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Immunity, immunosuppresant’s

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Immunity, immunosuppresant’s

  1. 1. IMMUNITY, IMMUNOSUPPRESANT’S NAVEEN KADIAN DEPARTMENT OF PJARMACHEMISTRY KLE’S COLLEGE OF PHARMACY BELGAUM-10
  2. 2. The Immune Response  ABILITY TO RESIST ALMOST ALL TYPES OF ORGANISMS OR TOXINS THAT TEND TO DAMAGE THE TISSUES AND ORGANS  Discriminate: Self / Non self  Destroy:  Infectious invaders  Dysregulated self (cancers)  Immunity:  Innate, Natural  Adaptive, Learned
  3. 3. Who are involved ?  Innate  Complement  Granulocytes  Monocytes/macrophages  NK cells  Mast cells  Basophils  Adaptive:  B and T lymphocytes  B: antibodies  T : helper, cytolytic, suppressor.
  4. 4. ACQUIRED IMMUNITY HUMORAL CELL MEDIATED IMMUNITY
  5. 5. FORMATION OF B LYMPHOCYTE
  6. 6. ROLE OF MACROPHAGE IN ACTIVATING LYMPHOCYTES  MACROPHAGES ARE PRESENT IN SINUSOIDS OF EPITHELIUM OF LYMPHOIDAL ORGANS  MOST ANTIGENS COME IN CONTACT WITH MACROPHAGE  PHAGOSITIZE THEM  ANTIGENIC PRODUCTS ARE LIBERATED IN CYTOSOL  AND THEY STIMULATE B CELLS BY CELL TO CELL CONTACT
  7. 7. ROLE OF T CELLS  T HELPER CELLS SECRETE SUBSTANCES (LYMPOKINES) ACTIVATE B CELLS
  8. 8. SPECIFIC ATTRIBUTES OF HUMORAL IMMUNITY
  9. 9.  MEMORY  A FEW OF LYMPHOBLAST DONOT FORM PLASMA CELLS INSTEAD BECOME B LYMPHOCYTES  THEY REMAIN DORMANT UNTIL THEY ARE ACTIVATED BY SAME ANTIGEN
  10. 10. RESPONSE
  11. 11. COMPLEMENT SYSTEM  20 PROTEINS  11 proteins are principle actors  C1-C9,B,D  CONSTANT PORTION ACTIVATES C1 AND A CASCADE OF REACTIONS BEGIN 
  12. 12. FUNCTIONS  OPONISATION & PHAGOCYTOSIS C3b  LYSIS C5b6789  AGGLUTINISTION  NEUTALISATION OF VIRUSES  CHEMOTAXIS C5a  ACTIVATION OF MAST CELLS C3a,C4a,C5a  INFLAMMATORY EFFECTS
  13. 13. IMMUNE MODIFIERS Immunosuppressants Immunostimulants ? Immune tolerance
  14. 14. Immunosuppressant's  Glucocorticoids  Calcineurin inhibitors  Cyclosporine  Tacrolimus  Antiproliferative / antimetabolic agents  Sirolimus  Everolimus  Azathioprine  Mycophenolate Mofetil  Others – methotrexate, cyclophosphamide, thalidomide and chlorambucil
  15. 15.  Antibodies  Antithymocyte globulin  Anti CD3 monoclonal antibody  Muromonab  Anti IL-2 receptor antibody –  Daclizumab, basiliximab  Anti TNF alpha – infliximab, etanercept
  16. 16. Immunosuppressants  Organ transplantation  Autoimmune diseases  Life long use  Infection, cancers  Nephrotoxicity  Diabetogenic Problem
  17. 17. 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
  18. 18. USES - Glucocorticoids  Transplant rejection  GVH – BM transplantation  Autoimmune diseases – RA, SLE, Hematological conditions  Psoriasis  Inflammatory Bowel Disease, Eye conditions
  19. 19. Toxicity  Growth retardation  Avascular Necrosis of Bone  Risk of Infection  Poor wound healing  Cataract  Hyperglycemia  Hypertension
  20. 20. Calcineurin inhibitors  Cyclosporine  Tacrolimus  Most effective immunosuppressive drugs  Target intracellular signaling pathways  Blocks Induction of cytokine genes
  21. 21. 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
  22. 22. Toxicity : Cyclosporine  Renal dysfunction  Tremor  Hirsuitism  Hypertension  Hyperlipidemia  Gum hyperplasia  Hyperuricemia – worsens gout  Calcineurin inhibitors + Glucocorticoids = Diabetogenic
  23. 23. Drug Interaction : Cyclosporine  CYP 3A4  Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juice  Inducers: Rifampicin, Phenytoin  Additive nephrotoxicity: NSAIDs
