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Immunomodulators

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Immunomodulators

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Immunomodulators

  1. 1. Immunomodulators PRESENTED BY SARATHLAL KC M PHARM PART 1 DEPT. OF PHARMACOLOGY
  2. 2. Contents • Introduction • Organ Rejection • Methods of Immunosuppression • Immunostimulants. • Conclusion • References
  3. 3. Introduction • Immunomodulators are drugs which either suppress or stimulate the immune system – (Immunosuppressants and Immunostimulants) • Have been in use for more than 50 years. • begin with non specific corticosteroids, antimetabolites and alkylating agents. • Now the specific inhibitors of immune responses are available.
  4. 4. Transplantation • The first successful transplant: 1954 kidney transplant between two identical twins. • No immunosuppression was used. • Currently, most organ transplantation occurs between unrelated individuals. • Donor and recipient tissues express different MHC molecules. • Recipient immune cells can recognize this MHC (consider the transplanted tissues as foreign. ) Richard and Ronald Herrick
  5. 5. Organ Rejection Divided into three major phases according to the time of onset. • Hyper acute • Acute • Chronic rejection Caused by different mechanisms and are therefore treated differently.
  6. 6. Hyper-acute Rejection • mediated by preformed recipient antibodies against donor antigen. • these antibodies are present in receiver at the time of organ implantation. • hyper acute rejection occurs immediately after reperfusion of the transplanted organ. • Can readily notice the changes within few minutes.
  7. 7. • The normal healthy, pink organ become cyanotic, mottled and flaccid. • This is by the compliment activation by the antibody, when it binds to the endothelial cells of transplanted organ. • Most commonly the recipients antibody reacts with blood group antigens. • Transplant from Matching blood group prevents the Hyper acute Rejection
  8. 8. Acute rejection  acute cellular rejection  acute humoral rejection Acute cellular • Mediated by the cytotoxic T cells, leads to interstitial and vascular damage. • Seen in months after transplantation. • Suppressing the T cells is effective at preventing the acute rejection.
  9. 9. Acute humoral rejection • Recipients B cells become sensitized to donor antigens. • Antibodies are produced within 7-10 days. • Antibody responses directs to endothelial cells (acute vascular rejection).
  10. 10. Chronic Rejection • believed to be both humoral and cellular in nature. • does not occur until months or years after transplantation. • chronic inflammation caused, by the response of activated T cells to donor antigen. • Activated T cells release cytokines that recruit macrophages into the graft.
  11. 11. • The macrophages induce chronic inflammation • The chronic changes eventually lead to irreversible organ failure. • effective treatment regimens are currently not available to eliminate chronic rejection.
  12. 12. Auto-immunity • when the body produces an immune response toward its own tissue. • failure to distinguish self tissues and foreign antigens. • Result is chronic inflammation. • Rheumatoid Arthritis, Crohns disease, Ulcerative colitis.
  13. 13. Immunosuppression 1. Inhibition of gene expression 2. cytotoxic agents. 3. Inhibition of lymphocyte signalling. 4. Cytokines inhibitors. 5. Depletion of specific immune cells. 6. Inhibition of co-stimulation 7. Blockade of cell adhesion 8. Inhibition of compliment activation
  14. 14. Inhibition of gene expression Glucocorticoids Steroid hormones, have broad anti inflammatory activity. Binds with glucocorticoid receptor. glucocorticoid - glucocorticoid receptor complex translocate to nucleus. Binds to GREs in specific genes Regulates the gene expression down regulate the inflammatory mediators. (IL1, IL4 TNFα etc.) ( glucocorticoid response elements)
  15. 15. Cytotoxic agents. Used for both immunosuppression and antineoplastic chemotherapy.  Antimetabolites  Alkylating agents Antimetabolites • Are powerful immunosuppressant. • No selectivity in immunosuppression • Acts on both cell mediated and humoral mediated immunity.
  16. 16. • Azathioprine and Methotraxate are older drugs which affect all rapidly dividing cells, and also damages the intestinal mucosa. • Mycophenolyte mofetil and leflunamide are newer ones, having less adverse effects.
  17. 17. Azathiprine/Aza • Pro-drug of 6 mercapto purine. • Which reacts with sulfhydryl compounds like glutathione. • Which slow down the release of 6 mercapto purine. • This favours immunosuppression N N N H N S N HN NH2 HN N N H N S Glutathione 6mercaptopurineazathiprine
  18. 18. Methotraxate/MTX • It provides anti-inflammatory action by increasing adenosine level. • Adenosine is potent endogenous anti-inflammatory mediator. • It inhibits neutrophil adhesion, phagocytosis, and super oxide generation. • MTX also causes apoptosis of activated CD4 and CD8 T cells
  19. 19. Mycophenolic Acid and Mycophenolate Mofetil/ MPA ,MMF • inhibitor of IMPDH (inosine mono-phosphate dehydrogenase ). • the rate-limiting enzyme in the formation of Guanosine • MPA has low oral bioavailability, it is usually administered as a sodium salt or in its prodrug form, mycophenolate mofetil (MMF). • MPA and MMF both act on lymphocytes. • lymphocytes are dependent on the de novo pathway of purine synthesis, whereas most other cells rely heavily on the salvage pathway.
