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Immunomodulators

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review on immunomodulators

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Immunomodulators

  1. 1. IMMUNOMODULATO RS Dr. Swarnank Parmar JR-3 Dept of Pharmacology GMC, Nagpur
  2. 2. Overview • Introduction • Types of immunity • Immunomodulators • Clinically used immunomodulators • Drugs affecting immune response • Immunosuppressant • Immunostimulants
  3. 3. Introduction • The word immunity is derived from the Latin word immunes which means “exempt from”. • Immunity is usually defined as a state of relative resistance to an infection. • Substances capable of stimulating immune mechanism are called as antigens.
  4. 4. • Components of immune system: – Lymphocytes – Cellular immunity – Humoral immunity – Immunoglobulin – Lymph nodes – Spleen – Thymus
  5. 5. • There are 2 types of immunity: • Active immunity. • Passive immunity
  6. 6. • The important components of immune system include: Granulocytes Complement synthesis & antibody formation Cellular immunity Mucocutaneous barriers
  7. 7. Mechanisms ofMechanisms of immunomodulationimmunomodulation • Drugs may modulate immune mechanism by either suppressing or by stimulating one or more of the following steps: – Antigen recognition & phagocytosis – Lymphocyte proliferation/differentiation – Synthesis of antibodies – Ag –Ab interaction – Release of mediators due to immune response – Modification of target tissue response
  8. 8. • The importance of immune system in protecting the body against harmful molecules is well recognized • However, in some instances, this protection can result in serious problems • E.g, the introduction of allograft can elicit a damaging immune response causing rejection of the transplanted tissue
  9. 9. • Benefits of immunomodulators stem from their ability to stimulate natural & adaptive defence mechanisms, such as cytokines, which enables the body to help itself • Natural immunomodulators act to strengthen weak immune systems & to moderate immune systems that are overactive • Plant sterols & sterolins are natural immunomodulators found in some raw fruits & vegetables & in the alga, spirulina
  10. 10. Phases of immune response Suppressants Enhancers Antigen recognisation & processing Corticosteroids Cyclophosphamide BCG vaccine Tetramisole Amplification L- Asparaginase Corticosteroids Cyclophosphamide 5-fluorouracil Concanavalin A Tetramisole Antibody formation Corticosteroids Cyclophosphamide Cyclosporin A Lipopolysaccaride Tetramisole
  11. 11. Phases of immune response Suppressants Enhancers Immune affector response Corticosteroids Cylcophosphamide Cyclosporin A Methotrexate Tetramisole
  12. 12. Immunomodulators types • All drugs which modify immune response generally categorized as immunomodulators. These can either function as: – 1. Immunosuppressants – 2. Immunostimulants • Some of these can have both the properties depending on which component of immune response they affect
  13. 13. Immunosupressants • Glucocorticoids • Calcineurin inhibitors – Cyclosporine – Tacrolimus • Antiproliferative / antimetabolic agents – Sirolimus – Everolimus – Azathioprine – Mycophenolate Mofetil – Others – methotrexate, cyclophosphamide, thalidomide & chlorambucil
  14. 14. • Antibodies – Antithymocyte globulin – Anti CD3 monoclonal antibody •Muromonab – Anti IL-2 receptor antibody – •Daclizumab, basiliximab – Anti TNF alpha – infliximab, etanercept
  15. 15. • Immunosupressants are the drugs which inhibit cellular/humoral or both types of immune responses, & have their major use in organ transplantation & autoimmune disease • Problems arising – Life long use Infection, cancers Nephrotoxicity Diabetogenic
  16. 16. Glucocorticoids • Induce redistribution of lymphocytes – decrease in peripheral blood lymphocyte counts • Down regulation of IL-1, IL-2, IL-3, IL-6 • Inhibition of T cell proliferation • Increase number of RBCs, platelets & neutrophils in circulation • Enhance rate of destruction of lymphoid cells
  17. 17. Uses • Transplant rejection • GVH – BM transplantation • Autoimmune diseases – RA, SLE, Hematological conditions • Psoriasis • Inflammatory Bowel Disease, Eye conditions
  18. 18. Toxicity • Growth retardation • Avascular Necrosis of Bone • Risk of Infection • Poor wound healing • Cataract • Hyperglycemia • Hypertension
  19. 19. Calcineurin inhibitors • Cyclosporine &Tacrolimus • Most effective immunosuppressive drugs • Target intracellular signaling pathways • Blocks Induction of cytokine genes
  20. 20. Cyclosporin • Cyclic peptide composed of 11 aa • Extracted from a soil fungus • Selectively inhibits T lymphocyte proliferation, IL-2 & other cytokine production & response of inducer T cells to IL-1, without any effect on suppressor T cells • Lymphocytes are arrested at G0 or G1 phase
