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IMMUNOMODULATORS
PURVI H KAKRANI
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The Immune Response - why and how ?
Discriminate: Self / Non self
Destroy:
Infectious invaders Dysregulated self (cancers)
Immunity:
Innate, Natural
Adaptive, Learned
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Who are involved ?
Innate
Complement
Granulocytes
Monocytes/macrophages NK cells
Mast cells
Basophils
Adaptive:
B and Tlymphocytes
B: antibodies T : helper,
cytolytic,suppressor.
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IMMUNE MODIFIERS
Immunosuppressants Immunostimulants
? Immune tolerance
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Immunosuppressants
Glucocorticoids
Calcineurin inhibitors Cyclosporine
Tacrolimus
Antiproliferative / antimetabolic agents Sirolimus
Everolimus
Azathioprine
Mycophenolate Mofetil Others methotrexate, cyclophosphamide,
thalidomide and chlorambucil
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Antibodies
Antithymocyte globulin
Anti CD3 monoclonal antibody Muromonab
Anti IL-2 receptor antibody
Daclizumab, basiliximab
Anti TNF alpha infliximab, etanercept
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Immunostimulants
Levamisole
Thalidomide
BCG Recombinant Cytokines
Interferons
Interleukin-2
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Immunosuppressants
Organ transplantation
Autoimmune diseases
Life long use
Infection, cancers
Nephrotoxicity
Diabetogenic
Problem
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Glucocorticoids
Induce redistribution of lymphocytes decrease in peripheral blood lymphocytecounts
Intracellular receptors regulate genetranscription
Down regulation of IL-1, IL-6
Inhibition of T cell proliferation
Neutrophils, Monocytes display poorchemotaxis
Broad anti-inflammatory effects onmultiple components of cellular immunity
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USES - Glucocorticoids
Transplant rejection
GVH BM transplantation
Autoimmune diseases RA, SLE,Hematological conditions
Psoriasis
Inflammatory Bowel Disease, Eye
conditions
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Calcineurin inhibitors
Cyclosporine
Tacrolimus
Most effective immunosuppressivedrugs
Target intracellular signalingpathways
Blocks Induction of cytokine genes
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Cyclosporine
More effective against T-cell dependentimmune mechanisms transplant rejection,autoimmunity
IV, Oral
Uses
Organ transplantation: Kidney, Liver, Heart Rheumatoid arthritis, IBD, uveitis
Psoriasis Aplastic anemia Skin Conditions- Atopic dermatitis, Alopecia
Areata, Pemphigus vulgaris, Lichen planus,Pyoderma gangrenosum
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Toxicity : Cyclosporine
Renal dysfunction
Tremor
Hirsuitism
Hypertension Hyperlipidemia
Gum hyperplasia
Hyperuricemia worsens gout
Calcineurin inhibitors + Glucocorticoids =Diabetogenic
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Drug Interaction : Cyclosporine
CYP 3A4
Inhibitors: CCB, Antifungals,Antibiotics, HIV PI, Grape juice
Inducers: Rifampicin, Phenytoin
Additive nephrotoxicity: NSAIDs
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Tacrolimus
Inhibits T-cell activation byinhibiting calcineurin
Use Prophylaxis of solid-organ allograft
rejection
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Toxicity - Tacrolimus
Nephrotoxicity
Neurotoxicity-Tremor, headache, motordisturbances, seizures
GI Complaints Hypertension
Hyperglycemia
Risk of tumors, infections
Drug interaction Synergistic nephrotoxicity with cyclosporine
CYP3A4
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Antiproliferative and Antimetabolic
drugs
Sirolimus
Everolimus
Azathioprine
Mycophenolate Mofetil Others:
Methotrexate
Cyclophosphamide
Thalidomide
Chlorambucil
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Sirolimus
Inhibits T-cell activation andProliferation
Complexes with an immunophilin,Inhibits a key enzyme in cell cycleprogression mammalian target ofrapamycin (mTOR)
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Sirolimus
Uses Prophylaxis of organ transplant rejection
along with other drugs
Toxicity Increase in serum cholesterol, Triglycerides Anemia Thrombocytopenia Hypokalemia Fever GI effects Risk of infection, tumors
Drug Interactions: CYP 3A45/3/2013 23PURVI H KAKRANI
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Everolimus
