in Cancer 47
STAT3 and IL-10 in Cancer-Promoting Inflammation 48
IL-10 Inhibition Facilitates Immune Responses to Tumors 48
Targeting STAT3 Facilitates Anti-Tumor Immune Responses 50
Conclusions 54
References 54
The Angiogenic Switch: Role of Immune Cells 62
Introduction 62
Innate Immunity 64
Macrophages and the Macrophage Polarization Paradigm 64
Tumor Associated Macrophages (TAMs) 65
Tie2 Expressing Macrophages 66
Myeloid Derived Suppressor Cells (MDSCS) 67
Granulocytes 67
Mast Cells 69
Dendritic Cells 70
DCs and Angiogenesis 70
NK Cells 71
NK Localization 72
Specific Immunity 72
Conclusions 72
References 73
Chemokines and Cytotoxic Effector Molecules in Rejection 81
Chemokines 82
Translation to Clinical Utility 85
Cytotoxic Effector Molecules 88
Conclusion 90
References 91
Clinical Applications of Activated Immune Cells 97
Introduction 97
Immune Therapy for Viral Infections 97
Cytomegalovirus 97
Immune Therapy for Viral Induce Malignancies 98
Posttransplant EBV-Associated Lymphoproliferative Disease 98
Immune Therapy for Leukemia 99
Donor Leukocyte Infusions 99
NK Cells 99
Immune Therapy for Cancer 100
Tumor Infiltrating Leukocytes for Melanoma 100
Dendritic Cells 101
New Directions 104
References 104
Part III:Circulating Patterns Associated with Chronic and Acute Immune Pathology 107
Blood Transcriptional Fingerprints to Assess the Immune Status of Human Subjects 108
Blood Transcript Profiling 108
Profiling Human Subjects in Health and Disease 110
Profiling Autoimmune Diseases 110
Profiling Infectious Diseases 111
Profiling other Diseases 112
Technology Primer (Fig. 1) 113
Microarray Data Analysis 114
Analysis Primer 115
Analysis of Significance Patterns 116
A Modular Analysis Framework 117
Interpretation 118
Conclusions 120
References 120
Innate Signatures of Immune Mediated Resolution and Persistence of Hepatitis C Virus Infections 129
HCV Disease and Therapy 130
Viral Clearance 130
HCV Viral Proteins Modulate the Innate Response 131
Acute HCV Infection and Intrahepatic Induction of ISGs 132
Chronic HCV Infection and Hepatic ISG Expression 134
IL28B (IFNl3) in HCV Viral Clearance and Response to Therapy 136
T Cell Response and Viral Clearance 137
Conclusions 139
References 139
Immune Signatures and Systems Biology of Vaccines 143
Vaccine Development 144
Immune Response 144
Vaccines 144
Innate Immunity and Vaccine Recognition 145
Innate Signaling and Translation to the AdaptiveImmune Response 146
Hitting Innate Immune System by Vaccines 148
TLRs Signaling for a Potent and Prolonged Adaptive Immune Responses 149
Vaccines Inducing Humoral or Cellular Immune Response 149
Platform of System Levels Analyses 151
Systems Biology in Vaccine Studies 151
Role of Transcriptomics 151
Proteomics 153
RNAi and miRNA to Study Innate Immunity 153
Genetic Polymorphisms in Innate Immunity Genes 154
Systems Biology for Prediction of Vaccine Immunogenicity 154
Gene Signatures of Yellow Fever Vaccine YF-17D 154
Gene Signatures of HIV-VLPs Vaccine 156
Polymorphisms and Response to Measle Vaccine 157
Polymorphisms and Response to Rubella Vaccine 158
Polymorphisms and Response to Pertussis Vaccine 159
Conclusions 160
References 161
Immune Signatures Associated with the Cancer Bearing State 170
Background 170
Signatures of Immune Dysfunction in Cancer Patients 171
Increased Apoptosis of Anti-Tumor Effector Cells 171
Impaired Effector Cell Activation and Function 172
Polarizing Immune Balance in Favor of Tumor Progression 173
Signatures of Tumor Rejection in Cancer Patients 175
Applications of Cancer-Associated Immune Signatures in Therapeutics and Diagnostics 178
Therapeutics 178
Prognostic and Predictive Cancer Testing 179
Summary 180
References 180
Part IV:Tissue-Specific Patterns Associated with Chronic Inflammatory Processes 188