  21. 21. • Binds to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes • This complex of cyclosporine & cyclophilin inhibit calcineurin, which, under normal circumstances, is responsible for activating the transcription of IL-2 • It also inhibits lymphokine production & IL release, leads to a reduced function of effector T-cells, does not affect cytostatic activity
  22. 22. Uses • Prevent rejection of kidney, liver, cardiac, BM & other allogeneic transplants • Can be used alone • More effective when glucocorticoids are also administered • Most active when administered before antigen exposure
  23. 23. • Useful in autoimmune disease as well • Alternative to methotrexate for the treatment of severe, active RA • Selectively suppresses CMI • 2nd line drug for uveitis, bronchial asthma, etc. • Free of toxic effects on BM & RE system
  24. 24. • For induction it is started orally 12 hrs before the transplant & continued for as long as needed • When graft rejection has started, it can be given i.v • Concentrated in RBCs & WBCs • Metabolized in liver excreted in bile • Biphasic t1 / : 4 -6hrs & 12 -18hrs
  25. 25. Toxicity : Cyclosporine • Renal dysfunction • Tremor • Hirsuitism • Hypertension • Hyperlipidemia • Gum hyperplasia • Hyperuricemia – worsens gout • Calcineurin inhibitors + Glucocorticoids = Diabetogenic
  26. 26. Tacrolimus (FK506)Tacrolimus (FK506) • Chemically different from cyclosporine, newer immunosuppressant • Macrolide that is isolated from soil fungus • Binds to different cytoplasmic immunophilin protein labelled FK506 binding protein(FKBP)
  27. 27. • Same MOA, 100 times more potent • Orally as well as i.v infusion • Metabolized by CYP3A4 & excreted in bile & plasma t1 /2is 12hrs • Clinical efficacy as well as toxicity profile are similar to cyclosporine
  28. 28. Toxicity - Tacrolimus • Nephrotoxicity • Neurotoxicity-Tremor, headache, motor disturbances, seizures • GI Complaints • Hypertension • Hyperglycemia • Risk of tumors, infections • Drug interaction – Synergistic nephrotoxicity with cyclosporine – CYP3A4
  29. 29. Antiproliferative & Antimetabolic drugs • Sirolimus • Everolimus • Azathioprine • Mycophenolate Mofetil • Others: – Methotrexate – Cyclophosphamide – Thalidomide – Chlorambucil
  30. 30. Sirolimus • Macrolide antibiotic • Binds to same immunoglobulin FKBP as Tacrolimus • Sirolimus-FKBP complex inhibits another kinase called ‘mammalian target of rapamycin (mTOR) (does not interact with calcineurin) • Leads to proliferation & differentiation of T-cells activated by IL-2
  31. 31. • Extensively metabolized mainly by CYP3A4 • Elimination primarily by biliary route • T1/2- approx 60 hours Uses • Prophylaxis of organ transplant rejection along with other drugs(cyclosporin/tacrolimus)
  32. 32. Sirolimus Toxicity • Increase in serum cholesterol, Triglycerides • Anemia • Thrombocytopenia • Hypokalemia • Fever • GI effects • Risk of infection, tumors
  33. 33. Everolimus • Similar to sirolimus in mechanism, clinical efficacy, doses & drug interactions • Better absorbed orally • Shorter half life (approx 40 hours) • Shorter time taken to reach steady state • Similar uses & toxicity
  34. 34. Azathioprine • Purine antimetabolite • Selectively affects differentiation & function of T- cells • Inhibits cytolytic T-lymphocytes, CMI is primarily depressed Uses • Prevention of renal & other graft rejections • Rheumatoid arthritis(lower doses)
  35. 35. Toxicity - Azathioprine • Bone marrow suppression- leukopenia, thrombocytopenia, anemia • Increased susceptibility to infection • Hepatotoxicity • Alopecia • GI toxicity • Drug interaction: Allopurinol
  36. 36. Mycophenolate Mofetil • Newer immunosupressant • Prodrug of Mycophenolic acid • Inhibits Inosine Monophosphate Dehydrogenase – enzyme in guanine synthesis • Inhibits lymphocyte proliferation, antibody production & CMI
  37. 37. Uses - Mycophenolate Mofetil • Prophylaxis of renal transplant rejection • Mycophenolate mofetil+glucocorticoid+sirolimus – non-nephrotoxic combination utilized in patients developing renal toxicity with cyclosporin/tacrolimus • Toxicity • GI, Hematological – Diarrhea, Leucopenia • Risk of Infection(CMV infections)
  38. 38. CyclophosphomideCyclophosphomide • More marked effect on B cells & humoral immunity • Used in BM transplantation in which short course with high dose is given • In other organ transplantations it is employed only as a reserve drug • In RA, it is rarely used • Low doses are occasionally employed for maintenance therapy in pemphigus, SLE & idiopathic thrombocytopenic purpura
