Pharmacology of Immunosuppression

Preface
Contents
The Biology and Molecular Basis of Organ Transplant Rejection
	1 Introduction and Overview
		1.1 Structure and Function of the Immune System and Some Molecules to Know
	2 Three-Signal Model of the Alloimmune T Cell Response in the SLO
	3 Effectors, Lesions, and Molecular Phenotype of Rejection
		3.1 T Cell-Mediated Rejection (TCMR)
			3.1.1 Tissue Injury in TCMR
		3.2 Antibody-Mediated Rejection
		3.3 Triggering of Host B Cell Clones with Cognate Receptors for Native Donor HLA Molecules
		3.4 Effector Mechanisms in ABMR
		3.5 Classification of ABMR
			3.5.1 Hyperacute ABMR
			3.5.2 Early Acute ABMR in Sensitized Patients (Type 1)
			3.5.3 ABMR Apparently Independent of Pre-Transplant Sensitization (Type 2)
		3.6 Late-Stage ABMR (LABMR)
		3.7 Mixed Rejection
		3.8 Sub-Threshold ABMR-Like Changes
		3.9 DSA-Negative ABMR
		3.10 Unsolved Issues in ABMR
	4 Donor-Derived Cell-Free DNA (dd-cfDNA)
	5 Host-Graft Adaptation
		5.1 Immune Checkpoint Molecules
		5.2 Regulatory T Cells
		5.3 Transplant Tolerance
	6 Late Slow Deterioration of Organ Transplants
	7 Effects of Injury
		7.1 Does Injury Evoke Rejection?
	8 Summary
	References
A Comprehensive Review of Calcineurin Inhibitors Used for Immunosuppression in Cardiac Transplantation
	1 History of Calcineurin Inhibitors
	2 Mechanisms of Action
	3 Medication Forms and Routes of Administration
	4 Pharmacodynamics and Therapeutic Drug Monitoring
	5 Interpersonal and Intrapersonal Variations in Drug Metabolism
	6 Commonly Used Medications and Interactions with CNIs
	7 Side Effects and Complications of Calcineurin Inhibitor Use
	8 Renal
	9 Cardiovascular
	10 Neurologic
	11 Endocrine and Metabolic
	12 Gastrointestinal
	13 Integumentary
	14 Calcineurin Minimization
	15 Conclusion
	References
Antiproliferatives and Transplantation
	1 Discovery
	2 Mechanism of Action
		2.1 Azathioprine
		2.2 Mycophenolic Acid
	3 Optimal Dose of Mycophenolic Acid
	4 Enteric-Coated Mycophenolic Acid
	5 Target Dose Monitoring of MMF
	6 Side Effects
	7 MMF and Azathioprine During Pregnancy
	8 MMF vs Azathioprine
	9 Clinical Trials
	References
Mechanistic Target of Rapamycin (mTOR) Inhibitors
	1 Introduction
	2 Mechanism of Action
		2.1 mTOR
		2.2 Rapamycin
		2.3 Rapamycin Analogs
		2.4 Pharmacokinetics
	3 Clinical Trials
		3.1 SMART Trial
		3.2 EXIST Trials
		3.3 BOLERO Trials
		3.4 RECORD Trials
	4 Clinical Uses
		4.1 Kidney Transplantation
		4.2 Heart Transplantation
		4.3 Tuberous Sclerosis Complex
		4.4 Lymphangioleiomyomatosis
		4.5 Cancer
		4.6 Metabolic Diseases
		4.7 Adverse Reactions
	5 Drug Interactions
	References
Corticosteroids in Immunosuppression
	1 Introduction
	2 Historical Perspective
	3 Mechanism of Action (Fig. 1)
	4 Types of Glucocorticoids and Dose
	5 Clinical Indications for Use in Solid Organ Transplant
		5.1 Intraoperative Steroids
		5.2 Maintenance Dosing and Steroid Withdrawal
		5.3 Treatment in Acute Rejections
