IMMUNOPHARMACOLOGY

1. IMMUNOPHARMACOLOGY BashirAlsiddiqyousef

2. *2 major components of the immune system: -INNATE Physical – skin, mucus membrane Biochemical – complement, lyzosyme Cellular – macrophages, neutrophils -ADAPTIVE Antibodies – HUMORAL immunity T-lymphocyte – CELL MEDIATED immunity Review

3. Macrophage APC B lymphocyte T lymphocyte IL-4,IL-5 IL-2 IL-2 TH1 TH2 IFN- TNF- IFN- IFN- • Plasma Cells: • IgG - IgM • IgA - IgD Activated Macrophage Activated Cytotoxic T cell Activated NK cells Memory B Cells CELL-MEDIATED IMMUNITY HUMORAL IMMUNITY

4. Hypersensitivity Autoimmune diseases Immunodeficiency Abnormal immune response

5. Types of Drugs *Immunosuppressants *Immunostimulants *Immunomodulators

6. Immunosuppressants

7. Major Steps in Immune Responses 1- Antigen recognition 2- IL-1 production 3- IL-2 and other cytokine expression 4- lymphocyte proliferation & differentiation

8. MAJOR STEPS IN IMMUNE RESPONSES CD8 T cell Antigen IL-2 cytotoxic T cells 1 4 3 2 primed CD4 T helper cell IL-2 IL-1 antigen presenting cell (macrophage, dendritic cell) CD4 T helper cell plasma cells 4 IL-2 B cell

9. SITES OF ACTION OF IMMUNOSUPPRESSIVE DRUGS CD8 T cell Antigen IL-2 X cytotoxic T cells X X primed CD4 T helper cell X X IL-2 IL-1 antigen presenting cell CD4 T helper cell plasma cells X cytokines

10. Corticosteroids Cyclosporine Tacrolimus Sirolimus Antimetabolites Antibodies Mycophenolatemofetil TNF-alpha binding drugs 15-Deoxyspergualin Thalidomide Immunosuppressants

11. Clinical uses *Prevention of organ transplant rejection *Treatment of autoimmune diseases -Multiple Sclerosis -SLE -Rheumatoid Arthritis -Crohn’sDisease *Treatment of allergic reactions like Bronchial asthma and Eczema.

12. (Steps 1 and 2 - T cell activation and IL2 production): IL-2 Protein: [Ca2+] IL-2 mRNA NFAT NFAT PO3 Nucleus IL-1 Calcineurin NFAT = Nuclear Factor of Activated T cells

13. T Cell T Cell T Cell (Step 3 - IL2 stimulation of T cell proliferation): IL2 Receptor T Cell mTOR Cell Proliferation Cytokine Production Activation of multiple types of immune cells

14. [Ca2+] Molecular basis for rejection (Steps 1 and 2 - T cell activation and IL2 production): T IL-1 Prednisone IL-2 Protein: Tacrolimus(FK506)/FKBP T Calcineurin T IL-2 mRNA Cyclosporine/Cyclophilin NFAT NFAT PO3 NFAT = Nuclear Factor of Activated T cells Nucleus

15. T Cell T Cell T Cell Molecular basis for rejection (Step 3 - IL2 stimulation of T cell proliferation): T Anti-IL-2 T Anti-IL-2 receptor IL2 Receptor T Cell mTOR T Cell Proliferation Sirolimus(rapamycin)/ FKBP T Cytokine Production • Cyclophosphamide • Methotrexate • Mycophenolate Mofetil Activation of multiple types of immune cells

16. Cyclosporine *lipophiliccyclic peptide Mechanism *inhibits transcription of IL-2 gene plus other cytokine expression (IL-3, gamma interferon) *site of action is a binding protein that inhibits calcineurin (a phosphatase) involved in signal transduction upon antigen stimulation of T cell receptor *used for transplant rejection and Autoimmune disorders.

17. Tacrolimus *macrolide(structure like erythromycin) produced by streptomycestsukubaensis. Mechanism *similiarto cyclosporine except binds to different protein that inhibits calcineurin (a phosphatase enzyme involved in gene transcription of IL-2, gamma interferon and other cytokines) *used for transplant rejection and Autoimmune disorders. *Pimecrolimus *Calcineurin inhibitor like Tacrolimus. *Approved for topical treatment of eczema.

