Immunosuppressants [autosaved]


Published on

Published in: Technology, Health & Medicine
  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Immunosuppressants [autosaved]

  2. 2. INTRODUCTION  Immunosuppression involves an act that reduces the activation or efficacy of the immune system  Immunosuppressants are used to control severe manifestations of allergic, autoimmune and transplant-related diseases  Now over 80 autoimmune diseases and several common allergic conditions in which immunosuppressant's are used  Prevent the rejection of transplanted organs and tissues  Treatment of autoimmune diseases or diseases that are most likely of autoimmune origin  Treatment of some other non-autoimmune inflammatory diseases
  3. 3. CLASSIFICATION OF IMMUNOSUPPRESSANTS 1.PHYSICAL IMMUNOSUPRESSANTS  Includes Total Lymphoid Irradiation, Plasmapheresis, thoracic duct drainage  Inhibits Cell division ,cell activation, Antibody production 2.CHEMICAL IMMUNOSUPPRESSANTS:  I. Corticosteroids  II. Cytostatics  III. Antibodies  IV. Drugs acting on Immunophilins 3.BIOLOGICAL IMMUNOSUPPRESSANTS:  interferon's, interleukins, colony-stimulating factors, monoclonal antibodies
  4. 4. PHYSICAL IMMUNOSUPPRESSANTS  Total Lymphoid Irradiation (TLI ):  Fractionated irradiation focused on Lymphoid tissues, with shielding of Bone marrow, Lungs ,Non lymphoid tissues  Induces formation of large granular Lymphocytes lacking T,B & Macrophage markers which non specifically suppresses Ag –specific cytolytic arm of Allogenic immune reactions  TLI can induce true Transplantation tolerance to Renal allografts in humans  UV-B light is absorbed by skin Urocanic acid & undergoes isomerization to Cis form which induces suppression through effect on Dendritic APC  Adverse Effects:  Myelosuppression  Skin changes  Nausea and vomiting
  5. 5. PHYSICAL IMMUNOSUPPRESSANTS  Plasmapheresis:  removing plasma hemocomponent that is circulating with pathogens and replacing it with a suitable solution Useful adjunct to chemotherapy for removing circulating immunoglobulins or immunoglobulin components in multiple myeloma and other dysproteinemias      Rapidly removes pathogenic antibody Must be combined with B lymphotoxic drug to prevent rebound (e.g. cyclophosphamide, steroids) Combination with IVIg very powerful Risks include cardiovascular instability
  6. 6. PHYSICAL IMMUNOSUPPRESSANTS Thoracic duct drainage:  Woodruff demonstrated that synergism of thoracic-duct drainage with lymphoid-depleting modality, antilymphocyte serum  effective and safe in decreasing the immunologic response of the recipient of renal transplants from genetically related donors  Lymphocytapheresis using TDD is very selective for removing lymphocytes (especially helper Tcells) 
  7. 7. CHEMICAL IMMUNOSUPRESSANTS  Corticosteroids: Prednisone , Prednisolone Dexamethasone,Methylpredinsolone  They have both anti-inflammatory action and immunosuppressant effects • Mechanism of action:  bind to glucocorticoid receptors and the complex interacts with DNA to inhibit gene transcription of inflammatory genes  stimulates migration of T cells from intravascular tissue to lymph nodes  Inhibit mitosis of lymphocytes  Reduce size and lymphoid content of the lymph node and spleen  Inhibit the production of inflammatory mediators, including PAF, leukotrienes, prostaglandins, histamine and bradykinin  Decrease production of cytokines IL-1, IL-2, interferon, TNF
  8. 8. Corticosteroids Dosage: Maintenance up to 20 mg/day; treatment of rejection 200 mg/day for 3 dats or 3 days Adverse Effects:  Sodium and fluid retention,  Muscle weakness,  Steroid myopathy,  Loss of muscle mass and osteoporosis,  Peptic ulcer with possible perforation and hemorrhage;  Pancreatitis, impaired wound healing, thin fragile skin  Increased tendency to diabetes mellitus  Hypertension 
  9. 9. Cytostatics  Cytostatics inhibit cell division  In immunotherapy, they are used in smaller doses than in the treatment of malignant diseases.  They affect the proliferation of both T cells and B cells.  Due to their highest effectiveness, purine analogs are most frequently administered.  It includes the following: Alkylating agents; Antimetabolites  ALKYLATING AGENTS:  The alkylating agents used in immunotherapy are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others  In small doses, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias,Wegener's granulomatosis and other immune diseases