	6 Side Effects (Saag and Furst 2019)
	7 Interactions of Glucocorticoids with Other Drugs (Liapi and Chrousos 1992)
	8 Conclusion
	References
Induction Therapy and Therapeutic Antibodies
	1 Introduction
	2 Induction Therapies
		2.1 Antibodies (Table 1)
			2.1.1 Muromunab-OKT3
			2.1.2 Antithymocyte Globulins (ATG)
			2.1.3 IL-2 Blockade
			2.1.4 Outcomes on IL2RA vs ATG Induction Regimen
				Kidney Transplantation
				Liver Transplantation
				Heart and Lung Transplantation
		2.2 Other Induction Therapies
			2.2.1 Alemtuzumab
			2.2.2 Costimulatory Blockade (Belatacept)
	3 Strategies to Neutralize the Effect of Pre-Formed Antibodies
	4 Monoclonal and Polyclonal Antibodies Outside Induction Therapy
		4.1 Prophylactic Therapy
		4.2 Intravenous Immunoglobulin (IVIg)
		4.3 Muromonab-OKT3
		4.4 Antithymocyte Globulins
		4.5 Alemtuzumab
		4.6 Interleukin-2 Receptor Antagonists
		4.7 Rituximab
		4.8 Obinutuzumab
		4.9 Tocilizumab
		4.10 Clazakizumab
		4.11 CD38 Antibodies
		4.12 Eculizumab
	References
Immunosuppression and Heart Transplantation
	1 Introduction
	2 Maintenance Immunosuppression
	3 Corticosteroid Weaning Protocols
	4 Induction Immunotherapy
	5 Immunosuppression in Selected Patient Populations
		5.1 Patients with CNI-Related Renal Toxicity
		5.2 Patients with Evidence of Cardiac Allograft Vasculopathy (CAV)
		5.3 Patients with History of Medication Nonadherence
		5.4 Patients with the Development of Cancer
	6 Summary
	References
Immunosuppression in Lung Transplantation
	1 History of Immunosuppression in Lung Transplantation
	2 Induction Immunosuppression in Lung Transplantation
		2.1 Anti-thymocyte Globulin
		2.2 Alemtuzumab
		2.3 Basiliximab
		2.4 Considerations for Induction Immunosuppression in Lung Transplantation
	3 Maintenance Immunosuppression in Lung Transplantation
		3.1 Calcineurin Inhibitors
		3.2 DNA Synthesis Inhibitors
		3.3 Corticosteroids
		3.4 mTOR Inhibitors
		3.5 Belatacept
	4 Rescue Immunosuppression for Lung Transplantation
		4.1 Acute Cellular Rejection
		4.2 Antibody-Mediated Rejection
		4.3 Chronic Lung Allograft Dysfunction
	5 Summary
	References
Immunosuppression and Kidney Transplantation
	1 Introduction
		1.1 Brief History
		1.2 Current Practices
		1.3 Alloimmune Reaction Targets
	2 Induction Therapy
		2.1 T-Cell Depleting Agents
			2.1.1 Monoclonal Antibodies
			2.1.2 Polyclonal Anti-thymocyte Globulin
				Rabbit Anti-Thymocyte Globulin
			2.1.3 Alemtuzumab
		2.2 Interleukin 2 Receptor Antagonists
	3 Maintenance Therapy
		3.1 Calcineurin Inhibitors
			3.1.1 Mechanism of Action
			3.1.2 Dose and Administration
			3.1.3 Metabolism and Drug-Drug Interaction
			3.1.4 Adverse Events
		3.2 Antimetabolites
			3.2.1 Mycophenolic Acid
			3.2.2 Azathioprine
		3.3 mTOR Inhibitors: Everolimus and Sirolimus
		3.4 Corticosteroids
		3.5 Belatacept
	4 Antibody Mediated Rejection
	References
Immunosuppression in Rheumatologic and Auto-immune Disease
	1 Introduction
