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  1. 1.  Immunomodulators are medications used to help, regulate or normalize the immune system  Immunomodulators or biological-response modifiers include both immunostimulatory and immunosuppressive agents
  2. 2.  Glucocorticoids  Calcineurin Inhibitors: Cyclosporine,Tacrolimus  Proliferation signal inhibitors (PSIs): Sirolimus, Everolimus,Temsirolimus, Zotarolimus  Cytotoxic Agents:  Alkylating agents: Cyclophosphamide, vinca alkaloids  Antimetabolites: Azathioprine, methotrexate, Mycophenolate mofetil, Leflunomide,Teriflunomide
  3. 3.  Others: Hydroxychloroquine,Thalidomide  IMiDs: Lenalidomide, Pomalidomide  Sphingosine-1-Phosphate Receptor Modulators:  Fingolimod, siponimod, ozanimod, and ponesimod.  Immunosuppressive antibodies: Antilymphocyte & Antithymocyte Antibodies  Immune Globulin Intravenous (IGIV)- Hyperimmune immunoglobulins
  4. 4.  Inhibitors of Immune CellAdhesion & Activation  Anti-LFA-1/LFA3 Mabs: Efalizumab,Alefacept  α-4 integrin inhibitor: Natalizumab  Tolerogens or Inhibitors of Immune Cell Costimulation:  Anti-CD80 &Anti CD86 Mabs: Abatacept
  5. 5.  CTLA-4 inhibitors: Ipilimumab  PD-1 inhibitor: Nivolumab  Miscellaneous: Rho (D) Immune Globulin  Immunostimulants: Bacillus Calmette-Guerin (BCG), Levamisole,Thalidomide  Recombinant Cytokines
  6. 6.  Lympholytic property- Glucocorticoids size & lymphoid content of the LN & spleen  Interfere with the cell cycle of activated lymphoid cells (CMI is more affected than humoral immunity)  Use: Immunosuppressant & anti- inflammatory agent majority of conditions
  7. 7.  It is a peptide antibiotic - act at an early stage in the antigen receptor induced differentiation ofT-cells & blocks their activation  It selectively suppress CMI  It is free of toxic effects on bone marrow & RE system
  8. 8.  May be given IV or PO; bioavailability is low  Metabolized in the liver by CYP3A4 & excreted in bile  Plasma t1/2 is biphasic 4-6 hr & 12-18 hr  Interactions:All nephrotoxic drugs enhance the toxicity  Failure of immunosuppression with inducers  Hyperkalemia with potassium supplements
  9. 9.  Standard drug for the transplantation of kidney, pancreas, liver, & cardiac transplantation  Cyclosporine+ methotrexate- prophylactic regimen in prevention of GVHD after allogeneic stem cell transplantation
  10. 10.  Autoimmune disorders, including uveitis, RA, psoriasis & asthma  Ophthalmic solution- Severe dry eye syndrome & ocular GVHD  A/E: Nephrotoxicity, 7 H, altered mental status, seizures, OI’s  Lymphoma & some cancers
  11. 11. Hypertension Hyperglycemia Hepatic dysfunction Hyperuricemia Hyperkalemia Hirsutism Hyperplasia of gums
  12. 12.  Macrolide antibiotic produced by Streptomyces tsukubaensis  On a weight basis it is 10-100 times more potent than cyclosporine in inhibiting immune responses  It has same M.O.A instead of cyclophilin it binds to FKBP-12 inhibit calcineurin
  13. 13.  It is valuable in liver transplantation because its absorption is not dependent on bile  It is considered as standard prophylactic agent ( with mtx or MMF ) in GVHD  It is also suitable for suppressing acute rejection that has set in
  14. 14. Rejection type Hyperacute Acute Chronic Mechanism Preformed recipient antibodies react with donor antigen & activate complement Cellular- Donor antigen activates recipientT cells Humoral: Recipient generates antibody response to donor antigen Both humoral & cellular in nature-- Chronic inflammation caused by the response of activated T cells to donor Antigen) Time course Minutes to hours Weeks to months Months to years Mode of damage Antibody- dependent, cell- mediated cytotoxicity or through activation of the complement cascade CytotoxicT cell mediated interstitial & vascular damage H- Antibody directed against endothelial cells (Acute vascular rejection) ActivatedT cells release cytokines i.e. recruit macrophages into the graft (chronic inflammation i.e. leads to intimal proliferation of the vasculature & scarring of the graft tissue). How suppressed Matching donor & recipient blood types Immunosuppression Cannot be suppressed (Major cause of graft loss)
  15. 15. Cyclosporine acts by decreasing the production of: ⓘ Start presenting to display the poll results on this slide.