HTLV-1 Infected CD4+CD25+CCR4+ T-Cells Disregulate Balance of Inflammation and Tolerance in HTLV-1 Associated Neuroinflammatory Disease 189
Human T-Lymphotropic Virus Type 1 (HTLV-1)and Associated Disorders 189
Immunopathogenesis of HAM/TSP 190
HTLV-1 and Regulatory T-Cells 192
HTLV-1 Infected Foxp3 CD4+CD25+CCR4+ T-Cells Are Proinflammatory and Increased in HAM/TSP Patients 192
Do THAM Cells Include exFoxp3+ Cells? 195
References 196
D/2 Predictors of Favorable Outcome in Cancer 199
Predictors of Favorable Outcome in Colorectal Cancer 200
Predictors of Favorable Outcome in Other Cancers 203
Immunotherapy in Cancer 206
Summary 208
References 208
The Microenvironment of Ovarian Cancer: Lessons on Immune Mediated Tumor Rejection or Tolerance 211
Introduction 211
T Cells in Ovarian Cancer and Their Correlation with Outcome 212
Polyfunctional T Cells Are Present in the OvarianCancer Microenvironment 214
Chemokines Recruiting Antitumor T Cells to the Tumor Microenvironment 217
Regulatory T Cells, Presence and Outcome 218
The Tumor Endothelial Barrier: Another Layer of Immune Regulation 219
Conclusions 223
References 223
Transcriptional Profiling of Melanoma as a Potential Predictive Biomarker for Response to Immunotherapy 229
Analysis of T Cell Responses in the Peripheral Blood with Melanoma Vaccines 230
Interrogation of the Melanoma Tumor Microenvironment 230
Chemokines and an Argument for Control at the Level of T Cell Trafficking into Tumor Site 232
Innate Immune Signals that May Drive “Sterile” Adaptive Immunity to Tumors 232
Immune Suppressive Mechanisms in the Tumor Microenvironment 233
Analysis of the Tumor Microenvironment with Other Immunotherapy Approaches: IL-2 and Anti-CTLA-4 mAb 234
Conclusions and Future Directions 235
References 236
Functional Pathway Analysis for Understanding Immunologic Signature of Rejection: Current Approaches and Outstanding Challenges 239
Introduction 239
Insights from Application of Microarrays in Solid Organ Transplant 241
Need for Functional Pathway Analysis 244
Current Functional Pathway Analysis Approaches and Existing Tools 245
Over-Representation Analysis (ORA) Approaches 245
Functional Class Scoring (FCS) Approaches 247
Pathway Topology (PT)-Based Approaches 249
Outstanding Challenges 251
References 252
Part V:Signatures Associatedwith Acute Rejection 257
Chronic Graft Versus Host Disease: Inflammation at the Crossroads of Allo and Auto Immunity 258
Acute GVHD: Initiation of Inflammation, Recruitment of Effectors and T Lineage Determined Tissue Damage 260
CGVHD: Consequences of Chronic Inflammation in Tissues, Humoral Immunity and Fibrosis 262
Systemic Involvement of IFN in CGVHD 265
CGVHD: Chronic Fibrosis 266
CGVHD as an Autoimmune Disorder of Dysregulated Immunity 268
Conclusion 273
References 274
Immune-Mediated Tumor Rejection 280
The Current Understanding of Immune Surveillance and Its Molecular Basis 281
Strategies to Understand the Mechanism of Tumor Rejection 283
Immunological Signatures from the Tumor Microenvironment 286
Immune Aspects of Chemotherapy 290
Immune Aspects of Viral Oncolytic Therapy 293
Immune-Mediated Tumor Rejection as a Mechanism Shared by Other Pathologies: The Immunologic Constant of Rejection 295
Conclusions 296
References 297
Signatures Associated with Acute Rejection: Allograft Rejection 304
A Brief Historical Perspective 305
Introduction 306
Early Studies in Kidney and Liver Acute Allograft Rejection and the Detection of Recurrent Themes 307
Studies in Heart and Lung Acute Allograft Rejection, and Continuum from Acute to Chronic Rejection 324
Acute Allograft Rejection in Heterogeneous Condition and the Emerging Role of B Cells 326
Other Studies in Kidneys Acute Allograft Rejection, Role of IL-10, and Molecular Analogies Among Cellular and Humoral Rejection 327
Comparative Analyses and Role of STAT-1/IRF-1 and NF-kB 329
Conclusions 334
References 335
Index 345