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Immunomodulators
This document provides an overview of immunomodulators. It begins with definitions of immunity and antigens. It describes the types of immunity and components of the immune system. It then discusses mechanisms of immunomodulation and how drugs can suppress or stimulate the immune response. The document focuses on clinically used immunomodulators, dividing them into immunosuppressants and immunostimulants. Several commonly used immunosuppressants are described in detail, including their mechanisms of action, uses, and toxicities.
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Immunomodulators
- 1. IMMUNOMODULATO RS Dr. Swarnank Parmar JR-3 Deptof Pharmacology GMC, Nagpur
- 2. Overview • Introduction • Typesof immunity • Immunomodulators • Clinically used immunomodulators • Drugs affecting immune response • Immunosuppressant • Immunostimulants
- 3. Introduction • The wordimmunity 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. • Components ofimmune system: – Lymphocytes – Cellular immunity – Humoral immunity – Immunoglobulin – Lymph nodes – Spleen – Thymus
- 5. • There are2 types of immunity: • Active immunity. • Passive immunity
- 6. • The importantcomponents of immune system include: Granulocytes Complement synthesis & antibody formation Cellular immunity Mucocutaneous barriers
- 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. • The importanceof 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. • Benefits ofimmunomodulators 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. Phases of immune response SuppressantsEnhancers 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. Phases of immune response SuppressantsEnhancers Immune affector response Corticosteroids Cylcophosphamide Cyclosporin A Methotrexate Tetramisole
- 12. Immunomodulators types • Alldrugs 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. Immunosupressants • Glucocorticoids • Calcineurininhibitors – Cyclosporine – Tacrolimus • Antiproliferative / antimetabolic agents – Sirolimus – Everolimus – Azathioprine – Mycophenolate Mofetil – Others – methotrexate, cyclophosphamide, thalidomide & chlorambucil
- 14. • Antibodies – Antithymocyteglobulin – Anti CD3 monoclonal antibody •Muromonab – Anti IL-2 receptor antibody – •Daclizumab, basiliximab – Anti TNF alpha – infliximab, etanercept
- 15. • Immunosupressants arethe 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. Glucocorticoids • Induce redistributionof 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. Uses • Transplant rejection •GVH – BM transplantation • Autoimmune diseases – RA, SLE, Hematological conditions • Psoriasis • Inflammatory Bowel Disease, Eye conditions
- 18. Toxicity • Growth retardation •Avascular Necrosis of Bone • Risk of Infection • Poor wound healing • Cataract • Hyperglycemia • Hypertension
- 19. Calcineurin inhibitors • Cyclosporine&Tacrolimus • Most effective immunosuppressive drugs • Target intracellular signaling pathways • Blocks Induction of cytokine genes
- 20. Cyclosporin • Cyclic peptidecomposed 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. • Binds tothe 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. Uses • Prevent rejectionof 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. • Useful inautoimmune 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. • For inductionit 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. Toxicity : Cyclosporine •Renal dysfunction • Tremor • Hirsuitism • Hypertension • Hyperlipidemia • Gum hyperplasia • Hyperuricemia – worsens gout • Calcineurin inhibitors + Glucocorticoids = Diabetogenic
- 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. • 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. 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. Antiproliferative & Antimetabolic drugs •Sirolimus • Everolimus • Azathioprine • Mycophenolate Mofetil • Others: – Methotrexate – Cyclophosphamide – Thalidomide – Chlorambucil
- 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. • Extensively metabolizedmainly 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. Sirolimus Toxicity • Increase inserum cholesterol, Triglycerides • Anemia • Thrombocytopenia • Hypokalemia • Fever • GI effects • Risk of infection, tumors
- 33. Everolimus • Similar tosirolimus 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. 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. Toxicity - Azathioprine •Bone marrow suppression- leukopenia, thrombocytopenia, anemia • Increased susceptibility to infection • Hepatotoxicity • Alopecia • GI toxicity • Drug interaction: Allopurinol
- 36. Mycophenolate Mofetil • Newerimmunosupressant • Prodrug of Mycophenolic acid • Inhibits Inosine Monophosphate Dehydrogenase – enzyme in guanine synthesis • Inhibits lymphocyte proliferation, antibody production & CMI
- 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. CyclophosphomideCyclophosphomide • More markedeffect 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. 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. Fingolimod(FTY720) • Sphingosine 1Phosphate 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. Toxicity • Lymphopenia • Bradycardia •Macular edema
- 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. Anti-thymocyte Globulin • Polyclonalantibody 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. Anti-CD3 Monoclonal Antibody • Murinemonoclonal 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. Muromonab-CD3 Antibody treatment Rapid internalizationof T-cell receptor Rapid T-cell depletion from blood Prevents subsequent antigen recognition
- 46. Use • Treatment ofacute organ transplant rejection Toxicity • “Cytokine release syndrome” • Aseptic meningitis, life threatening pulmonary edema(rare)
- 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. Campath-1H (Alemtuzumab) • Monoclonal antibodybinds CD52 – expressed on lymphocytes, monocytes, macrophages • Extensive lympholysis – Prolonged T & B cell depletion Uses • CLL, Bone marrow transplantation, Renal transplantation Toxicity • Opportunistic infections
- 49. Anti-TNF Agents • TNF– Cytokine at site of inflammation • Infliximab • Etanercept • Adalimumab
- 50. Infliximab • Chimeric monoclonalantibody 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. 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. 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. Sites of Actionof 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. Immunostimulants • Levamisole • Thalidomide •BCG • Recombinant Cytokines – Interferons – Interleukin-2
- 55. Immunization • Vaccines • ImmuneGlobulin • Rho (D) Immune Globulin
- 56. TETRAMISOLE (LEVAMISOLE) • Levamisoleis 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. • Leads todecrease 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. Thalidomide • Anxiolytic, antiemeticdrug 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. 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. • It causesstimulation 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. Interferons • Low molecularweight 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. Interferon alfa-2b • Hairycell leukemia • Malignant melanoma • Kaposi sarcoma • Chronic Hepatitis B Adverse reactions • Flu-like symptoms – fever, malaise, headache • CVS- hypotension, Arrhythmia • CNS- depression, altered behaviour
- 63. Interleukin-2 (aldesleukin) • Proliferationof 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. Immunization • Active –Stimulation with an Antigen • Passive – Preformed antibody
- 65. Active immunization Vaccines • Impartactive 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
- 67. Immune Globulin Indications • Individualis deficient in antibodies – immunodeficiency • Individual is exposed to an agent, inadequate time for active immunization – Rabies – Hepatitis B
- 68. • Nonspecific immunoglobulins –Antibody-deficiency disorders • Specific immune globulins – High titers of desired antibody – Hepatitis B, Rabies, Tetanus
- 69. Rho (D) ImmuneGlobulin • 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
- 70. Conclusion • Immunology isone 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
- 71. 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