  20. 20. • IMPDH is expressed in two isoforms, type 1. IMPDH type 2. IMPDH MPA preferentially inhibits type 2 IMPDH, the isoform expressed mainly in lymphocytes. Reduces intracellular Guanosine levels Elevates intracellular adenosine levels.
  21. 21. Leflunomide • Leflunomide is an inhibitor of pyrimidine synthesis. • blocks the synthesis of uridylate mono phosphate N H O O H+ H20 N H HN O O O O NAD NADH dihydroorotate dehydrogenase N HN O O OH HH HH OH O P O O O O n carbamoylaspartate dihydroorotate leflunamide UMP FK778, metabolite of leflunomide Astellas Pharma Inc, Europe
  22. 22. Alkylating Agents Cyclophosphamide/Cy • Highly toxic drug that alkylates DNA. • Able to attach the nucleophilic sites on the DNA. • Results in covalent attachment of an alkyl group. • N7 or O6 atoms are the place of attachment. • Guanosine base is more susceptible for alkylation. Which form bis- alkylation. • Leads to the cross linking of Guanosine residues – produces cytotoxicity.
  23. 23. DNA anomalies caused by • It cleaves the Guanosine imidazole ring, • Produces abnormal base pairing, • Depurination. O P H N O N Cl Cl Cyclophosphamaide
  24. 24. Inhibition of Lymphocyte signalling. Cyclosporine and Tacrolimus • Cyclosporine/CsA discovered in 1976. (also referred to as Cyclosporin A ) • CsA is a cyclic decapeptide isolated from a soil fungus, Tolypocladium inflatum. • Specific inhibitor of T-cell-mediated immunity. • It also inhibits the production of IL2 by activated T Cells. • IL2 activates and proliferates further T cells.
  25. 25. Activated T cells produces IL2 via Dephosphorilation of NAFT (nuclear factor activated T cell - a cytoplasmic transcription factor) Calceneurin is needed for dephosphorilation (Cytoplasmic Phosphatase) Translocates to nucleus Transcriptin of IL2 gene. • Cyclosporine bind s to cyclophilin - binding protein. • Tacrolimus binds to FKBP – FK binding protein.
  26. 26. (nuclear factor activated T cell) ISA 247 Aurinia Pharmaceuticals NCT00504543 Novartis Pharmaceuticals
  27. 27. Sirolimus (rapamycin) • Obtained from bacteria Streptomyces hygroscopicus. • Binds to FKBP, • FKBP- sirolimus complex does not inhibit calcineurin. • Instead it blocks IL2 receptor signalling required for T cell proliferation. • FKBP- sirolimus complex binds to molecular target of rapamycine (mTOR)
  28. 28. • Which inhibits p70 - S6 kinase and PHAS-1 activity, which responsible for translation. • Thus mTOR inhibition causes cell division arrests at G1 phase. molecular target of rapamycine
  29. 29. Cytokine Inhibition • Cytokines are critical signalling mediators in immune function. • They are pleiotropic (they exert different effects depending on the target cell) • 4 types 1) TNFα Inhibitors, 2) IL12/IL23 p40 inhibitors , 3) IL1 inhibitors. 4) Cytokine receptor antagonists.
  30. 30. • TNFα Inhibitors Etanercept is links the extracellular, ligand-binding domain of human TNF receptor. • IL-12/IL-23 p40 Inhibitors diffferntiation of naive T cells heterodimer composed of p40 and p35 subunits Ustekinumab that can binds to the p40 subunit. • IL1 inhibitors IL1 stimulates the production of IL6 enhances the expression of adhesion molecule Anakinra - IL1 receptor antagonist • Cytokine receptor antagonists Alternative approach to block the action of inflammatory cytokines. Tocilizumab administered for rheumatoid arthritis as i.v infusion for very 4 weeks.
  31. 31. Depletion of specific immune cells. Targeted antibody therapy can deplete the reactive immune cells. Polyclonal antibodies • ATG (anti thymocyte globulin) antibodies produced by injecting human thymocyte into rabbit or horse. • ATG targets all T cells and leads to profound lymphocyte depletion. • it produce broad immunosuppression, and can predispose to infections. • Used for renal transplant rejection.
  32. 32. Monoclonal antibodies OKT3 (Muromonab- CD3/anti CD3). • Mouse monoclonal antibody against human CD3 • CD3 expressed in both CD4 and CD8 • Treatment with OKT3 depletes T cell, via antibody mediated compliment activation. • Used for renal transplant rejection • Second line agent for CsA or Glucocorticoid failure.