Shorter half life compared tosirolimus
Shorter time taken to reach steadystate
Similar toxicity, drug interactions
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Azathioprine
Purine antimetabolite
Incorporation of false nucleotide
6 Thio-IMP 6Thio-GMP 6Thio-GTP
Inhibition of cell proliferation
Impairment of lymphocyte function
Uses
Prevention of organ transplantrejection
Rheumatoid arthritis
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Toxicity - Azathioprine
Bone marrow suppression-leukopenia, thrombocytopenia,anemia
Increased susceptibility to infection
Hepatotoxicity
Alopecia
GI toxicity
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Mycophenolate Mofetil
Prodrug Mycophenolic acid
Inhibits IMPDH enzyme in guanine
synthesis T, B cells are highly dependent on
this pathway for cell proliferation
Selectively inhibits lymphocyteproliferation, function Antibodyformation, cellular adhesion,migration
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Uses - Mycophenolate Mofetil
Prophylaxis of transplant rejection
Combination: Glucocorticoids
Calcineurin Inhibitors
Toxicity
GI, Hematological Diarrhea, Leucopenia
Risk of Infection
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Drug Interaction
Decreased absorption when co-administered with antacids
Acyclovir, Gancyclovir compete withmycophenolate for tubular secretion
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FTY720
S1P-R agonist sphingosine 1 receptor
Reduce recirculation of lymphocytes fromlymphatic system to blood and peripheral
tissuesLymphocyte homing periphery into
lymph node
Protects graft from T-cell-mediated attack
Uses Combination immunosuppression therapy
in prevention of acute graft rejection
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Toxicity
Lymphopenia
Negative chronotropic effect
S1P-receptor on human atrial myocytes
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Antibodies
Againstlymphocyte cell-surface antigens
Polyclonal /Monoclonal
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Antibodies
Antithymocyte Globulin
Monoclonal antibodies Anti-CD3 Monoclonal antibody (Muromonab-CD3)
Anti-IL-2 Receptor antibody (Daclizumab,
Basiliximab) Campath-1H (Alemtuzumab)
Anti-TNF Agents Infliximab
Etanercept Adalimumab
LFA-1 Inhibitor (lymphocyte function associated) Efalizumab
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Anti-thymocyte Globulin
Purified gamma globulin from serum ofrabbits immunized with human thymocytes
Cytotoxic to lymphocytes & block lymphocytefunction
Uses Induction of immunosuppression
transplantation Treatment of acute transplant rejection
Toxicity Hypersensitivity Risk of infection, Malignancy
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Anti-CD3 Monoclonal Antibody
Muromonab-CD3
Binds to CD3, a component of T-cell
receptor complex involved in antigen recognition
cell signaling & proliferation
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Muromonab-CD3
Antibody treatment
Rapid internalization of T-cellreceptor
Prevents subsequent antigenrecognition
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Uses
Treatment of acute organ transplantrejection
Toxicity
Cytokine release syndrome
High fever, Chills, Headache,Tremor, myalgia, arthralgia,weakness
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Anti-IL-2 Receptor Antibodies
Daclizumab and Basiliximab
Bind to IL-2 receptor on surface ofactivated T cells Block IL-2 mediated
T-cell activationUses
Prophylaxis of Acute organ rejection
Toxicity
Anaphylaxis, Opportunistic Infections
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Campath-1H (Alemtuzumab)
Targets CD52 expressed onlymphocytes, monocytes, Macrophages
Extensive lympholysis Prolonged T &B cell depletion
Uses
Renal transplantation
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Anti-TNF Agents
TNF Cytokine at site of inflammation
Infliximab Etanercept
Adalimumab
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Infliximab
Uses Rheumatoid arthritis Chrons disease fistulae Psoriasis Psoriatic arthritis Ankylosing spondylosis
Toxicity
Infusion reaction fever, urticaria,hypotension, dyspnoea
Opportunistic infections TB, RTI, UTI
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Etanercept
Fusion protein
Ligand binding portion of Human TNF-receptor fused to Fc portion of human
IgG1
Uses
Rheumatoid arthritis