  10. 10. Cyclophosphamide  Cyclophosphamide is an alkylating agent. It is a widely used as a cytotoxic agent.  It is given orally as well as intravenously with efficacy  Mechanism of action: suppress bone marrow function  It is inactive in parent form, and must be activated to cytotoxic form by liver CYT450 liver microsomal system to 4‐Hydroxycyclophamide and Aldophosphamide. 4‐Hydroxycyclophamide and Aldophosphamide are delivered to the dividing normal and tumor cells.  Aldophosphamide is converted into acrolein and phosphoramide mustard.They crosslink DNAs resulting in inhibition of DNA synthesis  Side effects: Usually large Doses of cyclophosphamide is associated with ‐  a. Pancytopenia  b. Hemorrhagic cystitis  c. Nausea and vomiting  d. Cardiac toxicity  e. Electrolyte imbalances
  11. 11. ANTIMETABOLITES  Includes folic acid analogues, such as methotrexate; purine analogues such as azathioprine and mercaptopurine pyrimidine analogues; protein synthesis inhibitors Azathioprine :          Prodrug that releases 6-mercaptopurine Mechanism of Action: Converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which is converted to thioguanine nucleotides that interfere with DNA synthesis; thioguanine derivatives may inhibit purine synthesis Uses: a. Used for graft rejection b. Normally used in combination with corticosteroids. Side effects: Bone marrow suppression (leukopenia, anemia), Skin rashes,nausea Liver toxicity ,macrocytosis Mycophenolate mofetil
  12. 12. Mycophenolate mofetil  Mycophenolic acid from penicillium molds  Mechanism of Action:  Prevents T- and B-cell proliferation by inhibition of de novo purine synthesis by inhibition of inosine monophosphate dehydrogenase  Dosage 1 to 2 g/day in divided doses  CLINICAL USE:  Solid organ transplants for refractory rejection.  Steroid-refractory hematopoietic stem cell transplant patients.  Combined with prednisone as alternative to CSA or tacrolimus.  Rheumatoid arthritis, & dermatologic disorders.  Adverse Effects:  Leukopenia, neutropenia.  Lymphoma  GIT toxicity
  13. 13. Leflunomide  Pyrimidine synthesis inhibitor  Active metabolite undergoes enterohepatic circulation  Arava oral administration as tablets containing 10, 20, or 100 mg  Mechanism of Action:  Dihydroorotate dehydrogenase inhibitor  antiproliferative activity  CLINICAL USE:  rheumatoid arthritis  Organ transplant  Adverse Effects: Elevation of liver enzymes Renal impairment Teratogenicity Cardiovascular effects
  14. 14. Methotrexate  a folic acid antagonist  Mechanism of Action:  Inhibits dihydrofolate reductase required for folic acid activation (tetrahydrofolic)  Inhibition of DNA, RNA &protein synthesis  Interferes with T cell replication.  Rheumatoid arthritis & psoriasis and Crohn disease  Adverse effects  Nausea-vomiting-diarrhea  Alopecia  Bone marrow depression  Pulmonary fibrosis  Renal & hepatic disorders
  15. 15. Antibodies  block T cell surface molecules involved in signaling immunoglobulins  They are of two types:  Polyclonal antibodies & Monoclonal antibodies  Polyclonal antibodies:  obtained from plasma or serum of horses hyper-immunized with human lymphocytes.  Inhibit T lymphocytes and cause their lysis, which is both complement mediated cytolysis and cell-mediated opsonization followed by removal of reticuloendothelial cells from the circulation in the spleen and liver. • Antithymocyte globulin (ATG) • Antilymphocyte globulin (ATGAM)
  16. 16. Polyclonal antibodies  Mechanism of Action:  agents contain antibodies specific for many common T cell antigens including CD2, CD3, CD4, CD8, CD11a, CD18  Blocks T-cell membrane proteins (CD2,CD3, CD45, and so forth), causing altered function, lysis, and prolonged T-cell depletion  CLINICAL USE:  Combined with cyclosporine for bone marrow transplantation.  To treat acute allograft rejection.  Steroid-resistant rejection.  Adverse Effects:  Leukopenia ,Thrombocytopenia  serum sickness  muscle pain  lymphopenia
  17. 17. Monoclonal antibodies  Monoclonal antibodies are antigen-specific immunosuppressants that will reduce immune response to alloantigens of the graft while preserving the response to alloantigens to unrelated antigens  Early rejection prophylaxis and treatment of rejection.  Muromonab-CD3 (OKT3):  Directed against CD3 component of T-cell–receptor  signal-transduction complex  Mechanism of Action:  Binds to CD3 associated with T-cell receptor,leading to initial activation and cytokine release, followed by blockade of function, lysis, and T-cell depletion  Adverse Effects:  Severe cytokine-release syndrome, pulmonary edema, acute renal failure, gastrointestinal disturbances, changes in central nervous system