  39. 39. MethotrexateMethotrexate • Folate antagonist, potent immunosupressant • Markedly depresses cytokine production & cellular immunity & has anti-inflammatory property • Used as 1st line drug in many autoimmune diseases like rapidly progressing RA, severe psoriasis, pemphigus, myasthenia gravis, uveitis, chronic active hepatitis • Low dose as maintenance therapy is relatively well tolerated
  40. 40. Fingolimod(FTY720) • Sphingosine 1 Phosphate Receptor agonist • Reduce recirculation of lymphocytes from lymphatic system to blood & peripheral tissues • “Lymphocyte homing” – periphery into lymph node • Protects graft from T-cell-mediated attack Uses • Combination immunosuppression therapy in
  41. 41. Toxicity • Lymphopenia • Bradycardia • Macular edema
  42. 42. 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
  43. 43. Anti-thymocyte Globulin • Polyclonal antibody purified from horse or rabbits immunized with human thymic lymphocytes • Binds to T lymphocytes & depletes them • Potent immunosupressant Uses • Induction of immunosuppression – transplantation • To suppress acute allograft rejection episodes Toxicity • Hypersensitivity • Risk of infection, Malignancy
  44. 44. Anti-CD3 Monoclonal Antibody • Murine monoclonal antibody against the CD3 glycoprotein expressed near to the T cell receptor on helper T cell • Binds to CD3, a component of T-cell receptor complex involved in – antigen recognition – cell signaling & proliferation
  45. 45. Muromonab-CD3 Antibody treatment Rapid internalization of T-cell receptor Rapid T-cell depletion from blood Prevents subsequent antigen recognition
  46. 46. Use • Treatment of acute organ transplant rejection Toxicity • “Cytokine release syndrome” • Aseptic meningitis, life threatening pulmonary edema(rare)
  47. 47. Anti-IL-2 Receptor Antibodies • Daclizumab & Basiliximab • Bind to IL-2 receptor with high affinity on surface of activated T cells  Block IL-2 mediated T-cell activation Uses • Prophylaxis of Acute organ rejection & maintenance of graft Toxicity • Anaphylaxis, Opportunistic Infections
  48. 48. Campath-1H (Alemtuzumab) • Monoclonal antibody binds CD52 – expressed on lymphocytes, monocytes, macrophages • Extensive lympholysis – Prolonged T & B cell depletion Uses • CLL, Bone marrow transplantation, Renal transplantation Toxicity • Opportunistic infections
  49. 49. Anti-TNF Agents • TNF – Cytokine at site of inflammation • Infliximab • Etanercept • Adalimumab
  50. 50. Infliximab • Chimeric monoclonal antibody against TNFα Uses • Rheumatoid arthritis • Chron’s disease – fistulae • Psoriasis • Psoriatic arthritis • Ankylosing spondylosis Toxicity • Infusion reaction – fever, urticaria, hypotension, dyspnoea • Opportunistic infections – TB, RTI, UTI
  51. 51. Etanercept • Fusion protein • Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1 • Neutralizes both TNFα & TNFß • Prevents activation of macrophages & T-cells Uses • Rheumatoid arthritis • Also approved for severe/refractory ankylosing spondylitis, plaque psoriasis
  52. 52. LFA-1 Inhibitor - Efalizumab • Recombinant humanized monoclonal Ab targeting CD11a subunit of lymphocyte function associated antigen 1 • Blocks T-cell adhesion, activation, trafficking Uses • Organ transplantation • Psoriasis • Withdrawn from market in 2009 due to fatal brain infections(bacterial sepsis, invasive fungal disease)
  53. 53. 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-CD3 T-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)
  54. 54. Immunostimulants • Levamisole • Thalidomide • BCG • Recombinant Cytokines – Interferons – Interleukin-2
  55. 55. Immunization • Vaccines • Immune Globulin • Rho (D) Immune Globulin
  56. 56. TETRAMISOLE (LEVAMISOLE) • Levamisole is orally active levo isomer of tetramisole, restores depressed T-cell function • Used as an adjunct in malignancies, aphthous ulcers & recurrent herpes, also used as disease modifying drug in Rheumatoid Arthritis • Mainly acts by raising c-GMP levels through interaction with thymopoietien receptor sites
  57. 57. • Leads to decrease in metabolic inactivation of c- GMP accompanied with increased breakdown of c- AMP • Increase in c-GMP level induces lymphocyte proliferation & augmentation of chemotactic responses • This reflects into increased antibody production, lymphokine production, increased phagocytosis
  58. 58. Thalidomide • Anxiolytic, antiemetic drug with antiinflammatory, cytokine modulatory activity • Enhanced T-cell production of cytokines – IL-2, IFN-γ • NK cell-mediated cytotoxicity against tumor cells USE: • Multiple myeloma, ENL
  59. 59. Bacillus Calmate Guerin(BCG) Vaccine • It is used as immunological enhancer to stimulate intact immune system (i.e. a non-specific immunoenhancer.) of the body. • BCG & its methanol extracted residue (MER) contain muramyl dipeptide as an active immunostimulant ingredient • T-lymphocytes are principle target cells for the action of BCG vaccine.
