immunomodulators dr. manjunath. the immune response - why and how ? discriminate: self / non self...
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IMMUNOMODULATORS
Dr. Manjunath
The Immune Response - why and how ?
Discriminate: Self / Non self Destroy:
Infectious invaders Dysregulated self (cancers)
Immunity: Innate, Natural Adaptive, Learned
Who are involved ?
Innate Complement Granulocytes Monocytes/macrophages NK cells Mast cells Basophils
Adaptive: B and T
lymphocytes B: antibodies T : helper,
cytolytic, suppressor.
IMMUNE MODIFIERS
Immunosuppressants Immunostimulants
? Immune tolerance
Immunosuppressants Glucocorticoids Calcineurin inhibitors
Cyclosporine Tacrolimus
Antiproliferative / antimetabolic agents Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others – methotrexate, cyclophosphamide,
thalidomide and chlorambucil
Antibodies Antithymocyte globulin Anti CD3 monoclonal antibody
Muromonab Anti IL-2 receptor antibody –
Daclizumab, basiliximab Anti TNF alpha – infliximab, etanercept
Immunostimulants
Levamisole Thalidomide BCG Recombinant Cytokines
Interferons Interleukin-2
Immunosuppressants
Organ transplantation Autoimmune diseases
Life long use Infection, cancers Nephrotoxicity Diabetogenic
Problem
Glucocorticoids
Induce redistribution of lymphocytes – decrease in peripheral blood lymphocyte counts
Intracellular receptors – regulate gene transcription
Down regulation of IL-1, IL-6 Inhibition of T cell proliferation Neutrophils, Monocytes display poor
chemotaxis Broad anti-inflammatory effects on
multiple components of cellular immunity
USES - Glucocorticoids
Transplant rejection GVH – BM transplantation Autoimmune diseases – RA, SLE,
Hematological conditions Psoriasis Inflammatory Bowel Disease, Eye
conditions
Toxicity
Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension
Calcineurin inhibitors
Cyclosporine Tacrolimus
Most effective immunosuppressive drugs
Target intracellular signaling pathways
Blocks Induction of cytokine genes
Cyclosporine More effective against T-cell dependent
immune 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
Toxicity : Cyclosporine
Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia – worsens gout Calcineurin inhibitors + Glucocorticoids =
Diabetogenic
Drug Interaction : Cyclosporine
CYP 3A4 Inhibitors: CCB, Antifungals, Antibiotics,
HIV PI, Grape juice Inducers: Rifampicin, Phenytoin
Additive nephrotoxicity: NSAIDs
Tacrolimus
Inhibits T-cell activation by inhibiting calcineurin
Use Prophylaxis of solid-organ allograft
rejection
Toxicity - Tacrolimus
Nephrotoxicity Neurotoxicity-Tremor, headache, motor
disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections
Drug interaction Synergistic nephrotoxicity with cyclosporine CYP3A4
Antiproliferative and Antimetabolic drugs
Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others:
Methotrexate Cyclophosphamide Thalidomide Chlorambucil
Sirolimus
Inhibits T-cell activation and Proliferation
Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR)
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 3A4
Everolimus
Shorter half life compared to sirolimus
Shorter time taken to reach steady state
Similar toxicity, drug interactions
Azathioprine Purine antimetabolite Incorporation of false nucleotide 6 Thio-IMP 6Thio-GMP 6Thio-GTP Inhibition of cell proliferation Impairment of lymphocyte functionUses Prevention of organ transplant
rejection Rheumatoid arthritis
Toxicity - Azathioprine
Bone marrow suppression- leukopenia, thrombocytopenia, anemia
Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity
Drug interaction: Allopurinol
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 lymphocyte
proliferation, function – Antibody formation, cellular adhesion, migration
Uses - Mycophenolate Mofetil
Prophylaxis of transplant rejection Combination: Glucocorticoids
Calcineurin Inhibitors
Toxicity GI, Hematological
Diarrhea, Leucopenia Risk of Infection
Drug Interaction
Decreased absorption when co-administered with antacids
Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion
FTY720
S1P-R agonist – sphingosine 1 receptor Reduce recirculation of lymphocytes from
lymphatic system to blood and peripheral tissues
“Lymphocyte homing” – periphery into lymph node
Protects graft from T-cell-mediated attack Uses
Combination immunosuppression therapy in prevention of acute graft rejection
Toxicity
Lymphopenia Negative chronotropic effect
S1P-receptor on human atrial myocytes
Antibodies
Against lymphocyte cell-surface antigens
Polyclonal / Monoclonal
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
Anti-thymocyte Globulin
Purified gamma globulin from serum of rabbits immunized with human thymocytes
