Chapter
Cytokine Regulation of T Cell Response
T Cell Response to Allograft
T Cell-Targeted Therapies for Transplantation
Tolerance in Transplantation
Memory T Cells in Transplantation
B Cell Biology in Transplantation
B Cells and Antibody Production
Antibody-Mediated Rejection and Treatments
Antigen-Presenting B Cells in Transplant Tolerance
Chapter 3 Historical Remarks of Immunosuppressive Therapy in Organ Transplantation
Azathioprine (1960s – 1980s)
Cyclophosphamide (1960s – 1980s)
Induction Therapies (1960s – Present)
Cyclosporine (1980s – 1990s)
Tacrolimus, Rapamycin and Mycophenolate Mofetil (1990s − 2010s)
Tacrolimus (FK506, Prograf)
Current Mainstay Immunosuppressants
Replacement of CNIs and Application of Biological Agents (2010s – Future)
CNIs Replacement with MMF and Sirolimus
Application of Biological Agents
Chapter 4 Animal Models in Immunosuppression
Rodent Models for Immunosuppression
Organ-Specific Rodent Transplant Models
Rodent Models of Rejection
Common Large Animal Models
Studies of Toxicity: Cyclosporine as Paradigm
Chapter 5 Ethical Issues of Immunosuppressive Drugs Use in Organ Transplantation
Basic Ethical Principles in ISD Treatment
Ethical Requirements in ISD Research
Independent Ethical Review of Research Proposals
Free and Informed Consent
Privacy, Confidentiality and Legal Hazard
Vulnerable Research Participants
Payment to Research Participants
Ethical Issues in Preclinical and Clinical ISD Research
Ethical Issues in Pre-Clinical Research
Ethical Issues in Clinical Trials
Transnational Research of ISD
Ethical Challenges in ISD Use
Ethical Issues in Individualization of ISD
ISD Application during Gestation Period
ISD Application in Children
Ageing and Immunosuppressive Therapy
ISD Application in Immunodeficiency Patients
Long-Term Exposure to ISD
Stem Cells As Immunosuppressive Therapy
Generic Immunosuppressive Drugs (GISD)
ISD Application in Tolerance Transplant
Part II: Therapeutic Agents
Chapter 6 Glucocorticoids
Structures and Metabolism
Regulation of Gene Transcription (Genomic Signaling)
Post-Transcriptional Effects (Nongenomic Regulation)
Humoral Immunity Suppression
Induction of Lymphocyte Apoptosis
Hyperglycemia and Diabetes Mellitus
Cushingoid Appearance and Weight Gain
Dyslipidemia and Hypertension
Cardiovascular Disease (CVD)
Osteoporosis, Osteonecrosis and Fracture
HPA-Axis Suppression (Adrenal Suppression, AS)
Central Nervous System Effects
Immunosuppressive Strategies in Solid Organ Transplantation
GC-Based Immunosuppression Regimens
GC Withdrawal and Avoidance Strategies
Early (Weeks to 6 Months) and Late (after One Year) GC Withdrawal
GC Avoidance (Rapid Steroid Discontinuation or Complete Steroid Avoidance)
Chapter 7 Small Molecules in Solid Organ Transplantation with Cytostatic Antiproliferative Effects
Agents Targeting Purine Biosynthesis
Pharmacokinetics and Pharmacodynamics
Side Effects and Toxicity
Clinical and Experimental Development and Indications
Azathioprine in Renal Transplantation
Azathioprine in Lung Transplantation
Azathioprine in Cardiac Transplantation
Experimental Studies with Azathioprine
Indications and Further Applications
Pharmacokinetics and Pharmacodynamics
Side Effects and Toxicity
Clinical and Experimental Development and Indications
Mycophenolate Mofetil in Renal Transplantation
MMF in Cardiac Transplantation
MMF in Liver Transplantation
Experimental Studies with MMF
Pharmacokinetics and Pharmacodynamics
Side Effects and Toxicity
Clinical and Experimental Development and Indications
Mizoribine in Clinical Studies
Mizoribine in Experimental Studies
Further Applications and Indications
Agents Targeting Pyrimidine Biosynthesis
Leflunomide and Malononitrilamides
Pharmacokinetics and Pharmacodynamics