  18. 18. Alemtuzumab  Humanized monoclonal antibody against CD52  Approved for use in B-cell chronic lymphocytic leukemia  Mechanism of Action:  Binds to CD52 on all B and T cells, most monocytes, macrophages, and natural killer cells, causing cell lysis and prolonged depletion  Efficacy:  effective as induction therapy for the prevention of acute rejection in kidney, liver, pancreas, intestinal, and lung transplants  Adverse Effects:  pancytopenia, neutropenia, thrombocytopenia, and lymphopenia  hypotension, fever, shortness of breath
  19. 19. Basiliximab and Daclizumab  Basiliximab is a chimeric human-mouse IgG (25% murine, 75% human protein).  Daclizumab is a humanized IgG (90% human protein).  Mechanism of Action:  Binds to and blocks the interleukin-2–Receptor a chain (CD25 antigen) on activated T cells, depleting them and inhibiting interleukin-2–induced T-cell activation  Efficacy:  Both basiliximab and daclizumab are approved for use in kidney transplantation in combination with cyclosporine and corticosteroids  Adverse Effects:  Hypersensitivity reactions (uncommon)  gastrointestinal disorders
  20. 20. Drugs acting on Immunophilins  Cyclosporine:  11-amino-acid cyclic peptide from Tolypocladium inflatum  Mechanism of Action:  Binds to cyclophilin intracellular protein receptors  complex inhibits calcineurin phosphatase and T-cell activation  CLINICAL USE:  Kidney, liver, heart organ transplantation used in combination with azathioprine and corticosteroids  Adverse Effects:  Nephrotoxicity, hemolytic–uremic syndrome, hypertension  neurotoxicity, gum hyperplasia  skin changes ,hirsutism,  post-transplantation diabetes mellitus  hyperlipidemia
  21. 21. Tacrolimus (FK506)  Macrolide antibiotic From Streptomyces tsukubaensis  Mechanism of Action:  Binds to FK-binding protein 12; inhibits synthesis and release of IL-2  CLINICAL USE:  Organ and stem cell transplantation  Prevention of rejection of liver and kidney transplants (with glucocorticoids).  TAC is 10 – 100 times more potent than CsA in inhibiting immune responses  Toxic effects :  lower incidence of hypertension, hyperlipidemia, skin changes, hirsutism, and gum hyperplasia  higher incidence of post-transplantation diabetes mellitus and neurotoxicity
  22. 22. Sirolimus (Rapamycin)   Triene macrolide antibiotic from Streptomyces hygroscopicus from Easter Island  Mechanism of Action:  Binds to FKBP12; complex inhibits target of rapamycin and interleukin-2– driven T-cell proliferation  Blocks the progression of activated T cells from G1 to S phase of cell cycle  Efficacy:  approved for the prophylaxis of rejection in kidney transplant patients  treatment of variety of tumors including small cell lung cancer, pancreatic cancer, leukemia ,lymphoma, rhabdomyosarcoma, neuroblastoma  Adverse Effects:  Hyperlipidemia, increased toxicity of calcineurin inhibitors,  thrombocytopenia, delayed wound healing,  delayed graft function
  23. 23. New Immunosuppressive Drugs  derived from myriocin, a fungus-derived sphingosine analogue  Mechanism of Action:  Works as an antagonist for sphingosine-1-phosphate receptors on lymphocytes, enhancing homing to lymphoid tissues and preventing egress, causing lymphopenia Prescribed for – Renal transplant – Multiple sclerosis • • Side effect – Reversible first-dose bradycardia, potentiated by general anesthetics and beta-blockers – nausea, vomiting, diarrhea, increased liver-enzyme
  24. 24. New Immunosuppressive Drugs  Etanercept (Enbrel)  Recombinant DNA drug  binds TNF (tumor necrosis factor) in the circulation and in the joint, preventing interaction with cell surface TNF receptors thereby reducing TNF activity  Subcutaneous injection  Side effects  Susceptibility to opportunistic infection  ISA 247  novel isomeric cyclosporine A analog mixture a calcineurin inhibitor.  treatment of psoriasis and prevention of organ rejection after transplantation
  25. 25. REFERENCE  TEXT BOOKS:  JANEWAY’S Immunobiology 7th ed  Kuby Immunology.6th ed  Ivan Roitt Essential Immunology 11th ed  WEBSITES & JOURNALS  Immunosuppression after Liver Transplantation  1/  The new england journal Of medicine  Erasmus Journal of Medicine • vol 1 - nr 2 - January 2011  Ultraviolet A Radiation: Its Role in Immunosuppression and Carcinogenesis  Current Concepts of Immunosuppression and Side Effects Anand Khurana and Daniel C. Brennan  Pancreas-Kidney Transplantation: Drugs (http:/ / www. pancreas-kidney. com/ drugs. html), a brief history of immunosuppressive drugs. Accessed on 21 August 2005  Immunosuppressants, Pharmacologic profile (http:/ / www. drugguide. com/ classification_articles/ immunosuppressants. htm). Accessed on 21 August 2005