	2 Rheumatologic Diseases
		2.1 Rheumatoid Arthritis
			2.1.1 Conventional Synthetic DMARDs
			2.1.2 Biologic DMARDs
				Tumor Necrosis Factor-α Inhibitors (TNFi)
				IL-6 Inhibitors
				IL-1 Inhibitors
				Co-stimulatory Blockade
				B-Cell Antagonists
			2.1.3 tsDMARDs
				JAK Inhibitors
		2.2 Seronegative Spondyloarthritis
			2.2.1 csDMARDs
			2.2.2 bDMARDs
				IL-17 Inhibitors
				IL-12/23 Inhibitors
			2.2.3 Targeted Synthetic DMARDs
				JAKi
				Phosphodiesterase 4 Inhibitors
		2.3 Systemic Lupus Erythematosus
			2.3.1 csDMARDs
				Anti-malarial Agents
				Cyclophosphamide
				Mycophenolate Mofetil
				Calcineurin Inhibitors
			2.3.2 bDMARDs
				Belimumab
				Anifrolumab
		2.4 Autoinflammatory Disorders
			2.4.1 Colchicine
			2.4.2 IL-1 Inhibitors
		2.5 Systemic Vasculitis
	3 Conclusions
	References
Immune Suppression in Allogeneic Hematopoietic Stem Cell Transplantation
	1 Introduction
	2 Clinical Features of aGVHD
	3 Influence of Donor Graft, MHC Matching, and Conditioning on aGVHD
	4 Chronic GVHD
	5 Immunobiology of aGVHD
		5.1 Tissue Injury and Inflammation from Pre-transplant Conditioning (aGVHD Triggers and Sensors)
		5.2 Stimulation, Differentiation, and Proliferation of Effector T Cells (aGVHD Mediators)
		5.3 Tissue Damage by Effectors and Inflammatory Cytokines (aGVHD Effectors and Amplifiers)
		5.4 Tissue Repair and Anti-inflammatory Mechanisms (aGVHD Modulators)
	6 GVHD Prophylaxis
		6.1 Calcineurin Inhibitors
		6.2 Mycophenolate Mofetil
		6.3 Methotrexate
		6.4 Sirolimus
		6.5 Anti-Thymocyte Globulin
		6.6 Cyclophosphamide
		6.7 Experimental Therapies
	7 Acute GVHD Treatment
		7.1 Corticosteroids
		7.2 Ruxolitinib
		7.3 Tumor Necrosis Factor (TNF)-Inhibitors
		7.4 Alemtuzumab
		7.5 Pentostatin
		7.6 Interleukin-2 Receptor (CD25-Alpha) Antibodies
		7.7 Brentuximab
		7.8 Tocilizumab
		7.9 Vedolizumab
		7.10 Additional Immunosuppression Medications for Non-GVHD Indications
		7.11 Rituximab
		7.12 Bortezomib
		7.13 Eculizumab
	8 Conclusions
	References
Immunosuppression in Multiple Sclerosis and Other Neurologic Disorders
	1 Introduction
	2 Current Strategies to Promote Immunosuppression in Multiple Sclerosis
		2.1 Pleiotropic Immunosuppressants
		2.2 Drugs Interfering with DNA Synthesis/Repair
		2.3 Reagents That Sequester Peripheral Leukocytes
		2.4 Reagents Depleting Immune Cells
	3 Looking Ahead: The Future of Immunosuppressive Therapies for Multiple Sclerosis
		3.1 Targeting B Cells
		3.2 Stem Cell Therapies
	4 Immunosuppressants for Other Neurologic Disorders
		4.1 Neuromyelitis Optica Spectrum Disorders
		4.2 Myasthenia Gravis
		4.3 Guillain-Barré Syndrome
	5 Conclusion
	References
Novel Immunosuppression in Solid Organ Transplantation
	1 Introduction
		1.1 Monoclonal Antibodies
	2 Basiliximab
	3 Daclizumab
	4 Campath-1 H/Alemtuzumab
	5 Rituximab
	6 CTLA-4-Ig/Belatacept
	7 Calcineurin Inhibitors (Cyclosporine and Tacrolimus)
		7.1 Cyclosporine (CSA) and Tacrolimus (TAC)