Clinical Pharmacokinetics
Side Effects and Toxicity
Clinical and Experimental Development and Indications
MNAs in Experimental Studies
Other Small Molecules with Cytostatic, Antiproliferative Effects
Chapter 8 Calcineurin Inhibitors
Structure and Molecular Effects of CNIs
Effect on Calcineurin and NFAT
Effect on the JNK and p38 Pathways
Pharmacokinetics/Pharmacodynamics of CNIs
Pharmacodynamic Monitoring
Current CNIs Therapeutic Strategies
Cytomegalovirus Infection
BK Polyoma Virus Infection
Mycobacterium Tuberculosis Infection
Calcineurin Inhibitor Sparing Strategies
CNI Withdrawal with mTORi
Late CNI Withdrawal with mTORi Immunosuppression
CNI Elimination for Transplant Dysfunction
Chapter 9 Inhibitors of Mammalian Target of Rapamycin
Mechanism of mTOR inhibitors
Immunosuppression Mechanism of mTORi
Impact on Innate Immunity
Impact on Adaptive Immunity
mTOR Inhibitors and Derivatives
Pharmacological Properties of mTOR Inhibitors
Drug interactions between mTOR Inhibitors and Other Agents
mTOR Inhibitors − MMF and Steroids
mTOR Inhibitors and Pharmacogenomic
Clinical Effects of mTOR Inhibitors in Organ Transplantation
Immunosuppressive Efficacy of mTOR Inhibitors
mTOR Inhibitors and Proteinuria
Clinical Strategies and Issues in Organ Transplantation
Short-Term and Long-Term Use of mTOR Inhibitors
Very Low CNIs Exposure in Association with EVL
CNI withdrawal – mTOR inhibitors
Corticosteroid Withdrawal
mTOR Inhibitos and Antiviral Activity
Chapter 10 Immunomodulation Therapy by the Control of Immune Cell Trafficking
Basic Understanding of Major Immune Responses in Organ Transplantation
Cell Trafficking of Effector and Memory T Cells for the Allografts
Control Agents of Cell Trafficking and Adhesion
Characterization of FTY720 As a S1P Agonist
Biological Mode of Action of FTY720
Pharmacological Characteristics of FTY720
Development of S1P-Related Immunomodulators
Potential Therapeutic Options: S1P Agonists for Organ Transplantation
Chapter 11 Protein Kinase C Inhibitors
Immunosuppressive or Graft-Protective PKCIs
Chapter 12 Agents Targeting JAK3 in Organ Transplantation
3. JAK Family of Tyrosine Kinases (JAKs)
4. Signal Transducer and Activator of Transcription (STAT) Proteins
4.1. Structure of the STATs
4.2. Function of the STATs
5. JAK/STAT Signalling Pathway
6. Rationale for Targeting JAK3 in Preventing Organ Transplant Rejection
7. Controversy over Targeting JAK3
8. JAK3 Inhibitor, CP-690,550
8.2. Pharmacokinetics (PK)
8.3. Efficacy of CP-690,550 in Experimental Allograft Rejection
8.3.1. Rodent Organ Transplantation
8.3.2. NHP Kidney Transplantation
8.4. Clinical Trial with CP-690,550 in Transplantation
8.4.1. Phase 1 Clinical Trial
8.4.2. Phase 2a Clinical Trial
8.4.3. Phase 2b Clinical Trial
9. Other Agents Targeting JAK3
Chapter 13 Costimulation Blockers
Costimulatory Signals Required for Optimal T Cell Activation
Costimulatory Receptors and Their Ligands
The Immunoglobulin Superfamily
Agents Targeting Costimulation
Chapter 14 Adhesion Molecules: Therapeutic Targets for Allograft Rejection and Ischemia-Reperfusion Injury
The Role of Adhesion Molecules in Inflammation and Graft Rejection
Immunoglobulin Superfamily
Human CLINICAL TRIALS with Anti-Adhesion Molecules Agents in Bone Marrow, Kidney and Islet Transplantation
Chapter 15 Agents Targeting B-Cells and the Humoral Responses
The Immunologic Response after Organ Transplantation
B-Cells and Antibody-Mediated Rejection
Donor-Specific Antibodies
B-Cell Depletion in Organ Transplantation
Pharmacokinetics and Pharmacodynamics of Rituximab
Pharmacokinetics and Pharmacodynamics of Alemtuzumab
The Clinical Use of Rituximab and Alemtuzumab
Rituximab and Alemtuzumab for Desensitization Prior to Living Donor Kidney Transplantation