  24. 24. Tacrolimus  Inhibits T-cell activation by inhibiting calcineurin  Use  Prophylaxis of solid-organ allograft rejection
  25. 25. Toxicity - Tacrolimus  Nephrotoxicity  Neurotoxicity-Tremor, headache, motor disturbances, seizures  GI Complaints  Hypertension  Hyperglycemia  Risk of tumors, infections  Drug interaction  Synergistic nephrotoxicity with cyclosporine  CYP3A4
  26. 26. Antiproliferative and Antimetabolic drugs  Sirolimus  Everolimus  Azathioprine  Mycophenolate Mofetil  Others:  Methotrexate  Cyclophosphamide  Thalidomide  Chlorambucil
  27. 27. Sirolimus  Inhibits T-cell activation and Proliferation  Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR)
  28. 28. 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
  29. 29. Everolimus  Shorter half life compared to sirolimus  Shorter time taken to reach steady state  Similar toxicity, drug interactions
  30. 30. 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
  31. 31. Toxicity - Azathioprine  Bone marrow suppression- leukopenia, thrombocytopenia, anemia  Increased susceptibility to infection  Hepatotoxicity  Alopecia  GI toxicity  Drug interaction: Allopurinol
  32. 32. 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
  33. 33. Uses - Mycophenolate Mofetil  Prophylaxis of transplant rejection  Combination: Glucocorticoids Calcineurin Inhibitors  Toxicity  GI, Hematological  Diarrhea, Leucopenia  Risk of Infection
  34. 34. Drug Interaction  Decreased absorption when co- administered with antacids  Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion
  35. 35. 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
  36. 36. Toxicity  Lymphopenia  Negative chronotropic effect  S1P-receptor on human atrial myocytes
  37. 37. Antibodies  Against lymphocyte cell- surface antigens  Polyclonal / Monoclonal
  38. 38. 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
  39. 39. 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
  40. 40. Anti-CD3 Monoclonal Antibody  Muromonab-CD3  Binds to CD3, a component of T-cell receptor complex involved in  antigen recognition  cell signaling & proliferation
  41. 41. Muromonab-CD3 Antibody treatment Rapid internalization of T-cell receptor Prevents subsequent antigen recognition
  42. 42. Uses  Treatment of acute organ transplant rejection Toxicity  “Cytokine release syndrome”  High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness  Prevention: Steroids
  43. 43. 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
  44. 44. Campath-1H (Alemtuzumab)  Targets CD52 – expressed on lymphocytes, monocytes, Macrophages  Extensive lympholysis – Prolonged T & B cell depletion Uses  Renal transplantation
  45. 45. Anti-TNF Agents  TNF – Cytokine at site of inflammation  Infliximab  Etanercept  Adalimumab
  46. 46. 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
  47. 47. Etanercept  Fusion protein  Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1 Uses  Rheumatoid arthritis
  48. 48. moderate to severely active crohn’s disease AdalimumabAdalimumab Recombinant human anti-TNF mAbRecombinant human anti-TNF mAb
  49. 49. LFA-1 Inhibitor - Efalizumab  Monoclonal Ab Targeting Lymphocyte Function Associated Antigen  Blocks T-cell Adhesion, Activation, Trafficking Uses  Organ transplantation  Psoriasis
  50. 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)
  51. 51. Summary  Immunosuppresion  Calcineurin inhibitors  Glucocorticoids  Antimetabolites  Newer immunosuppresive agents  Effective control of rejection  Glucocorticoid withdrawal

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