18. Corticosteroid Steriod receptors

19. Corticosteroid

20. Corticosteroid *Inhibition of IL-1 and TNF gene expression and synthesis *Decreased activation of T lymphocytes by decreasing IL-1 release *Decreased neutrophil functions espchemotaxis *Decreased antibody production (high doses) *Decreased release of kinins and proinflammatoryeicosanoids (prostaglandins and leukotrienes) *Affects cell-mediated immunity more than humoral immunity

21. Autoimmune disorders • Modulate allergic reactions - asthma • Organ transplantation – rejection crisis

22. Sirolimus (Rapamycin) *macrolidesimiliar to tacrolimus isolated from streptomyceshygroscopicus. Mechanism *binds to immunophilin protein that binds to a key regulatory kinase required for T cell activation *(new unique mechanism to inhibit T lymphocyte activation by IL-2) *different site of action than cyclosporine and tacrolimus

23. Sirolimus -Inhibits mammalian target of rapamycin (mTOR) *mTORis a protein kinase that plays pivotal role in IL-2 receptor responses *IL-2 binds to its receptor on T cells and leads to mTOR activation *mTORinitiates cascade of events (including cyclin dependent kinases) that promote T lymphocyte proliferation and differentiation *Inhibition of mTOR blocks IL-2 dependent cell-cycle progression at G1→S phase transition

24. Sirolimus other theoretical actions include: *blockade of B cell Ig synthesis *inhibition of antibody-dependent cellular toxicity *inhibition of lymphocyte activated killer cells *inhibition of natural killer cells *inhibition of immune and nonimmune cell proliferation (via inhibition of growth factor signaling) (may explain antitumor actions)

25. MycophenolateMofetil *derivative of mycophenolic acid which isolated from penicilliumglaucum. Mechanism *inhibits inosinemonophosphatedehydrogenase involved in de novo synthesis of purines *selectively suppressess T- and B-cell proliferation *Also suppresses some macrophage functions (may explain anti-inflammatory actions) *used for transplanations.

26. NAD+ aspartate + GTP GDP + Pi NADH Gln + ATP fumarate Glu+AMP+PPi guanosine monophosphate (GMP) adenosine monophosphate (AMP) GDP ADP GTP ATP IMP IMP dehydrogenase adenylosuccinase 6-mercaptopurine adenylosuccinate XMP MycophenolateMofetil Formation of AMP and GMP from IMP

27. *Mizoribine inhibit same nucleotide synthesis pathway and very effective in kidney transplants. *BrequinarSodium inhibit de novo pathway of pyrimidinesynthesis and used for cancer & organ transplantation

28. Antimetabolites (Cytotoxic drugs) *Immunosuppresionby inhibition of lymphocyte proliferation and cause bone marrow suppression -Azathioprine -Cyclophosphamide -Leflunomide

29. Azathioprine *Metabolized to 6-mercaptopurines *Inhibit purine synthesis interferes with nucleic acid metabolism  inhibits cellular & humoralresponses *used for Renal allograft, SLE,rheumatoid arthritis, Crohn’s disease.

30. Leflunomide *Prodrugof an inhibitor of pyrimidinesynthesis *Inhibits lymphoid cells proliferation. *Approved for treatment of rheumatoid arthritis.

31. Cyclophosphamide *Most potent immunosuppressive drug act as alkylating agent. *Destroys proliferating lymphoid cells *Used for Autoimmune disorders: SLE

32. Other cytotoxic agents *Methotrexate has been used extensively in rheumatoid arthritis and in the treatment of graftversus- host disease. *dactinomycin has also been used with some success at the time of impending renal transplant rejection. *Vincristineappears to be quite useful in idiopathic thrombocytopenic purpura refractory to prednisone.