  33. 33. Anti-CD20 mAb Rituximab is a partially humanized anti-CD20 monoclonal antibody. (CD20 expressed in all B cells.) Anti-CD25 mAb • Daclizumab and basiliximab are monoclonal antibodies against CD25. ( have high affinity towards IL-2 receptor.) • CD25 is expressed in activated T cells. • It selectively targets T cells that have been activated by an MHC-antigen • T10B9.1A monoclonal antibody & (MedImmune LLC) • FTY720 (Novartis phase III)
  34. 34. • MHC : Antigen : TCR interaction (signal 1) • B7 : CD28 (signal 2) • B7 - Abatacept complex prevents delivery of a costimulatory signal and the T cell develops anergy • Abatacept therapy down-regulats prolifertion & differentiation of T cells. • Belatacept is a structural congener of Abatacept. Fig 1 Fig 2 Inhibition of Co-stimulation
  35. 35. Blockade of Cell Adhesion The recruitment and accumulation of inflammatory cells at sites of inflammation is an essential element of autoimmune diseases Alpha - 4 integrins are critical to immune-cell adhesion Two types : α4β1 integrins (mediates immune-cell interactions with cells expressing vascular cell adhesion molecule 1 (VCAM-1) α4β7 integrins (mediates immune-cell binding to cells expressing mucosal cell adhesion molecule 1 (MCAM-1) Natalizumab is a monoclonal antibody act against α4 integrin that inhibits immune cell interactions with cells expressing VCAM-1 or MCAM-1
  36. 36. Inhibition of Complement Activation Provides innate immune responses ( by classical, alternative or lectin pathway) Foreign bodies/antigen activation of complement proteins (C3a , C3b) activation of complement proteins C5 Membrane Attack Complex - MAC (a multiprotein structure that can cause cell lysis) Eculizumab is a humanized monoclonal antibody against C5, (Responsible for activation and triggers assembly of the membrane attack complex.)
  37. 37. Immunostimulants immunostimulatory drugs have been developed with applicability to infection, immunodeficiency, They works on cellular as well as humoral immune system or both Levamisole: • Levamisole was synthesized originally as an anthelmintic • but it restores the depressed immune function of B lymphocytes, T lymphocytes, monocytes and macrophages • ADR: Flu-like symptoms, allergic manifestation, nausea and muscle pain.
  38. 38. Thalidomide: • Increases TNFα in patients who are HIV-seropositive. • But Decreases circulating TNFα in patients with erythema nodosm leprosum • suggested that the drug affects angiogenesis. • Teratogenicity is an undesirable effect. Isoprinosine: • Isoprinosine is a complex of the pacetamidobenzoate salt of N,N- dimethylamino-2- propanol and inosine (3:1 molar ratio)
  39. 39. Mechanism of action: • Leads the production of cytokine such as IL-1, IL-2 and IFN-γ. • Increases proliferation of lymphocytes. • ADR: Minor CNS depressant, transient nausea and rise of uric acid in serum and urine.
  40. 40. Immunisation Vaccines and immunoglobulins (Rho Ig) Bacillus Calmette-Guerin (BCG) • Live culture of Bacillus Calmette-Guerin strain of Mycobacterium bovis. • Induces granulomatous reaction at the site of administration. Therapeutic uses: • Treatment and prophylaxis of carcinoma of the urinary bladder, • prophylaxis of primary and recurrent stage of papillary tumors Adr : Hypersensitivity, shock, chills, fever, malaise,
  41. 41. Recombinant Cytokines Interferon gamma-1b a recombinant polypeptide that activates phagocytes induces the generation of oxygen metabolites that are toxic to a number of microorganisms. Interferon beta-1a 166-amino acid recombinant glycoprotein interferon beta-1b 165-amino acid recombinant glycoprotein Both have antiviral and immunomodulatory properties
  42. 42. Conclusion • Several approaches are available for the pharmacologic suppression of immunity, • ranging from the relatively low-specificity approaches to the more specific cell-signalling inhibitors and antibody therapies. • Novel ideas for the manipulation of the immune system are emerging.. • microRNAs (miRNAs) have been shown to have important regulatory roles in immunity, • Immunostimulnts are used in immunodeficient people. And also to improve the resistance to infection
  43. 43. References. • Golan D.E, Tajshjian A.H, Armstrong E.J, Armstrong A.W, Principles of pharmacology The pathophysiologic basis of drug therapy,3rd Edition, Lippincott Wlliams & Wilkins,2012,790-806. • Brunton LL, Lazo JS, Parker LK, Goodman & Gilman's The Pharmacological Basis Of Therapeutics, 11th Ed., McGraw-Hill, 2006,1291-1306. • Rang.H.P, Dale.M.M, Ritter.J.M, FlouerR.J, Pharmacology, Philadelphia, Churchil livingstone-elsevier,2003,244-260 • Patil U.S, Jaydeokar A.V, Bandawane D.D, immunomodulators : a pharmacological review, international journal of pharmacy and pharmaceutical sciences, vol 4, suppl 1, 2012. • http://www.pbs.org/wgbh/aso/databank/entries/dm54ki.html accessed on 24/6/2014

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