ABO-Incompatible Kidney Transplantation
HLA-Incompatible Organ Transplantation
Rituximab and Alemtuzumab As Induction Therapy to Prevent Acute Allograft Rejection
Rituximab and Alemtuzumab As Treatment of Acute Antibody-Mediated Rejection
Novel B-Cell Directed Therapies with Future Potential Use in Transplantation
Blockers of BAFF and APRIL
Chapter 16 Agents Targeting Plasma Cells
B-Cells, PLASMA CELLS, and Allo-Antibodies
Proteasome Inhibition, the Plasma Cell, and Alloantibodies
Mechanisms of Bortezomib Action
Bortezomib‟s Use in Clinical Transplantation
Bortezomib‟s Phamacokinetics and Phamacodynamics
Bortezomib Treatment of Acute Humoral Rejection
Bortezomib as Induction Therapy
Bortezomib‟s Effect on Chronic Alloantibody- Mediated Rejection
Desensitization with Bortezomib
Other Biological Inhibitors
Chapter 17 Immunosuppressive Antibodies
The Well-Studied and FDA Approved Antibodies
Chapter 18 Complement Inhibitors
Description of the Complement System
Impact of Complement in Cell-Mediated Immunity
Complement and the Coagulation System
Recombinant Human C1 Inhibitor (rhC1-INH)
Vaccinia Virus Complement Control Protein (VCP)
Other Complement Therapies
Intravenous Immunoglobulin (IVIG)
Anaphylatoxin Receptor Antagonists (C5aR Antibodies and Antagonists)
Other Complement Inhibitors
Importance of Complement for Transplantation
Therapeutic Approaches to Regulate the Complement System
Genetic Manipulation of the Graft
Delivery of Therapeutic Agents into the Graft through Donor or Graft Treatment
Systemic Delivery of Complement Inhibitors or Regulators to the Recipient
Complement-Mediated Ischemia Reperfusion Injury
Complement Regulators Used in Ischemia Reperfusion Injury
Complement Inhibitors in Ischemia Reperfusion Injury
Chapter 19 Agents Targeting Ischemia-Reperfusion Injury
The Time Factor for Transplantation-Related Ischemia-Reperfusion in the Clinical Practice
Pathophysiology of Ischemia-Reperfusion Injury
The Effect of Hypoxia on Cells
Innate and Adaptive Immune Responses
Microcirculatory and Micro-Rheological Alterations
Some Organ-Specific Alterations
Organization - Reducing Ischemic Time
Static Hypothermic Storage - Intracellular Solutions
Static Hypothermic Storage – Extracellular Solutions
Static and Dynamic Preservation
Agents Targeting Inflammatory Processes
Ischemic Pre- and Postconditioning, and Trophic Factors in Organ Preservation
Part III: Cell Therapy in Induction of Transplant Tolerance
Chapter 20 Cellular Therapies in Induction of Transplantation Tolerance
Origin of MDSCs and Phenotype
MDSC Activation and Expansion
Mechanisms of Suppression
Induction of Regulatory T Cells
Chapter 21 Stem Cell-Derived Immunosuppressive Cells Therapy in Organ Transplantation
Pluripotent Stem Cells as the Potential Source of Regenerative Cell Medicine
Hematopoietic Differentiation in Embryogenesis
Generation of Hematopoietic Lineage Cells from Pluripotent Stem Cells
Generation of Mature Hematopoietic Cells from Pluripotent Stem Cells
Generation of Immunosuppressive Cells from Pluripotent Stem Cells
Myeloid-Derived Suppressor Cells
Regulatory Dendritic Cells
Chapter 22 Does MSCs Have a Place in Transplantation?†
MSCs Modulation of Immune Cells
MSCs and Sold Organ Transplantation in Animal Models
MSCs and Immunosuppressive Regimen
MSCs and Solid Organ Clinical Trials
MSCs Role in Wound Healing
Chapter 23 Donor Hematopoietic Stem Cells
Discovery of Chimerism and “Natural Tolerance”
Tolerance through Induction of Microchimerism
Tolerance through Induction of Macrochimerism
Current Immunosuppressive Therapy in Organ Transplantation
( Organ Transplantation Research Horizons )
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