Prof. Mervat Hesham

1. Prof. Mervat Hesham

2. The Immune Response - why and how ? • Discriminate: Self / Non self • Destroy: • Infectious invaders • Dysregulated self (cancers) • Immunity: • Innate, Natural • Adaptive, Learned

3. • Innate immune response – first line of defense against an antigenic insult. Includes • defenses like physical (skin), • Biochemical (complement, lysozyme, interferons) • cellular components (neutrophils, monocytes, macrophages). • Adaptive immune response a) Humoral immunity - Antibody production – killing extracellular organisms. b) Cell mediated immunity – cytotoxic / killer T cells – killing virus and tumour cells.

4. Who are involved ? • Innate • Complement • Granulocytes • Monocytes/macrophages • NK cells • Mast cells • Basophils • Adaptive: • B and T lymphocytes • B: antibodies • T : helper, cytolytic, suppressor.

5. ABNORMAL IMMUNERESPONSE • Hypersensitivity reactions Type 1 – Anaphylactic shock Type 2 – mismatched blood transfusion Type 3 – Serum Sickness, glomerulonephritis and arthritis. Type 4 – TB, leishmaniasis.

6. Autoimmunity – Autoimmune diseases arise when the body mounts an immune response against itself as a result of failure to distinguish self tissues and cells from foreign antigens. Rheumatoid Arthritis, S.L.E, Type 1 Diabetes Mellitus, Multiple Sclerosis etc…. • Immunodeficiency Diseases a) Congenital – Di George’s syndrome, SCID due to ADA deficiency. b) Extrinsic – HIV causing AIDS.

8. DEFINITION Immunomodulators are drugs which either suppress the immune system – Immunosuppressants or stimulate the immune system – Immunostimulants

10. Immunosuppressants • Glucocorticoids - Prednisolone. • Calcineurin inhibitors • Cyclosporine • Tacrolimus • Antiproliferative / antimetabolic agents • Sirolimus • Everolimus • Azathioprine • Mycophenolate Mofetil • Others – methotrexate, cyclophosphamide, thalidomide and chlorambucil , Interferon

11. Antibodies • Antithymocyte globulin • Anti CD3 monoclonal antibody • Muromonab • Anti IL-2 receptor antibody – • Daclizumab, basiliximab • Anti TNF alpha – infliximab, etanercept

13. Immunosuppressants • Organ transplantation • Autoimmune diseases Problem Life long use Infection, cancers Nephrotoxicity Diabetogenic

14. 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

15. USES - Glucocorticoids • Transplant rejection • GVH – BM transplantation • Autoimmune diseases – RA, SLE, Hematological conditions • Psoriasis • Inflammatory Bowel Disease, Eye conditions

16. Toxicity • Growth retardation • Avascular Necrosis of Bone • Risk of Infection • Poor wound healing • Cataract • Hyperglycemia • Hypertension

17. CALCINEURIN INHIBITORS •Calcineurin (CN) is a protein phosphatase activates the T cells of the immune system and can be blocked by drugs. Cyclosporine – • – bind to the cytosolic protein cyclophilin(an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits the phosphatase calcineurin, which under normal circumstances induces the transcription of interleukin-2. • The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.

18. 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

19. Toxicity : Cyclosporine • Renal dysfunction • Tremor • Hirsuitism • Hypertension • Hyperlipidemia • Gum hyperplasia • Hyperuricemia – worsens gout • Calcineurin inhibitors + Glucocorticoids = Diabetogenic

20. Tacrolimus ( FK 506, Prograf ) – It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects. Use -Prophylaxis of solid-organ allograft rejection –Topical preparation available for use in atopic dermatitis and psoriasis.

21. Toxicity - Tacrolimus • Nephrotoxicity • Neurotoxicity-Tremor, headache, motor disturbances, seizures • GI Complaints • Hypertension • Hyperglycemia • Risk of tumors, infections

22. Sirolimus (rapamycin, trade name Rapamune) • Contrary to ciclosporin and tacrolimus, drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second one( namely signal transduction and lymphocyte clonal proliferation). • It binds to FKBP1A like tacrolimus, however the complex does not inhibit calcineurin but another protein, mTOR (mammalian target of rapamycin ).

23. It indirectly inhibits several T lymphocyte-specific kinases and phosphatases, hence preventing their transition from G1 to S phase of the cell cycle. • Sirolimus prevents B cell differentiation into plasma cells, • reducing production of IgM, IgG, and IgA antibodies.