  60. 60. • It causes stimulation of macrophage function, phagocytic activity, lysosomal enzyme activity & chemotaxis mechanisms • It induces the production of lymphocyte-activity factor resulting of phase I of immune response. • Because of its activity against tumour antigen it is beneficial in treatment of lung & breast cancer, acute lympholytic & myelogeneous leukaemia. • It is available as unlyophilized, live or killed lyophilized form.
  61. 61. Interferons • Low molecular weight glycoprotein cytokines produced by host cells in response to viral infections • Immunomodulatory activity • Bind to cell surface receptors – initiate intracellular events – Enzyme induction – Inhibition of cell proliferation – Affect viral replication – Increased Phagocytosis
  62. 62. Interferon alfa-2b • Hairy cell leukemia • Malignant melanoma • Kaposi sarcoma • Chronic Hepatitis B Adverse reactions • Flu-like symptoms – fever, malaise, headache • CVS- hypotension, Arrhythmia • CNS- depression, altered behaviour
  63. 63. Interleukin-2 (aldesleukin) • Proliferation of cellular immunity – Lymphocytosis, eosinophilia, release of multiple cytokines – TNF, IL-1, IFN-γ • Promotes differentiation of T-cells Uses • Metastatic renal cell carcinoma • Malignant Melanoma Toxicity • Flu- like symptoms- fever, headache, fatigue • Hypotension, drowsiness, confusion, loss of appetite
  64. 64. Immunization • Active – Stimulation with an Antigen • Passive – Preformed antibody
  65. 65. Active immunization Vaccines • Impart active immunity • Active immunization more efficacious & longer lasting than passive immunization • Booster doses required at certain intervals • Anticancer vaccines – immunizing patients with APCs expressing tumor antigen
  66. 66. Immune Globulin Indications • Individual is deficient in antibodies – immunodeficiency • Individual is exposed to an agent, inadequate time for active immunization – Rabies – Hepatitis B
  67. 67. • Nonspecific immunoglobulins – Antibody-deficiency disorders • Specific immune globulins – High titers of desired antibody – Hepatitis B, Rabies, Tetanus
  68. 68. Rho (D) Immune Globulin • Antibodies against Rh(D) antigen on the surface of RBC • Binds the Rho antigens & does not allow them to induce antibody formation in Rh –ve individuals • Used for prevention of postpartum/post-abortion formation of antibodies in Rho-D –ve women (Hemolytic disease of newborn) • Given at 28th week of pregnancy
  69. 69. Conclusion • Immunology is one of the most rapidly developing areas of medical biotechnology research • Immunomodulators are going to be central part of 21st centuary medicine • Immunomodulation is a normalising process which correct weak immune systems & temper immune systems that are overactive • Immunomodulators are becoming a viable adjunct to established modalities offering a novel approach for the treatment of infectious disease in coming decades
  70. 70. References • Patil U.S, Jaydeokar A.V, Bandawane D.D, immunomodulators : a pharmacological review, international journal of pharmacy & pharmaceutical sciences, vol 4, suppl 1, 2012 • Essentials of Medical Pharmacology: K.D. Tripathi, 7th edition • Rang.H.P, Dale.M.M, Ritter.J.M, FlouerR.J, Pharmacology, Philadelphia, Churchil livingstone-elsevier, 7th edition

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