33. 15-Deoxyspergualin *isolated from Bacillus laterosporus. *Potent antimonocytic (by ↓ MHC antigen expression, ↓ antigen processing and presentation and inhibition generation of free radical) *antilymphocytic effect (by inhibiting antibody production and suppressing cytotoxic cell generation) *Inhibits T & B lymphocyte response *Renal transplants; pancreas & heart transplants

34. Thalidomide *Sedative drug *Favors TH2 over TH1 (immunomodulatory action) with up-regulation of IL-4 and IL-5. *Suppress TNF-αproduction *Anti-angiogenesis action related for teratogenicity& anticancer activity. *Indications -Erythemanodosumleprosum (skin manifestations of SLE) -Lung transplantation

35. FTY720 *prodrug: requires phosphorylation *Sphingosine1-phosphate receptor (S1P-R) agonist *Reduces recirculation of lymphocytes from lymphatic system to the blood *Lymphocyte homing action which reversibly sequesters host lymphocytes into lymph nodes *Useful in combination therapy but not alone for autoimmune diseases such as RA.

36. Drugs that target receptors Anakinra: *Human IL-1 receptor antagonist *Disease modifier agent for Rheumatoid arthritis

37. TNF-α receptors antagonist Infliximab, etanercept, and adalimumab: *are new biologic agents that bind and block TNF receptors. results in suppression of downstream inflammatory cytokines such as IL-1 and IL-6 and adhesion molecules involved in leukocyte activation and migration. *Used for Crohn's disease, rheumatoid arthritis, and psoriatic arthritis.

38. Antibodies OKT3 (Muromonab-CD3) *monoclonal antibody to CD3 on T cell *inhibits cytotoxic T killer cell function *opsonizescirculating T lymphocytes and enhances their removal *used to prevent or reverse acute graft rejection Antilymphocyte Globulin *polyclonal antibody similiar to OKT3

39. AntithymocyteGlobulin-Rabbit (Thymoglobulin): *Rabbit gamma immune globulin preparation *Composed of antibodies to variety of T cell markers *Mechanisms -removal of T cells from circulation -modulation of T cell activation, homing and cytotoxicity -decreases cytokine induced reactions

40. IL-2 Receptor Antibodies -Basiliximab and Daclizumab: *monoclonal antibodies against human IL-2 receptor alpha subunit of activated T to block T cell *Blocks activation and inhibits clonal expansion of T cells *Used to induce immunosuppression and to prolong organ transplants in combination with immunosuppressants

41. Alefacept *Recombinant DNA-derived humanized monoclonal antibody *It inhibits activation of T cells by binding to cell surface CD2 and inhibiting the normal CD2/LFA-3 interaction *approved for the treatment of plaque psoriasis

42. Efalizumab *is a humanized IgG1mAb targeting the LFA-1 (lymphocyte function associated antigen). *Efalizumab binds to LFA-1 and prevents the LFA-1-ICAM (intercellular adhesion molecule) interaction to block T-cell adhesion, trafficking, and activation. *used for graft rejection and psoriasis.

43. Alemtuzumab *New Immunosuppressant *Recombinant DNA-derived humanized monoclonal antibody *Binds to CD52. a nonmodulating antigen present on surface of all T and B cells *Some bone marrow cells express CD52 including some CD34+ cells *Produces profound T cell depletion *Used for for selected leukemias and lymphomas also for stem cell transplant procedures

44. Other Antibody Preparations Rh(D) Immune Globulin *for Rh (neg.) mother after delivery of Rh(pos.) baby. Abciximab *for surface receptor on activated platelets to prevent restenosis after coronary angioplasty Rituximab *for CD20 on pre-B and mature B cells to treat non-hodgkins lymphoma

45. Palivizumab *monoclonal antibody that binds to the fusion protein of respiratory syncytial virus, preventing infection in susceptible cells in the airways. Trastuzumab *monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor HER-2/neu. Used for treatment of metastatic breast CA

46. View Notes

47. Immunostimulants

48. *These drugs increase the immune response for patients therefore used in: • Infection treatment. • Immunodeficiency • cancer

50. Immunostimulatory Cytokines Interleukins *IL-2 (enhance antitumor actions of cytotoxic T cells and NK cells) and therefore use for treatment of cancer such as renal carcinoma and malignant melanoma. Colony Stimulating Factors *G-CSF (neutropenia) and GM-CSF (bone marrow transplant patients) *GM-CSF can itself stimulate an antitumor immune response, resulting in tumor regression in melanoma and prostate cancer