24. CELL CYCLE

25. Sirolimus Uses • Prophylaxis of organ transplant rejection with other drugs Toxicity • Increase in serum cholesterol, Triglycerides • Anemia • Thrombocytopenia • Hypokalemia • Fever • GI effects • Risk of infection, tumors

26. Azathioprine (Imuran ) • the main immunosuppressive cytotoxic substance. It is nonenzymatically cleaved to mercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis. • By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. Uses • Prevention of organ transplant rejection • Rheumatoid arthritis

27. Toxicity - Azathioprine • Bone marrow suppression- leukopenia, thrombocytopenia, anemia • Increased susceptibility to infection • Hepatotoxicity • Alopecia • GI toxicity • Drug interaction: Allopurinol

28. Mycophenolate Mofetil • Prodrug  Mycophenolic acid • Inhibits IMPDH – enzyme in guanine synthesis (Inosine monophosphate dehydrogenase (IMPDH) is a major target for both antitumor and immunosuppresive drug design.) • T, B cells are highly dependent on this pathway for cell proliferation • Selectively inhibits lymphocyte proliferation, function , Antibody formation, cellular adhesion, migration

29. Uses - Mycophenolate Mofetil • Prophylaxis of transplant rejection • Combination: Glucocorticoids Calcineurin Inhibitors • Toxicity • GI, Hematological • Diarrhea, Leucopenia • Risk of Infection

30. Drug Interaction • Decreased absorption when co-administered with antacids • Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion

31. Antibodies • Against lymphocyte cell-surface antigens • Polyclonal / Monoclonal

32. 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

33. 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

34. Anti-CD3 Monoclonal Antibody(Muromonab-CD3 ) • Binds to CD3, a component of T-cell receptor complex involved in • antigen recognition • cell signaling & proliferation

35. Uses • Treatment of acute organ transplant rejection Toxicity • “Cytokine release syndrome” High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness • Prevention: Steroids

36. Cytokine release syndrome • is a common immediate complication occurring with the use of anti-T cellantibody infusions such as ATG, OKT3 • The pathogenesis is that the antibodies bind to the T cell receptor, activating the T cells before they are destroyed. The cytokines released by the activated T cells produce a type of systemic inflammatory response similar to that found in severe infection characterised by hypotension, pyrexia and rigors. • the cytokine release syndrome is effectively a type of non-infective fever.

37. 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

38. Anti-TNF Agents • TNF – Cytokine at site of inflammation • Infliximab • Etanercept • Adalimumab

40. 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

41. Etanercept • Fusion protein produced through expression of recombinant DNA. • Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1 Uses • Rheumatoid arthritis

42. Uses :moderate to severely active crohn’s disease Adalimumab Recombinant human anti-TNF mAb

43. LFA-1 Inhibitor - Efalizumab • Monoclonal Ab Targeting Lymphocyte Function Associated Antigen • Blocks T-cell Adhesion, Activation, Trafficking Uses • Organ transplantation • Psoriasis

44. SUMMARY Glucocorticoids – Lympholytic activity, antiinflammatory property. • Used as 1st line immunosuppressive therapy in solid and heamatopoietic stem cell transplant, ITP, RA etc…. • Sirolimus – inhibits protein kinase and inhibits T cell response to IL-2. – Blocks cell cycle progression

45. Thalidomide– inhibits angiogenesis, reduces phagocytosis, enhances cell mediated immunity – Increases levels of IL-10. – Used in multiple myeloma, graft versus host disease, myelodysplastic syndrome, colon and prostrate Cancer. • Mycophenolate Mofetil – mycophenolic acid – Inhibits inosine monophosphate dehydrogenase which is a key enzyme in guanine nucleotide synthesis. – Used in steroid refractory GVHD, RA, SLE.

46. Leflunomide – it inhibits pyrimidine synthesis. Used in RA. • Cyclophosphamide – alkylating agent which destroys proliferating lymphoid cells. Used in SLE, autoimmune haemolytic anaemia, multiple sclerosis, Wegener’s granulomatosis. • Muromonab CD3 – T cell receptor complex ( blocks Ag recognition ). – Used in steroid resistant rejection. • Daclizumab, Basiliximab – IL-2 receptor (blocks IL-2 mediated T cell activation ). – Used in acute organ rejection in renal transplant patients.

47. Azathioprine ( Mercaptopurine ) – interferes with purine nucleic acid metabolism and incorporates false nucleotide. –Used in Renal allograft, RA, SLE, ITP, Crohn’s disease, glomerulonephritis Interferons - IFN alpha- immune enhancing action - melanoma. – IFN beta - multiple sclerosis – IFN gamma - chronic granulomatous disease.

49. Immunostimulants USES: • immunodeficiency disorders • Chronic infections • cancer

50. specific Immunostimulants • Levamisole • Thalidomide • BCG • Recombinant Cytokines Interferons Interleukin-2 • Other drugs – inosiplex, azimexon, imexon, thymosin, methylinosine monophosphate • Immunization Vaccines , Immune Globulin , Rho (D) Immune Globulin