	8 Proliferation Signal Inhibitors/Mammalian Target of Rapamycin Inhibitors
		8.1 Everolimus
	9 Sirolimus
	10 Bortezomib
	11 Eculizumab
	12 IVIG
	13 Other
	References
Adverse Effects of Immunosuppression: Infections
	1 Introduction
	2 Non-Biologic Disease-Modifying Therapies and Disease-Modifying Antirheumatic Drugs
		2.1 Methotrexate
		2.2 Aminosalicylates
		2.3 Pyrimidine Synthesis Inhibitors
		2.4 Thiopurines
		2.5 Sphingosine Analog
		2.6 Dimethyl Fumarate
	3 Janus Kinase (JAK) Inhibitors
	4 Integrin Antibodies and Adhesion-Molecule Inhibitors
		4.1 Natalizumab
		4.2 Vedolizumab
	5 Tumor Necrosis Factor (TNF)-Alpha Inhibitors
	6 T-Cell Costimulatory Blockers
		6.1 Abatacept
		6.2 Belatacept
	7 Selective B-Cell Depletion and Inhibition
		7.1 Anti-CD 20 Monoclonal Antibodies
			7.1.1 Rituximab
			7.1.2 Obinutuzumab, Ofatumumab, Ocrelizumab
		7.2 Other Anti-B-Cell Agents
		7.3 Lymphocyte Depleting Agents
			7.3.1 Alemtuzumab
			7.3.2 Antithymocyte Globulin
			7.3.3 Brentuximab Vedotin
	8 Interleukin Inhibitors
		8.1 IL-1 Inhibitors
		8.2 IL-2 Inhibitors
		8.3 IL-6 Inhibitors
		8.4 Tocilizumab
		8.5 IL-12/23 Inhibitors
	9 Complement Inhibitor
	10 Calcineurin Inhibitors
	11 Mammalian Target of Rapamycin (mTOR) Inhibitors
	12 Mycophenolic Acids
	References
Malignancy: An Adverse Effect of Immunosuppression
	1 Introduction
	2 Epidemiology of Malignancy in Immunocompromised Patients
	3 Pathogenesis of Malignancy in Solid Organ Transplant Recipients
		3.1 Immune Surveillance
		3.2 Role of Viral Infections in Carcinogenesis
		3.3 Direct Effect of Immunosuppressive Agents in Carcinogenesis
	4 Carcinogenesis in Immunocompromised Patients: Risk Factors
		4.1 Patient Related Factors
		4.2 Environmental Factors
		4.3 Transplant Related Factors
		4.4 Management Related Factors
	5 Classification of Malignancies in SOTRs
		5.1 Recurrence of Pre-Transplant Malignancy in Solid Organ Transplant Recipients
		5.2 Donor Derived Malignancy in Solid Organ Transplant Recipients
		5.3 De Novo Malignancies in Solid Organ Transplant Recipients
			5.3.1 Skin Cancers
			5.3.2 Lip Cancer
			5.3.3 Kaposi Sarcoma
			5.3.4 Anogenital Cancers
			5.3.5 Post-Transplant Lymphoproliferative Disorders
			5.3.6 Thyroid Cancer
			5.3.7 Lung Cancer
	6 Immunosuppression in Organ Transplantation
	7 Conclusions
	References
Adverse Effects of Immunosuppression: Nephrotoxicity, Hypertension, and Metabolic Disease
	1 Introduction
	2 Immunosuppression and Nephrotoxicity
		2.1 Corticosteroids
		2.2 Calcineurin Inhibitors
		2.3 Antimetabolites
		2.4 Azathioprine
		2.5 Mycophenolic Acid
		2.6 Proliferation Signal Inhibitors/Mammalian Target of Rapamycin (mTOR) Inhibitors
		2.7 Induction Therapy
	3 Immunosuppression: Hypertension and Metabolic Disease
		3.1 Corticosteroids
		3.2 Calcineurin Inhibitors (CNIs)
		3.3 Mammalian Target of Rapamycin (mTOR) Inhibitors: (Rapamycin/Sirolimus)
		3.4 Antimetabolites: MMF (CellCept)
	References