  16. 16.  GVHD is a major complication of allogeneic bone marrow or stem cell transplantation  Occurs when transplanted immune cells attack the cells of the recipient.  GVHD ranges from mild to life-threatening  Ameliorated by removingT cells from the donor bone marrow before transplantation
  17. 17.  Other uses: FistulatingCrohn’s disease,  Topically:Atopic dermatitis & Psoriasis  Hypertension, hirsutism, gum hyperplasia & hyperuricemia are less marked than CSA  Tacrolimus is more likely to precipitate diabetes, cause neurotoxicity, alopecia & diarrhea. Dose-limiting toxicity is renal
  18. 18.  Sirolimus binds the circulating immunophilin FK506-binding protein 12 → an active complex i.e. inhibits the kinase activity of mTOR (mammalian target of rapamycin)  Blockade of mTOR – inhibition of interleukin drivenT-cell proliferation  t1/2 of sirolimus is- 60 hrs & i.e. of everolimus is 43 hrs
  19. 19.  To prevent rejection of solid organ allografts  Prophylaxis & as therapy for steroid-refractory acute & chronic GVHD in hematopoietic stem cell transplant recipients  Sirolimus eluting coronary stents  Topically –in dermatological disorders & in combination with cyclosporine in uveoretinitis
  20. 20.  Prophylaxis of liver & kidney transplant rejection  Others: Cardiac stents  Advanced renal cell cancer, hormone receptor- positive Her-2 negative advanced breast cancer  Pancreatic neuroendocrine tumours
  21. 21.  Myelosuppression (esp. thrombocytopenia)  Hepatotoxicity, diarrhea, headache, hypertriglyceridemia & pneumonitis  ↑ use in stem cell transplantation regimens with tacrolimus has revealed an ↑ incidence of HUS
  22. 22.  Azathioprine : is a prodrug that is converted first to 6-mercaptopurine (6-MP) & then to the corresponding nucleotide, thioinosinic acid  They inhibit de novo purine synthesis & cause damage to DNA  Cellular immunity as well as primary & secondary serum antibody responses can be blocked
  23. 23.  Azathioprine is well absorbed PO & is metabolized primarily 6-MP, XO splits much of the active material to 6-thiouric acid  Much of the drug’s inactivation depends on XO , patients who are also receiving allopurinol for control of hyperuricemia should have azathioprine dose-↓ ½ to 1/3
  24. 24.  Uses: Maintaining renal allografts  Management of acute glomerulonephritis & in the renal component of SLE  RA, Crohn’s disease & MS  Prednisone-resistant antibody-mediated ITP & AIHA  A/E: BM suppression, skin rash, fever, nausea, vomiting, diarrhoea & hepatic dysfunction
  25. 25.  Inhibiting DHFRase & thymidylate synthase  It markedly depresses cytokine production & cellular immunity & has anti-inflammatory property  Uses: Autoimmune diseases like rapidly progressive RA, MG, psoriasis, uveitis etc.
  26. 26.  Semisynthetic derivative of mycophenolic acid, isolated from - mold Penicillium glaucus  M.O.A: MPA, a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) an important enzyme in the de novo pathway of guanine nucleotide synthesis
  27. 27.  MMF undergoes rapid & complete metabolism to MPA after PO or IV administration  The t1/2 of MPA is ~16 hours  Uses: For prophylaxis of transplant rejection, in combination with glucocorticoids & a calcineurin inhibitor  Prophylaxis & Rx of both acute & chronic GVHD in hematopoietic stem cell transplant patients
  28. 28.  Prevention of chronic allograft vasculopathy in cardiac transplant recipients  New applications: Lupus nephritis, RA, IBD, & some dermatological disorders  A/E: GI disturbances, headache, hypertension  Reversible myelosuppression (Neutropenia)  Predisposition for infections, esp.CMV
  29. 29.  Leflunomide: It is a prodrug of teriflunomide  Dihydroorotate dehydrogenase
  30. 30.  It inhibitsTNF-α, reduces phagocytosis by neutrophils, ↑ production of IL-10, alters adhesion molecule expression & ↑ CMI  Uses: Multiple myeloma- at initial diagnosis or relapsed-refractory disease with dexamethasone  GVHD, ENL, Skin manifestations of SLE
  31. 31.  A/E: Peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, & ↑ risk of DVT  Immunomodulatory derivatives of thalidomide (IMiD’s):  Lenalidomide- MDS with 5q deletion, primary and relapse/refractory myeloma  Pomalidomide- Relapse or refractory MM
  32. 32.  Polyclonal: IGIV, Rho(D) Immune globulin micro-dose, hyperimmune immunoglobulins  Monoclonal antibodies:  Muromonab-CD3: It is murine MAB against CD 3 glycoprotein expressed near to theTCR on helperT cells  It obstructs approach of the MHCII-antigen complex to theT-cell receptor
  33. 33.  Acute renal allograft rejection & steroid resistant acute cardiac & hepatic transplant rejection  A/E: Initial doses are associated with cytokine release syndrome with flu like symptoms  Occasionally aseptic meningitis, intragraft thrombosis, pulmonary edema, seizures & shock like state is produced  Rx- High dose corticosteroid pretreatment