Cytotoxic to lymphocytes & block lymphocyte function
Uses Induction of immunosuppression –
transplantation Treatment of acute transplant rejection
Toxicity Hypersensitivity Risk of infection, Malignancy
Anti-CD3 Monoclonal Antibody
Muromonab-CD3 Binds to CD3, a component of T-cell
receptor complex involved in antigen recognition cell signaling & proliferation
Muromonab-CD3
Antibody treatment
Rapid internalization of T-cell receptor
Prevents subsequent antigen recognition
Uses
Treatment of acute organ transplant rejection
Toxicity “Cytokine release syndrome” High fever, Chills, Headache, Tremor,
myalgia, arthralgia, weakness Prevention: Steroids
Anti-IL-2 Receptor Antibodies
Daclizumab and Basiliximab Bind to IL-2 receptor on surface of
activated T cells Block IL-2 mediated T-cell activation
Uses Prophylaxis of Acute organ rejection
Toxicity Anaphylaxis, Opportunistic Infections
Campath-1H (Alemtuzumab)
Targets CD52 – expressed on lymphocytes, monocytes, Macrophages
Extensive lympholysis – Prolonged T & B cell depletion
Uses Renal transplantation
Anti-TNF Agents
TNF – Cytokine at site of inflammation
Infliximab Etanercept Adalimumab
Infliximab
Uses Rheumatoid arthritis Chron’s disease – fistulae Psoriasis Psoriatic arthritis Ankylosing spondylosis
Toxicity Infusion reaction – fever, urticaria,
hypotension, dyspnoea Opportunistic infections – TB, RTI, UTI
Etanercept Fusion protein Ligand binding portion of Human TNF-α
receptor fused to Fc portion of human IgG1
Uses Rheumatoid arthritis
moderate to severely active crohn’s disease
Adalimumab Adalimumab Recombinant human anti-TNF mAbRecombinant human anti-TNF mAb
LFA-1 Inhibitor - Efalizumab
Monoclonal Ab Targeting Lymphocyte Function Associated Antigen
Blocks T-cell Adhesion, Activation, Trafficking
Uses Organ transplantation Psoriasis
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
(blocks antigen recognition) Cyclosporine Calcineurin (inhibits phosphatase
activity) Tacrolimus Calcineurin (inhibits phosphatase
activity) Azathioprine Deoxyribonucleic acid (false
nucleotide incorporation) Mycophenolate Mofetil Inosine monophosphate
dehydrogenase (inhibits activity) Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated
T-cell activation) Sirolimus Protein kinase involved in cell-
cycle progression (mTOR) (inhibits activity)
Immunostimulants
Levamisole Thalidomide BCG Recombinant Cytokines
Interferons Interleukin-2
Immunization
Vaccines Immune Globulin Rho (D) Immune
Globulin
Levamisole
Antihelminthic Restores depressed immune function
of B, T cells, Monocytes, Macrophages Adjuvant therapy with 5FU in colon
cancer
Toxicity Agranulocytosis
Thalidomide
Birth defect Contraindicated in women with
childbearing potential Enhanced T-cell production of
cytokines – IL-2, IFN-γ NK cell-mediated cytotoxicity against
tumor cells
USE: Multiple myeloma
Bacillus Calmette-Guerin
Live, attenuated culture of BCG strain of Mycobacterium Bovis
Carcinoma Bladder
Adverse Effects Hypersensitivity Shock Chills
Interferons
Antiviral Immunomodulatory activity Bind to cell surface receptors –
initiate intracellular events Enzyme induction Inhibition of cell proliferation Enhancement of immune activities Increased Phagocytosis
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
Interleukin-2 (aldesleukin)
Proliferation of cellular immunity – Lymphocytosis, eosinophilia, release of multiple cytokines – TNF, IL-1, IFN-γ
Uses Metastatic renal cell carcinoma Melanoma Toxicity Cardiovascular: capillary leak syndrome,
Hypotension
Immunization
Active – Stimulation with an Antigen Passive – Preformed antibody
Active immunization
Vaccines Administration of antigen as a whole,
killed organism, or a specific protein or peptide constituent of an organism
Booster doses Anticancer vaccines – immunizing
patients with APCs expressing tumor antigen.
Immune Globulin
Indications Individual is deficient in antibodies –
immunodeficiency Individual is exposed to an agent,
inadequate time for active immunization Rabies Hepatitis B
Nonspecific immunoglobulins Antibody-deficiency disorders
Specific immune globulins High titers of desired antibody Hepatitis B, Rabies, Tetanus
Rho (D) Immune Globulin
Antibodies against Rh(D) antigen on the surface of RBC
Rh-negative women may be sensitized to “Foreign” Rh antigen on fetal RBC
Anti-RH Antibodies produced in mother can damage subsequent fetuses by lysing RBC’s
Hemolytic disease of newborn
Immune tolerance
Induction and maintenance of immunologic tolerance - active state of antigenic specific nonresponsiveness
Still experimental
Summary
Immunosuppresion Calcineurin inhibitors Glucocorticoids Antimetabolites
Newer immunosuppresive agents Effective control of rejection Glucocorticoid withdrawal