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moderate to severely active crohns disease
Adalimumab
Recombinant human anti-TNF mAb
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LFA-1 Inhibitor - Efalizumab
Monoclonal Ab TargetingLymphocyte Function AssociatedAntigen
Blocks T-cell Adhesion, Activation,Trafficking
Uses Organ transplantation
Psoriasis
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Sites of Action of Selected Immunosuppressive Agents on
T-Cell Activation
DRUG SITE OF ACTION Glucocorticoids Glucocorticoid response elements in
DNA (regulate gene transcription)
Muromonab- CD3T-cell receptor complex (blocksantigen recognition)
Cyclosporine Calcineurin (inhibits phosphataseactivity)
Tacrolimus Calcineurin (inhibits phosphataseactivity)
Azathioprine Deoxyribonucleic acid (falsenucleotide incorporation)
Mycophenolate Mofetil Inosine monophosphatedehydrogenase (inhibits activity)
Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediatedT-cell activation)
Sirolimus Protein kinase involved in cell-cycleprogression (mTOR) (inhibits
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Immunostimulants
Levamisole
Thalidomide
BCG Recombinant Cytokines
Interferons
Interleukin-2
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Immunization
Vaccines
Immune Globulin
Rho (D) Immune
Globulin
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Levamisole
Antihelminthic
Restores depressed immunefunction of B, T cells, Monocytes,Macrophages
Adjuvant therapy with 5FU in coloncancer
Toxicity
Agranulocytosis5/3/2013 54PURVI H KAKRANI
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Thalidomide
Birth defect
Contraindicated in women withchildbearing potential
Enhanced T-cell production ofcytokines IL-2, IFN-
NK cell-mediated cytotoxicity againsttumor cells
USE:
Multiple myeloma
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Bacillus Calmette-Guerin
Live, attenuated culture of BCGstrain of Mycobacterium Bovis
Carcinoma Bladder
Adverse Effects
Hypersensitivity
Shock
Chills
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Interferons
Antiviral
Immunomodulatory activity
Bind to cell surface receptors initiate intracellular events
Enzyme induction
Inhibition of cell proliferation
Enhancement of immune activities
Increased Phagocytosis
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Interferon alfa-2b
Hairy cell leukemia Malignant melanoma
Kaposi sarcoma
Hepatitis B
Adverse reactions
Flu-like symptoms fever, chills,headache
CVS- hypotension, Arrhythmia
CNS- depression, confusion
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Interleukin-2 (aldesleukin)
Proliferation of cellular immunity Lymphocytosis, eosinophilia, release ofmultiple cytokines TNF, IL-1, IFN-
Uses
Metastatic renal cell carcinoma
Melanoma
Toxicity
Cardiovascular: capillary leak syndrome,Hypotension
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Immunization
Active Stimulation with an Antigen
Passive Preformed antibody
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Active immunization
Vaccines
Administration of antigen as awhole, killed organism, or a specificprotein or peptide constituent of anorganism
Booster doses
Anticancer vaccines immunizingpatients with APCs expressingtumor antigen.
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Immune Globulin
Indications
Individual is deficient in antibodies immunodeficiency
Individual is exposed to an agent,inadequate time for activeimmunization
Rabies Hepatitis B
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Nonspecific immunoglobulins
Antibody-deficiency disorders
Specific immune globulins
High titers of desired antibody
Hepatitis B, Rabies, Tetanus
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Rho (D) Immune Globulin
Antibodies against Rh(D)antigen on the surface ofRBC
Rh-negative women may be
sensitized to Foreign Rhantigen on fetal RBC
Anti-RH Antibodiesproduced in mother candamage subsequent fetusesby lysing RBCs
Hemolytic disease ofnewborn
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Immune tolerance
Induction and maintenance ofimmunologic tolerance - active stateof antigenic specific
nonresponsiveness
Still experimental
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Summary
Immunosuppresion
Calcineurin inhibitors
Glucocorticoids
Antimetabolites
Newer immunosuppresive agents
Effective control of rejection
Glucocorticoid withdrawal
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