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Presentation on theme: "IMMUNOMODULATORS Dr. Manjunath."— Presentation transcript:


2 The Immune Response - why and how ?
Discriminate: Self / Non self Destroy: Infectious invaders Dysregulated self (cancers) Immunity: Innate, Natural Adaptive, Learned

3 Who are involved ? Innate Adaptive: Complement Granulocytes
Monocytes/macrophages NK cells Mast cells Basophils Adaptive: B and T lymphocytes B: antibodies T : helper, cytolytic, suppressor.


5 Immunosuppressants Immunostimulants IMMUNE MODIFIERS
? Immune tolerance

6 Immunosuppressants Glucocorticoids Calcineurin inhibitors
Cyclosporine Tacrolimus Antiproliferative / antimetabolic agents Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others – methotrexate, cyclophosphamide, thalidomide and chlorambucil

7 Antibodies Antithymocyte globulin Anti CD3 monoclonal antibody
Muromonab Anti IL-2 receptor antibody – Daclizumab, basiliximab Anti TNF alpha – infliximab, etanercept

8 Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines
Interferons Interleukin-2

9 Immunosuppressants Problem Organ transplantation Autoimmune diseases
Life long use Infection, cancers Nephrotoxicity Diabetogenic

10 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

11 USES - Glucocorticoids
Transplant rejection GVH – BM transplantation Autoimmune diseases – RA, SLE, Hematological conditions Psoriasis Inflammatory Bowel Disease, Eye conditions

12 Toxicity Growth retardation Avascular Necrosis of Bone
Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension

13 Calcineurin inhibitors
Cyclosporine Tacrolimus Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes


15 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

16 Toxicity : Cyclosporine
Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia – worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic

17 Drug Interaction : Cyclosporine
CYP 3A4 Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juice Inducers: Rifampicin, Phenytoin Additive nephrotoxicity: NSAIDs

18 Tacrolimus Inhibits T-cell activation by inhibiting calcineurin Use
Prophylaxis of solid-organ allograft rejection

19 Toxicity - Tacrolimus Nephrotoxicity
Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections Drug interaction Synergistic nephrotoxicity with cyclosporine CYP3A4

20 Antiproliferative and Antimetabolic drugs
Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others: Methotrexate Cyclophosphamide Thalidomide Chlorambucil

21 Sirolimus Inhibits T-cell activation and Proliferation
Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR)


23 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

24 Everolimus Shorter half life compared to sirolimus
Shorter time taken to reach steady state Similar toxicity, drug interactions

25 Azathioprine Purine antimetabolite Incorporation of false nucleotide
6 Thio-IMP Thio-GMP Thio-GTP Inhibition of cell proliferation Impairment of lymphocyte function Uses Prevention of organ transplant rejection Rheumatoid arthritis

26 Toxicity - Azathioprine
Bone marrow suppression- leukopenia, thrombocytopenia, anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity Drug interaction: Allopurinol

27 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

28 Uses - Mycophenolate Mofetil
Prophylaxis of transplant rejection Combination: Glucocorticoids Calcineurin Inhibitors Toxicity GI, Hematological Diarrhea, Leucopenia Risk of Infection

29 Drug Interaction Decreased absorption when co-administered with antacids Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion

30 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

31 Toxicity Lymphopenia Negative chronotropic effect
S1P-receptor on human atrial myocytes

32 Antibodies Against lymphocyte cell-surface antigens
Polyclonal / Monoclonal

33 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

34 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

35 Anti-CD3 Monoclonal Antibody
Muromonab-CD3 Binds to CD3, a component of T-cell receptor complex involved in antigen recognition cell signaling & proliferation

36 Muromonab-CD3 Antibody treatment
Rapid internalization of T-cell receptor Prevents subsequent antigen recognition

37 Uses Treatment of acute organ transplant rejection Toxicity
“Cytokine release syndrome” High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness Prevention: Steroids

38 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

39 Campath-1H (Alemtuzumab)
Targets CD52 – expressed on lymphocytes, monocytes, Macrophages Extensive lympholysis – Prolonged T & B cell depletion Uses Renal transplantation


41 Anti-TNF Agents TNF – Cytokine at site of inflammation Infliximab
Etanercept Adalimumab




45 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

46 Etanercept Fusion protein
Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1 Uses Rheumatoid arthritis


48 moderate to severely active crohn’s disease
Adalimumab Recombinant human anti-TNF mAb moderate to severely active crohn’s disease

49 LFA-1 Inhibitor - Efalizumab
Monoclonal Ab Targeting Lymphocyte Function Associated Antigen Blocks T-cell Adhesion, Activation, Trafficking Uses Organ transplantation Psoriasis

50 Sites of Action of Selected Immunosuppressive Agents on
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)

51 Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines
Interferons Interleukin-2

52 Immunization Vaccines Immune Globulin Rho (D) Immune Globulin


54 Levamisole Antihelminthic
Restores depressed immune function of B, T cells, Monocytes, Macrophages Adjuvant therapy with 5FU in colon cancer Toxicity Agranulocytosis

55 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

56 Bacillus Calmette-Guerin
Live, attenuated culture of BCG strain of Mycobacterium Bovis Carcinoma Bladder Adverse Effects Hypersensitivity Shock Chills

57 Interferons Antiviral Immunomodulatory activity
Bind to cell surface receptors – initiate intracellular events Enzyme induction Inhibition of cell proliferation Enhancement of immune activities Increased Phagocytosis

58 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

59 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

60 Immunization Active – Stimulation with an Antigen
Passive – Preformed antibody

61 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.

62 Immune Globulin Indications
Individual is deficient in antibodies – immunodeficiency Individual is exposed to an agent, inadequate time for active immunization Rabies Hepatitis B

63 Nonspecific immunoglobulins Specific immune globulins
Antibody-deficiency disorders Specific immune globulins High titers of desired antibody Hepatitis B, Rabies, Tetanus

64 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

65 Immune tolerance Induction and maintenance of immunologic tolerance - active state of antigenic specific nonresponsiveness Still experimental

66 Summary Immunosuppresion Newer immunosuppresive agents
Calcineurin inhibitors Glucocorticoids Antimetabolites Newer immunosuppresive agents Effective control of rejection Glucocorticoid withdrawal


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