IMMUNOMODULATORS

1. IMMUNOMODULATORS Dr. Manjunath

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

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

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

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 6Thio-GMP 6Thio-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

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 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)